Trial Outcomes & Findings for Tiotropium +Olodaterol Fixed Dose Combination (FDC) Versus Tiotropium and Olodaterol in Chronic Obstructive Pulmonary Disease (COPD) (NCT NCT01431287)

NCT ID: NCT01431287

Last Updated: 2015-07-16

Results Overview

FEV1 AUC(0-3h) was calculated as the area under the FEV1- time curve from 0 to 3 h post-dose using the trapezoidal rule, divided by the duration (3 h) to report in litres. FEV1 AUC(0-3h) response was defined as FEV1 AUC(0-3h) minus baseline FEV1. Baseline was defined as the mean of the 2 pre-dose measurements performed 1 h and 10 min prior to administration of the first dose at visit 2 (day 1). The adjusted means (SE) were obtained from fitting an Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within-patient errors and Kenward-Roger approximation for denominator degrees of freedom. Number of participants analyzed are the number of patients contributing to the MMRM model in each treatment group.

• Recruitment status: COMPLETED
• Study phase: PHASE3
• Target enrollment: 2539 participants
• Primary outcome timeframe: 1 hour (h) and 10 minutes (min) prior to dose to on the first day of randomized treatment and on Day 169 and 5 min, 15 min, 30 min, 1 h, 2 h, 3 h post-dose on Day 169
• Results posted on: 2015-07-16

Participant Flow

This trial was one of 2 confirmatory Phase III 52-week, multi-centre, multi-national, randomised, double-blind, parallel group studies to evaluate the long-term efficacy and safety of once daily treatment with orally inhaled Tio+Olo FDC (2.5/5μg; 5/5μg) compared with the individual components (2.5μg; 5μg Tiotropium, 5μg Olodaterol) in COPD patients

Participant milestones

Measure	Olodaterol (5 μg) Oral inhalation of Olodaterol 5 μg (2.5 μg per actuation), 2 puffs from the RESPIMAT inhaler, once daily, in the morning.	Tiotropium (2.5 μg) Oral inhalation of Tiotropium 2.5 μg (1.25 μg per actuation), 2 puffs from the RESPIMAT inhaler, once daily, in the morning.	Tiotropium (5 μg) Oral inhalation of Tiotropium 5 μg (2.5 μg per actuation), 2 puffs from the RESPIMAT inhaler, once daily, in the morning.	Tio+Olo FDC (2.5/5 μg) Oral inhalation of fixed dose combination (FDC) of Tiotropium 2.5 μg and Olodaterol 5 μg (Tiotropium: 1.25 μg per actuation and Olodaterol: 2.5 μg per actuation), 2 puffs from the RESPIMAT inhaler, once daily, in the morning.	Tio+Olo FDC (5/5 μg) Oral inhalation of FDC of Tiotropium 5 μg and Olodaterol 5 μg (Tiotropium and Olodaterol: 2.5 μg per actuation), 2 puffs from the RESPIMAT inhaler, once daily, in the morning.
Overall Study STARTED	510	507	507	508	507
Overall Study COMPLETED	412	409	410	445	430
Overall Study NOT COMPLETED	98	98	97	63	77

Reasons for withdrawal

Measure	Olodaterol (5 μg) Oral inhalation of Olodaterol 5 μg (2.5 μg per actuation), 2 puffs from the RESPIMAT inhaler, once daily, in the morning.	Tiotropium (2.5 μg) Oral inhalation of Tiotropium 2.5 μg (1.25 μg per actuation), 2 puffs from the RESPIMAT inhaler, once daily, in the morning.	Tiotropium (5 μg) Oral inhalation of Tiotropium 5 μg (2.5 μg per actuation), 2 puffs from the RESPIMAT inhaler, once daily, in the morning.	Tio+Olo FDC (2.5/5 μg) Oral inhalation of fixed dose combination (FDC) of Tiotropium 2.5 μg and Olodaterol 5 μg (Tiotropium: 1.25 μg per actuation and Olodaterol: 2.5 μg per actuation), 2 puffs from the RESPIMAT inhaler, once daily, in the morning.	Tio+Olo FDC (5/5 μg) Oral inhalation of FDC of Tiotropium 5 μg and Olodaterol 5 μg (Tiotropium and Olodaterol: 2.5 μg per actuation), 2 puffs from the RESPIMAT inhaler, once daily, in the morning.
Overall Study not treated	0	0	1	0	0
Overall Study Adverse Event	59	57	53	33	41
Overall Study Non compliant with protocol	6	6	5	6	5
Overall Study Lost to Follow-up	0	3	2	3	1
Overall Study Consent withdrawn not due to AE	29	30	34	19	29
Overall Study not stated above	4	2	2	2	1

Baseline Characteristics

Tiotropium +Olodaterol Fixed Dose Combination (FDC) Versus Tiotropium and Olodaterol in Chronic Obstructive Pulmonary Disease (COPD)

Baseline characteristics by cohort

Measure	Olodaterol (5 μg) n=510 Participants Oral inhalation of Olodaterol 5 μg (2.5 μg per actuation), 2 puffs in the morning.	Tiotropium (2.5 μg) n=507 Participants Oral inhalation of Tiotropium 2.5 μg (1.25 μg per actuation), 2 puffs in the morning.	Tiotropium (5 μg) n=506 Participants Oral inhalation of Tiotropium 5 μg (2.5 μg per actuation), 2 puffs in the morning.	Tio+Olo FDC (2.5/5 μg) n=508 Participants Oral inhalation of FDC of Tiotropium 2.5 μg and Olodaterol 5 μg (Tiotropium: 1.25 μg per actuation and Olodaterol: 2.5 μg per actuation), 2 puffs in the morning.	Tio+Olo FDC (5/5 μg) n=507 Participants Oral inhalation of FDC of Tiotropium 5 μg and Olodaterol 5 μg (Tiotropium and Olodaterol: 2.5 μg per actuation), 2 puffs in the morning.	Total n=2538 Participants Total of all reporting groups
Age, Continuous	64.7 years STANDARD_DEVIATION 8.3 • n=93 Participants	63.9 years STANDARD_DEVIATION 8.7 • n=4 Participants	63.5 years STANDARD_DEVIATION 8.7 • n=27 Participants	64.1 years STANDARD_DEVIATION 7.6 • n=483 Participants	62.7 years STANDARD_DEVIATION 8.4 • n=36 Participants	63.8 years STANDARD_DEVIATION 8.4 • n=10 Participants
Sex: Female, Male Female	132 Participants n=93 Participants	146 Participants n=4 Participants	134 Participants n=27 Participants	140 Participants n=483 Participants	158 Participants n=36 Participants	710 Participants n=10 Participants
Sex: Female, Male Male	378 Participants n=93 Participants	361 Participants n=4 Participants	372 Participants n=27 Participants	368 Participants n=483 Participants	349 Participants n=36 Participants	1828 Participants n=10 Participants

PRIMARY outcome

Timeframe: 1 hour (h) and 10 minutes (min) prior to dose to on the first day of randomized treatment and on Day 169 and 5 min, 15 min, 30 min, 1 h, 2 h, 3 h post-dose on Day 169

Population: The Full analysis set (FAS) included all patients who were randomised, who were dispensed study medication, were documented to have taken any dose of study medication and who had a non-missing baseline and at least one non-missing post-baseline measurement before or at Week 24 for any of the primary and key secondary efficacy endpoints.

FEV1 AUC(0-3h) was calculated as the area under the FEV1- time curve from 0 to 3 h post-dose using the trapezoidal rule, divided by the duration (3 h) to report in litres. FEV1 AUC(0-3h) response was defined as FEV1 AUC(0-3h) minus baseline FEV1. Baseline was defined as the mean of the 2 pre-dose measurements performed 1 h and 10 min prior to administration of the first dose at visit 2 (day 1).

The adjusted means (SE) were obtained from fitting an Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within-patient errors and Kenward-Roger approximation for denominator degrees of freedom. Number of participants analyzed are the number of patients contributing to the MMRM model in each treatment group.

Outcome measures

Measure	Olodaterol (5 μg) n=507 Participants Oral inhalation of Olodaterol 5 μg (2.5 μg per actuation), 2 puffs in the morning.	Tiotropium (2.5 μg) n=504 Participants Oral inhalation of Tiotropium 2.5 μg (1.25 μg per actuation), 2 puffs in the morning.	Tiotropium (5 μg) n=500 Participants Oral inhalation of Tiotropium 5 μg (2.5 μg per actuation), 2 puffs in the morning.	Tio+Olo FDC (2.5/5 μg) n=506 Participants Oral inhalation of FDC of Tiotropium 2.5 μg and Olodaterol 5 μg (Tiotropium: 1.25 μg per actuation and Olodaterol: 2.5 μg per actuation), 2 puffs in the morning.	Tio+Olo FDC (5/5 μg) n=502 Participants Oral inhalation of FDC of Tiotropium 5 μg and Olodaterol 5 μg (Tiotropium and Olodaterol: 2.5 μg per actuation), 2 puffs in the morning.
Forced Expiratory Volume in One Second (FEV1) Area Under the Curve (AUC) (0-3h) Response on Day 169	0.136 Litres Standard Error 0.009	0.125 Litres Standard Error 0.009	0.165 Litres Standard Error 0.009	0.256 Litres Standard Error 0.009	0.268 Litres Standard Error 0.009

PRIMARY outcome

Timeframe: 1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and at 23 h and at 23 h 50 min after inhalation of study medication on Day 170

Population: FAS. Since it is possible for the patient to meet the data criterion for only a subset of the primary endpoints, it is possible that the number of patients used in the FAS analysis for different endpoints will vary.

Trough FEV1 was defined as the FEV1 value at the end of the dosing interval (24 hours) and was calculated as the mean of the 2 FEV1 measurements performed at 23 h and at 23 h 50 min after inhalation of study medication at the clinic visit on the previous day.

Trough FEV1 response was defined as trough FEV1 minus baseline FEV1. Baseline was defined as the mean of the 2 pre-dose measurements performed 1 h and 10 min prior to administration of the first dose at visit 2 (day 1).

The adjusted means (SE) were obtained from fitting an MMRM including fixed effects of treatment, planned test day, treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within-patient errors and Kenward-Roger approximation for denominator degrees of freedom.

Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures (MMRM) model in each treatment group.

Outcome measures

Measure	Olodaterol (5 μg) n=503 Participants Oral inhalation of Olodaterol 5 μg (2.5 μg per actuation), 2 puffs in the morning.	Tiotropium (2.5 μg) n=499 Participants Oral inhalation of Tiotropium 2.5 μg (1.25 μg per actuation), 2 puffs in the morning.	Tiotropium (5 μg) n=498 Participants Oral inhalation of Tiotropium 5 μg (2.5 μg per actuation), 2 puffs in the morning.	Tio+Olo FDC (2.5/5 μg) n=500 Participants Oral inhalation of FDC of Tiotropium 2.5 μg and Olodaterol 5 μg (Tiotropium: 1.25 μg per actuation and Olodaterol: 2.5 μg per actuation), 2 puffs in the morning.	Tio+Olo FDC (5/5 μg) n=497 Participants Oral inhalation of FDC of Tiotropium 5 μg and Olodaterol 5 μg (Tiotropium and Olodaterol: 2.5 μg per actuation), 2 puffs in the morning.
Trough FEV1 Response on Day 170	0.057 Litres Standard Error 0.009	0.062 Litres Standard Error 0.009	0.096 Litres Standard Error 0.009	0.125 Litres Standard Error 0.009	0.145 Litres Standard Error 0.009

PRIMARY outcome

Timeframe: Day 169

Population: FAS. Since it is possible for the patient to meet the data criterion for only a subset of the primary endpoints, it is possible that the number of patients used in the FAS analysis for different endpoints will vary.

The SGRQ is designed to measure health impairment in patients with COPD. It is divided into 2 parts: part 1 produces the symptoms score, and part 2 the activity and impacts scores. A total score is also produced. Each subscale score is the sum of the weights for the items in the subscale as a percent of the sum of the weights for a patient in the worst possible condition. The total score uses the same calculation except that the weights are summed over the entire questionnaire. The individual subscales as well as the total score can range from 0 to 100 with a lower score denoting a better health status.

Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures model (MMRM) in each treatment group.

Outcome measures

Measure	Olodaterol (5 μg) n=954 Participants Oral inhalation of Olodaterol 5 μg (2.5 μg per actuation), 2 puffs in the morning.	Tiotropium (2.5 μg) n=960 Participants Oral inhalation of Tiotropium 2.5 μg (1.25 μg per actuation), 2 puffs in the morning.	Tiotropium (5 μg) n=954 Participants Oral inhalation of Tiotropium 5 μg (2.5 μg per actuation), 2 puffs in the morning.	Tio+Olo FDC (2.5/5 μg) n=990 Participants Oral inhalation of FDC of Tiotropium 2.5 μg and Olodaterol 5 μg (Tiotropium: 1.25 μg per actuation and Olodaterol: 2.5 μg per actuation), 2 puffs in the morning.	Tio+Olo FDC (5/5 μg) n=979 Participants Oral inhalation of FDC of Tiotropium 5 μg and Olodaterol 5 μg (Tiotropium and Olodaterol: 2.5 μg per actuation), 2 puffs in the morning.
Saint George's Respiratory Questionnaire (SGRQ) Total Score on Day 169 From the Two Twin Trials, Present 1237.6 (NCT01431287) and 1237.5 (NCT01431274).	38.366 points on a scale Standard Error 0.396	37.792 points on a scale Standard Error 0.390	37.907 points on a scale Standard Error 0.393	37.335 points on a scale Standard Error 0.385	36.674 points on a scale Standard Error 0.386

SECONDARY outcome

Timeframe: Day 169

Population: FAS. Since it is possible for the patient to meet the data criterion for only a subset of the primary endpoints, it is possible that the number of patients used in the FAS analysis for different endpoints will vary.

Mahler Transitional Dyspnoea Index (TDI) focal score on Day 169 From the Two Twin Trials, Present 1237.6 (NCT01431287) and 1237.5 (NCT01431274) is the key secondary endpoint.

The Mahler Dyspnoea questionnaire is an instrument which measures change from the baseline state The TDI focal score was used to measure the effect of Tio+Olo FDC on patients' dyspnoea after 24 weeks of treatment (Day 169). The focal score is the sum of the subscale scores for Functional Impairment, Magnitude of Effort and Magnitude of Task. Scores for each subscale range from -3 to 3 so that the Focal score ranges from -9 to 9. For all subscale scores and the Focal score a higher value indicates a better outcome.

Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures model (MMRM) in each treatment group.

Outcome measures

Measure	Olodaterol (5 μg) n=984 Participants Oral inhalation of Olodaterol 5 μg (2.5 μg per actuation), 2 puffs in the morning.	Tiotropium (2.5 μg) n=982 Participants Oral inhalation of Tiotropium 2.5 μg (1.25 μg per actuation), 2 puffs in the morning.	Tiotropium (5 μg) n=978 Participants Oral inhalation of Tiotropium 5 μg (2.5 μg per actuation), 2 puffs in the morning.	Tio+Olo FDC (2.5/5 μg) n=992 Participants Oral inhalation of FDC of Tiotropium 2.5 μg and Olodaterol 5 μg (Tiotropium: 1.25 μg per actuation and Olodaterol: 2.5 μg per actuation), 2 puffs in the morning.	Tio+Olo FDC (5/5 μg) n=992 Participants Oral inhalation of FDC of Tiotropium 5 μg and Olodaterol 5 μg (Tiotropium and Olodaterol: 2.5 μg per actuation), 2 puffs in the morning.
Mahler Transitional Dyspnoea Index (TDI) Focal Score on Day 169 From the Two Twin Trials, Present 1237.6 (NCT01431287) and 1237.5 (NCT01431274)	1.564 points on a scale Standard Error 0.096	1.690 points on a scale Standard Error 0.095	1.627 points on a scale Standard Error 0.096	1.980 points on a scale Standard Error 0.095	1.983 points on a scale Standard Error 0.095

SECONDARY outcome

Timeframe: 1 hour (h) and 10 minutes (min) prior to dose to 5 min, 15 min, 30 min, 1 h, 2 h, 3 h post-dose on the first day of randomized treatment

Population: FAS. Since it is possible for the patient to meet the data criterion for only a subset of the primary endpoints, it is possible that the number of patients used in the FAS analysis for different endpoints will vary.

FEV1 AUC(0-3h) was calculated as the area under the FEV1- time curve from 0 to 3 h post-dose using the trapezoidal rule, divided by the duration (3 h) to report in litres.

FEV1 AUC(0-3h) response was defined as FEV1 AUC(0-3h) minus baseline FEV1. Baseline was defined as the mean of the 2 pre-dose measurements performed 1 h and 10 min prior to administration of the first dose of randomised treatment at Day1.

The adjusted means (SE) were obtained from fitting an Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within-patient errors and Kenward-Roger approximation for denominator degrees of freedom.

Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures (MMRM) model in each treatment group.

Outcome measures

Measure	Olodaterol (5 μg) n=507 Participants Oral inhalation of Olodaterol 5 μg (2.5 μg per actuation), 2 puffs in the morning.	Tiotropium (2.5 μg) n=504 Participants Oral inhalation of Tiotropium 2.5 μg (1.25 μg per actuation), 2 puffs in the morning.	Tiotropium (5 μg) n=500 Participants Oral inhalation of Tiotropium 5 μg (2.5 μg per actuation), 2 puffs in the morning.	Tio+Olo FDC (2.5/5 μg) n=506 Participants Oral inhalation of FDC of Tiotropium 2.5 μg and Olodaterol 5 μg (Tiotropium: 1.25 μg per actuation and Olodaterol: 2.5 μg per actuation), 2 puffs in the morning.	Tio+Olo FDC (5/5 μg) n=502 Participants Oral inhalation of FDC of Tiotropium 5 μg and Olodaterol 5 μg (Tiotropium and Olodaterol: 2.5 μg per actuation), 2 puffs in the morning.
FEV1 AUC(0-3h) Response on Day 1	0.196 Litres Standard Error 0.009	0.135 Litres Standard Error 0.009	0.164 Litres Standard Error 0.009	0.228 Litres Standard Error 0.009	0.229 Litres Standard Error 0.009

SECONDARY outcome

Timeframe: 1 hour (h) and 10 minutes (min) prior to dose to on the first day of randomized treatment and on Day 85 and 5 min, 15 min, 30 min, 1 h, 2 h, 3 h post-dose on Day 85

Population: FAS (on day 85). Since it is possible for the patient to meet the data criterion for only a subset of the primary endpoints, it is possible that the number of patients used in the FAS analysis for different endpoints will vary.

FEV1 AUC(0-3h) was calculated as the area under the FEV1- time curve from 0 to 3 h post-dose using the trapezoidal rule, divided by the duration (3 h) to report in litres.

FEV1 AUC(0-3h) response was defined as FEV1 AUC(0-3h) minus baseline FEV1. Baseline was defined as the mean of the 2 pre-dose measurements performed 1 h and 10 min prior to administration of the first dose of randomised treatment at Day1.

The adjusted means (SE) were obtained from fitting an Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within-patient errors and Kenward-Roger approximation for denominator degrees of freedom.

Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures (MMRM) model in each treatment group.

Outcome measures

Measure	Olodaterol (5 μg) n=507 Participants Oral inhalation of Olodaterol 5 μg (2.5 μg per actuation), 2 puffs in the morning.	Tiotropium (2.5 μg) n=504 Participants Oral inhalation of Tiotropium 2.5 μg (1.25 μg per actuation), 2 puffs in the morning.	Tiotropium (5 μg) n=500 Participants Oral inhalation of Tiotropium 5 μg (2.5 μg per actuation), 2 puffs in the morning.	Tio+Olo FDC (2.5/5 μg) n=506 Participants Oral inhalation of FDC of Tiotropium 2.5 μg and Olodaterol 5 μg (Tiotropium: 1.25 μg per actuation and Olodaterol: 2.5 μg per actuation), 2 puffs in the morning.	Tio+Olo FDC (5/5 μg) n=502 Participants Oral inhalation of FDC of Tiotropium 5 μg and Olodaterol 5 μg (Tiotropium and Olodaterol: 2.5 μg per actuation), 2 puffs in the morning.
FEV1 AUC(0-3h) Response on Day 85	0.153 Litres Standard Error 0.009	0.165 Litres Standard Error 0.009	0.187 Litres Standard Error 0.009	0.272 Litres Standard Error 0.009	0.297 Litres Standard Error 0.009

SECONDARY outcome

Timeframe: 1 hour (h) and 10 minutes (min) prior to dose to on the first day of randomized treatment and on Day 365 and 5 min, 15 min, 30 min, 1 h, 2 h, 3 h post-dose on Day 365

Population: FAS (on day 365). Since it is possible for the patient to meet the data criterion for only a subset of the primary endpoints, it is possible that the number of patients used in the FAS analysis for different endpoints will vary.

FEV1 AUC(0-3h) was calculated as the area under the FEV1- time curve from 0 to 3 h post-dose using the trapezoidal rule, divided by the duration (3 h) to report in litres.

FEV1 AUC(0-3h) response was defined as FEV1 AUC(0-3h) minus baseline FEV1. Baseline was defined as the mean of the 2 pre-dose measurements performed 1 h and 10 min prior to administration of the first dose of randomised treatment at Day1.

The adjusted means (SE) were obtained from fitting an Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within-patient errors and Kenward-Roger approximation for denominator degrees of freedom.

Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures (MMRM) model in each treatment group.

Outcome measures

Measure	Olodaterol (5 μg) n=507 Participants Oral inhalation of Olodaterol 5 μg (2.5 μg per actuation), 2 puffs in the morning.	Tiotropium (2.5 μg) n=504 Participants Oral inhalation of Tiotropium 2.5 μg (1.25 μg per actuation), 2 puffs in the morning.	Tiotropium (5 μg) n=500 Participants Oral inhalation of Tiotropium 5 μg (2.5 μg per actuation), 2 puffs in the morning.	Tio+Olo FDC (2.5/5 μg) n=506 Participants Oral inhalation of FDC of Tiotropium 2.5 μg and Olodaterol 5 μg (Tiotropium: 1.25 μg per actuation and Olodaterol: 2.5 μg per actuation), 2 puffs in the morning.	Tio+Olo FDC (5/5 μg) n=502 Participants Oral inhalation of FDC of Tiotropium 5 μg and Olodaterol 5 μg (Tiotropium and Olodaterol: 2.5 μg per actuation), 2 puffs in the morning.
FEV1 AUC(0-3h) Response on Day 365	0.105 Litres Standard Error 0.010	0.105 Litres Standard Error 0.010	0.124 Litres Standard Error 0.010	0.223 Litres Standard Error 0.009	0.237 Litres Standard Error 0.010

SECONDARY outcome

Timeframe: 1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and at 10 min pre-dose on day 15

Population: FAS (day 15). Since it is possible for the patient to meet the data criterion for only a subset of the primary endpoints, it is possible that the number of patients used in the FAS analysis for different endpoints will vary.

Trough FEV1 was defined as the FEV1 value at the end of the dosing interval (24 hours), calculated as the mean of the pre-dose measurements.

Trough FEV1 response was defined as trough FEV1 minus baseline FEV1. Baseline was defined as the mean of the 2 pre-dose measurements performed 1 h and 10 min prior to administration of the first dose of randomised treatment at Day1.

Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures (MMRM) model in each treatment group.

Outcome measures

Measure	Olodaterol (5 μg) n=503 Participants Oral inhalation of Olodaterol 5 μg (2.5 μg per actuation), 2 puffs in the morning.	Tiotropium (2.5 μg) n=499 Participants Oral inhalation of Tiotropium 2.5 μg (1.25 μg per actuation), 2 puffs in the morning.	Tiotropium (5 μg) n=498 Participants Oral inhalation of Tiotropium 5 μg (2.5 μg per actuation), 2 puffs in the morning.	Tio+Olo FDC (2.5/5 μg) n=500 Participants Oral inhalation of FDC of Tiotropium 2.5 μg and Olodaterol 5 μg (Tiotropium: 1.25 μg per actuation and Olodaterol: 2.5 μg per actuation), 2 puffs in the morning.	Tio+Olo FDC (5/5 μg) n=497 Participants Oral inhalation of FDC of Tiotropium 5 μg and Olodaterol 5 μg (Tiotropium and Olodaterol: 2.5 μg per actuation), 2 puffs in the morning.
Trough FEV1 Response on Day 15	0.083 Litres Standard Error 0.009	0.085 Litres Standard Error 0.009	0.112 Litres Standard Error 0.009	0.147 Litres Standard Error 0.009	0.148 Litres Standard Error 0.009

SECONDARY outcome

Timeframe: 1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and at 10 min pre-dose on day 43

Population: FAS (day 43). Since it is possible for the patient to meet the data criterion for only a subset of the primary endpoints, it is possible that the number of patients used in the FAS analysis for different endpoints will vary.

Trough FEV1 was defined as the FEV1 value at the end of the dosing interval (24 hours), calculated as the mean of the pre-dose measurements.

Trough FEV1 response was defined as trough FEV1 minus baseline FEV1. Baseline was defined as the mean of the 2 pre-dose measurements performed 1 h and 10 min prior to administration of the first dose of randomised treatment at Day1.

Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures (MMRM) model in each treatment group.

Outcome measures

Measure	Olodaterol (5 μg) n=503 Participants Oral inhalation of Olodaterol 5 μg (2.5 μg per actuation), 2 puffs in the morning.	Tiotropium (2.5 μg) n=499 Participants Oral inhalation of Tiotropium 2.5 μg (1.25 μg per actuation), 2 puffs in the morning.	Tiotropium (5 μg) n=498 Participants Oral inhalation of Tiotropium 5 μg (2.5 μg per actuation), 2 puffs in the morning.	Tio+Olo FDC (2.5/5 μg) n=500 Participants Oral inhalation of FDC of Tiotropium 2.5 μg and Olodaterol 5 μg (Tiotropium: 1.25 μg per actuation and Olodaterol: 2.5 μg per actuation), 2 puffs in the morning.	Tio+Olo FDC (5/5 μg) n=497 Participants Oral inhalation of FDC of Tiotropium 5 μg and Olodaterol 5 μg (Tiotropium and Olodaterol: 2.5 μg per actuation), 2 puffs in the morning.
Trough FEV1 Response on Day 43	0.070 Litres Standard Error 0.009	0.085 Litres Standard Error 0.009	0.103 Litres Standard Error 0.009	0.146 Litres Standard Error 0.009	0.150 Litres Standard Error 0.009

SECONDARY outcome

Timeframe: 1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and at 1hr and 10 min pre-dose on day 85

Population: FAS (day 85). Since it is possible for the patient to meet the data criterion for only a subset of the primary endpoints, it is possible that the number of patients used in the FAS analysis for different endpoints will vary.

Trough FEV1 was defined as the FEV1 value at the end of the dosing interval (24 hours), calculated as the mean of the pre-dose measurements.

Trough FEV1 response was defined as trough FEV1 minus baseline FEV1. Baseline was defined as the mean of the 2 pre-dose measurements performed 1 h and 10 min prior to administration of the first dose of randomised treatment at Day1.

Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures (MMRM) model in each treatment group.

Outcome measures

Measure	Olodaterol (5 μg) n=503 Participants Oral inhalation of Olodaterol 5 μg (2.5 μg per actuation), 2 puffs in the morning.	Tiotropium (2.5 μg) n=499 Participants Oral inhalation of Tiotropium 2.5 μg (1.25 μg per actuation), 2 puffs in the morning.	Tiotropium (5 μg) n=498 Participants Oral inhalation of Tiotropium 5 μg (2.5 μg per actuation), 2 puffs in the morning.	Tio+Olo FDC (2.5/5 μg) n=500 Participants Oral inhalation of FDC of Tiotropium 2.5 μg and Olodaterol 5 μg (Tiotropium: 1.25 μg per actuation and Olodaterol: 2.5 μg per actuation), 2 puffs in the morning.	Tio+Olo FDC (5/5 μg) n=497 Participants Oral inhalation of FDC of Tiotropium 5 μg and Olodaterol 5 μg (Tiotropium and Olodaterol: 2.5 μg per actuation), 2 puffs in the morning.
Trough FEV1 Response on Day 85	0.047 Litres Standard Error 0.009	0.081 Litres Standard Error 0.009	0.088 Litres Standard Error 0.009	0.129 Litres Standard Error 0.009	0.147 Litres Standard Error 0.009

SECONDARY outcome

Timeframe: 1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and at 1hr and 10 min pre-dose on day 169

Population: FAS (day 169). Since it is possible for the patient to meet the data criterion for only a subset of the primary endpoints, it is possible that the number of patients used in the FAS analysis for different endpoints will vary.

Trough FEV1 was defined as the FEV1 value at the end of the dosing interval (24 hours), calculated as the mean of the pre-dose measurements.

Trough FEV1 response was defined as trough FEV1 minus baseline FEV1. Baseline was defined as the mean of the 2 pre-dose measurements performed 1 h and 10 min prior to administration of the first dose of randomised treatment at Day1.

Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures (MMRM) model in each treatment group.

Outcome measures

Measure	Olodaterol (5 μg) n=503 Participants Oral inhalation of Olodaterol 5 μg (2.5 μg per actuation), 2 puffs in the morning.	Tiotropium (2.5 μg) n=499 Participants Oral inhalation of Tiotropium 2.5 μg (1.25 μg per actuation), 2 puffs in the morning.	Tiotropium (5 μg) n=498 Participants Oral inhalation of Tiotropium 5 μg (2.5 μg per actuation), 2 puffs in the morning.	Tio+Olo FDC (2.5/5 μg) n=500 Participants Oral inhalation of FDC of Tiotropium 2.5 μg and Olodaterol 5 μg (Tiotropium: 1.25 μg per actuation and Olodaterol: 2.5 μg per actuation), 2 puffs in the morning.	Tio+Olo FDC (5/5 μg) n=497 Participants Oral inhalation of FDC of Tiotropium 5 μg and Olodaterol 5 μg (Tiotropium and Olodaterol: 2.5 μg per actuation), 2 puffs in the morning.
Trough FEV1 Response on Day 169	0.034 Litres Standard Error 0.009	0.041 Litres Standard Error 0.009	0.068 Litres Standard Error 0.009	0.111 Litres Standard Error 0.009	0.119 Litres Standard Error 0.009

SECONDARY outcome

Timeframe: 1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and at 1 hr and 10 min pre-dose on day 365

Population: FAS (day 365). Since it is possible for the patient to meet the data criterion for only a subset of the primary endpoints, it is possible that the number of patients used in the FAS analysis for different endpoints will vary.

Trough FEV1 was defined as the FEV1 value at the end of the dosing interval (24 hours), calculated as the mean of the pre-dose measurements.

Trough FEV1 response was defined as trough FEV1 minus baseline FEV1. Baseline was defined as the mean of the 2 pre-dose measurements performed 1 h and 10 min prior to administration of the first dose of randomised treatment at Day1.

Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures (MMRM) model in each treatment group.

Outcome measures

Measure	Olodaterol (5 μg) n=503 Participants Oral inhalation of Olodaterol 5 μg (2.5 μg per actuation), 2 puffs in the morning.	Tiotropium (2.5 μg) n=499 Participants Oral inhalation of Tiotropium 2.5 μg (1.25 μg per actuation), 2 puffs in the morning.	Tiotropium (5 μg) n=498 Participants Oral inhalation of Tiotropium 5 μg (2.5 μg per actuation), 2 puffs in the morning.	Tio+Olo FDC (2.5/5 μg) n=500 Participants Oral inhalation of FDC of Tiotropium 2.5 μg and Olodaterol 5 μg (Tiotropium: 1.25 μg per actuation and Olodaterol: 2.5 μg per actuation), 2 puffs in the morning.	Tio+Olo FDC (5/5 μg) n=497 Participants Oral inhalation of FDC of Tiotropium 5 μg and Olodaterol 5 μg (Tiotropium and Olodaterol: 2.5 μg per actuation), 2 puffs in the morning.
Trough FEV1 Response on Day 365	0.011 Litres Standard Error 0.009	0.022 Litres Standard Error 0.009	0.040 Litres Standard Error 0.009	0.077 Litres Standard Error 0.009	0.093 Litres Standard Error 0.009

SECONDARY outcome

Timeframe: 1 hour (h) and 10 minutes (min) prior to dose to 5 min, 15 min, 30 min, 1 h, 2 h, 3 h post-dose on the first day of randomized treatment

Population: FAS (day 1). Since it is possible for the patient to meet the data criterion for only a subset of the primary endpoints, it is possible that the number of patients used in the FAS analysis for different endpoints will vary.

FVC AUC(0-3h) was calculated as the area under the FVC- time curve from 0 to 3 h post-dose using the trapezoidal rule, divided by the duration (3 h) to report in litres.

FVC AUC(0-3h) response was defined as FVC AUC(0-3h) minus baseline FVC.Baseline was defined as the mean of the 2 pre-dose measurements performed 1 h and 10 min prior to administration of the first dose at visit 2 (day 1).

The adjusted means (SE) were obtained from fitting an Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within-patient errors and Kenward-Roger approximation for denominator degrees of freedom.

Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures (MMRM) model in each treatment group.

Outcome measures

Measure	Olodaterol (5 μg) n=507 Participants Oral inhalation of Olodaterol 5 μg (2.5 μg per actuation), 2 puffs in the morning.	Tiotropium (2.5 μg) n=504 Participants Oral inhalation of Tiotropium 2.5 μg (1.25 μg per actuation), 2 puffs in the morning.	Tiotropium (5 μg) n=500 Participants Oral inhalation of Tiotropium 5 μg (2.5 μg per actuation), 2 puffs in the morning.	Tio+Olo FDC (2.5/5 μg) n=506 Participants Oral inhalation of FDC of Tiotropium 2.5 μg and Olodaterol 5 μg (Tiotropium: 1.25 μg per actuation and Olodaterol: 2.5 μg per actuation), 2 puffs in the morning.	Tio+Olo FDC (5/5 μg) n=502 Participants Oral inhalation of FDC of Tiotropium 5 μg and Olodaterol 5 μg (Tiotropium and Olodaterol: 2.5 μg per actuation), 2 puffs in the morning.
Forced Vital Capacity (FVC) AUC(0-3h) Response on Day 1	0.341 Litres Standard Error 0.018	0.264 Litres Standard Error 0.018	0.298 Litres Standard Error 0.018	0.411 Litres Standard Error 0.018	0.397 Litres Standard Error 0.018

SECONDARY outcome

Timeframe: 1 hour (h) and 10 minutes (min) prior to dose to on the first day of randomized treatment and on Day 85 and 5 min, 15 min, 30 min, 1 h, 2 h, 3 h post-dose on Day 85

Population: FAS (day 85). Since it is possible for the patient to meet the data criterion for only a subset of the primary endpoints, it is possible that the number of patients used in the FAS analysis for different endpoints will vary.

FVC AUC(0-3h) was calculated as the area under the FVC- time curve from 0 to 3 h post-dose using the trapezoidal rule, divided by the duration (3 h) to report in litres.

FVC AUC(0-3h) response was defined as FVC AUC(0-3h) minus baseline FVC.Baseline was defined as the mean of the 2 pre-dose measurements performed 1 h and 10 min prior to administration of the first dose at visit 2 (day 1).

The adjusted means (SE) were obtained from fitting an Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within-patient errors and Kenward-Roger approximation for denominator degrees of freedom.

Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures (MMRM) model in each treatment group.

Outcome measures

Measure	Olodaterol (5 μg) n=507 Participants Oral inhalation of Olodaterol 5 μg (2.5 μg per actuation), 2 puffs in the morning.	Tiotropium (2.5 μg) n=504 Participants Oral inhalation of Tiotropium 2.5 μg (1.25 μg per actuation), 2 puffs in the morning.	Tiotropium (5 μg) n=500 Participants Oral inhalation of Tiotropium 5 μg (2.5 μg per actuation), 2 puffs in the morning.	Tio+Olo FDC (2.5/5 μg) n=506 Participants Oral inhalation of FDC of Tiotropium 2.5 μg and Olodaterol 5 μg (Tiotropium: 1.25 μg per actuation and Olodaterol: 2.5 μg per actuation), 2 puffs in the morning.	Tio+Olo FDC (5/5 μg) n=502 Participants Oral inhalation of FDC of Tiotropium 5 μg and Olodaterol 5 μg (Tiotropium and Olodaterol: 2.5 μg per actuation), 2 puffs in the morning.
Forced Vital Capacity (FVC) AUC(0-3h) Response on Day 85	0.250 Litres Standard Error 0.018	0.306 Litres Standard Error 0.018	0.326 Litres Standard Error 0.018	0.460 Litres Standard Error 0.018	0.469 Litres Standard Error 0.018

SECONDARY outcome

Timeframe: 1 hour (h) and 10 minutes (min) prior to dose to on the first day of randomized treatment and on Day 169 and 5 min, 15 min, 30 min, 1 h, 2 h, 3 h post-dose on Day 169

Population: FAS (day 169). Since it is possible for the patient to meet the data criterion for only a subset of the primary endpoints, it is possible that the number of patients used in the FAS analysis for different endpoints will vary.

FVC AUC(0-3h) was calculated as the area under the FVC- time curve from 0 to 3 h post-dose using the trapezoidal rule, divided by the duration (3 h) to report in litres.

FVC AUC(0-3h) response was defined as FVC AUC(0-3h) minus baseline FVC. Baseline was defined as the mean of the 2 pre-dose measurements performed 1 h and 10 min prior to administration of the first dose at visit 2 (day 1).

The adjusted means (SE) were obtained from fitting an Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within-patient errors and Kenward-Roger approximation for denominator degrees of freedom.

Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures (MMRM) model in each treatment group.

Outcome measures

Measure	Olodaterol (5 μg) n=507 Participants Oral inhalation of Olodaterol 5 μg (2.5 μg per actuation), 2 puffs in the morning.	Tiotropium (2.5 μg) n=504 Participants Oral inhalation of Tiotropium 2.5 μg (1.25 μg per actuation), 2 puffs in the morning.	Tiotropium (5 μg) n=500 Participants Oral inhalation of Tiotropium 5 μg (2.5 μg per actuation), 2 puffs in the morning.	Tio+Olo FDC (2.5/5 μg) n=506 Participants Oral inhalation of FDC of Tiotropium 2.5 μg and Olodaterol 5 μg (Tiotropium: 1.25 μg per actuation and Olodaterol: 2.5 μg per actuation), 2 puffs in the morning.	Tio+Olo FDC (5/5 μg) n=502 Participants Oral inhalation of FDC of Tiotropium 5 μg and Olodaterol 5 μg (Tiotropium and Olodaterol: 2.5 μg per actuation), 2 puffs in the morning.
Forced Vital Capacity (FVC) AUC(0-3h) Response on Day 169	0.231 Litres Standard Error 0.018	0.247 Litres Standard Error 0.018	0.283 Litres Standard Error 0.018	0.439 Litres Standard Error 0.018	0.429 Litres Standard Error 0.018

SECONDARY outcome

Timeframe: 1 hour (h) and 10 minutes (min) prior to dose to on the first day of randomized treatment and on Day 365 and 5 min, 15 min, 30 min, 1 h, 2 h, 3 h post-dose on Day 365

Population: FAS (day 365). Since it is possible for the patient to meet the data criterion for only a subset of the primary endpoints, it is possible that the number of patients used in the FAS analysis for different endpoints will vary.

FVC AUC(0-3h) was calculated as the area under the FVC- time curve from 0 to 3 h post-dose using the trapezoidal rule, divided by the duration (3 h) to report in litres.

FVC AUC(0-3h) response was defined as FVC AUC(0-3h) minus baseline FVC. Baseline was defined as the mean of the 2 pre-dose measurements performed 1 h and 10 min prior to administration of the first dose at visit 2 (day 1).

The adjusted means (SE) were obtained from fitting an Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within-patient errors and Kenward-Roger approximation for denominator degrees of freedom.

Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures (MMRM) model in each treatment group.

Outcome measures

Measure	Olodaterol (5 μg) n=507 Participants Oral inhalation of Olodaterol 5 μg (2.5 μg per actuation), 2 puffs in the morning.	Tiotropium (2.5 μg) n=504 Participants Oral inhalation of Tiotropium 2.5 μg (1.25 μg per actuation), 2 puffs in the morning.	Tiotropium (5 μg) n=500 Participants Oral inhalation of Tiotropium 5 μg (2.5 μg per actuation), 2 puffs in the morning.	Tio+Olo FDC (2.5/5 μg) n=506 Participants Oral inhalation of FDC of Tiotropium 2.5 μg and Olodaterol 5 μg (Tiotropium: 1.25 μg per actuation and Olodaterol: 2.5 μg per actuation), 2 puffs in the morning.	Tio+Olo FDC (5/5 μg) n=502 Participants Oral inhalation of FDC of Tiotropium 5 μg and Olodaterol 5 μg (Tiotropium and Olodaterol: 2.5 μg per actuation), 2 puffs in the morning.
Forced Vital Capacity (FVC) AUC(0-3h) Response on Day 365	0.180 Litres Standard Error 0.019	0.216 Litres Standard Error 0.018	0.198 Litres Standard Error 0.019	0.397 Litres Standard Error 0.018	0.381 Litres Standard Error 0.019

SECONDARY outcome

Timeframe: 1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and at 10 min pre-dose on day 15

Population: FAS (day 15). Since it is possible for the patient to meet the data criterion for only a subset of the primary endpoints, it is possible that the number of patients used in the FAS analysis for different endpoints will vary.

Trough FVC was defined as the FVC value at the end of the dosing interval (24 hours), calculated as the mean of the pre-dose measurements.

Trough FVC response was defined as trough FVC minus baseline FVC. Baseline was defined as the mean of the 2 pre-dose measurements performed 1 h and 10 min prior to administration of the first dose at visit 2 (day 1).

Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures (MMRM) model in each treatment group.

The adjusted means (SE) were obtained from fitting an Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within-patient errors and Kenward-Roger approximation for denominator degrees of freedom.

Outcome measures

Measure	Olodaterol (5 μg) n=503 Participants Oral inhalation of Olodaterol 5 μg (2.5 μg per actuation), 2 puffs in the morning.	Tiotropium (2.5 μg) n=499 Participants Oral inhalation of Tiotropium 2.5 μg (1.25 μg per actuation), 2 puffs in the morning.	Tiotropium (5 μg) n=498 Participants Oral inhalation of Tiotropium 5 μg (2.5 μg per actuation), 2 puffs in the morning.	Tio+Olo FDC (2.5/5 μg) n=500 Participants Oral inhalation of FDC of Tiotropium 2.5 μg and Olodaterol 5 μg (Tiotropium: 1.25 μg per actuation and Olodaterol: 2.5 μg per actuation), 2 puffs in the morning.	Tio+Olo FDC (5/5 μg) n=497 Participants Oral inhalation of FDC of Tiotropium 5 μg and Olodaterol 5 μg (Tiotropium and Olodaterol: 2.5 μg per actuation), 2 puffs in the morning.
Trough FVC Response on Day 15	0.163 Litres Standard Error 0.018	0.209 Litres Standard Error 0.018	0.222 Litres Standard Error 0.018	0.293 Litres Standard Error 0.018	0.285 Litres Standard Error 0.018

SECONDARY outcome

Timeframe: 1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and at 10 min pre-dose on day 43

Population: FAS (day 43). Since it is possible for the patient to meet the data criterion for only a subset of the primary endpoints, it is possible that the number of patients used in the FAS analysis for different endpoints will vary.

Trough FVC was defined as the FVC value at the end of the dosing interval (24 hours), calculated as the mean of the pre-dose measurements.

Trough FVC response was defined as trough FVC minus baseline FVC. Baseline was defined as the mean of the 2 pre-dose measurements performed 1 h and 10 min prior to administration of the first dose at visit 2 (day 1).

Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures (MMRM) model in each treatment group.

The adjusted means (SE) were obtained from fitting an Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within-patient errors and Kenward-Roger approximation for denominator degrees of freedom.

Outcome measures

Measure	Olodaterol (5 μg) n=503 Participants Oral inhalation of Olodaterol 5 μg (2.5 μg per actuation), 2 puffs in the morning.	Tiotropium (2.5 μg) n=499 Participants Oral inhalation of Tiotropium 2.5 μg (1.25 μg per actuation), 2 puffs in the morning.	Tiotropium (5 μg) n=498 Participants Oral inhalation of Tiotropium 5 μg (2.5 μg per actuation), 2 puffs in the morning.	Tio+Olo FDC (2.5/5 μg) n=500 Participants Oral inhalation of FDC of Tiotropium 2.5 μg and Olodaterol 5 μg (Tiotropium: 1.25 μg per actuation and Olodaterol: 2.5 μg per actuation), 2 puffs in the morning.	Tio+Olo FDC (5/5 μg) n=497 Participants Oral inhalation of FDC of Tiotropium 5 μg and Olodaterol 5 μg (Tiotropium and Olodaterol: 2.5 μg per actuation), 2 puffs in the morning.
Trough FVC Response on Day 43	0.129 Litres Standard Error 0.018	0.206 Litres Standard Error 0.018	0.222 Litres Standard Error 0.018	0.281 Litres Standard Error 0.018	0.293 Litres Standard Error 0.018

SECONDARY outcome

Timeframe: 1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and on day 85

Population: FAS (day 85). Since it is possible for the patient to meet the data criterion for only a subset of the primary endpoints, it is possible that the number of patients used in the FAS analysis for different endpoints will vary.

Trough FVC was defined as the FVC value at the end of the dosing interval (24 hours), calculated as the mean of the pre-dose measurements.

Trough FVC response was defined as trough FVC minus baseline FVC. Baseline was defined as the mean of the 2 pre-dose measurements performed 1 h and 10 min prior to administration of the first dose at visit 2 (day 1).

Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures (MMRM) model in each treatment group.

The adjusted means (SE) were obtained from fitting an Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within-patient errors and Kenward-Roger approximation for denominator degrees of freedom.

Outcome measures

Measure	Olodaterol (5 μg) n=503 Participants Oral inhalation of Olodaterol 5 μg (2.5 μg per actuation), 2 puffs in the morning.	Tiotropium (2.5 μg) n=499 Participants Oral inhalation of Tiotropium 2.5 μg (1.25 μg per actuation), 2 puffs in the morning.	Tiotropium (5 μg) n=498 Participants Oral inhalation of Tiotropium 5 μg (2.5 μg per actuation), 2 puffs in the morning.	Tio+Olo FDC (2.5/5 μg) n=500 Participants Oral inhalation of FDC of Tiotropium 2.5 μg and Olodaterol 5 μg (Tiotropium: 1.25 μg per actuation and Olodaterol: 2.5 μg per actuation), 2 puffs in the morning.	Tio+Olo FDC (5/5 μg) n=497 Participants Oral inhalation of FDC of Tiotropium 5 μg and Olodaterol 5 μg (Tiotropium and Olodaterol: 2.5 μg per actuation), 2 puffs in the morning.
Trough FVC Response on Day 85	0.063 Litres Standard Error 0.018	0.178 Litres Standard Error 0.018	0.184 Litres Standard Error 0.018	0.246 Litres Standard Error 0.018	0.274 Litres Standard Error 0.019

SECONDARY outcome

Timeframe: 1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and at 23h and at 23h 50 min after inhalation of study medication on day 170

Population: FAS. Since it is possible for the patient to meet the data criterion for only a subset of the primary endpoints, it is possible that the number of patients used in the FAS analysis for different endpoints will vary.

Trough FVC was defined as the FVC value at the end of the dosing interval (24 hours) and was calculated as the mean of the 2 FVC measurements performed at 23h and at 23h 50 min after inhalation of study medication at the clinic visit on the previous day.

Trough FVC response was defined as trough FVC minus baseline FVC. Baseline was defined as the mean of the 2 pre-dose measurements performed 1 h and 10 min prior to administration of the first dose at visit 2 (day 1).

The adjusted means (SE) were obtained from fitting an MMRM including fixed effects of treatment, planned test day, treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within-patient errors and Kenward-Roger approximation for denominator degrees of freedom.

Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures (MMRM) model in each treatment group.

Outcome measures

Measure	Olodaterol (5 μg) n=503 Participants Oral inhalation of Olodaterol 5 μg (2.5 μg per actuation), 2 puffs in the morning.	Tiotropium (2.5 μg) n=499 Participants Oral inhalation of Tiotropium 2.5 μg (1.25 μg per actuation), 2 puffs in the morning.	Tiotropium (5 μg) n=498 Participants Oral inhalation of Tiotropium 5 μg (2.5 μg per actuation), 2 puffs in the morning.	Tio+Olo FDC (2.5/5 μg) n=500 Participants Oral inhalation of FDC of Tiotropium 2.5 μg and Olodaterol 5 μg (Tiotropium: 1.25 μg per actuation and Olodaterol: 2.5 μg per actuation), 2 puffs in the morning.	Tio+Olo FDC (5/5 μg) n=497 Participants Oral inhalation of FDC of Tiotropium 5 μg and Olodaterol 5 μg (Tiotropium and Olodaterol: 2.5 μg per actuation), 2 puffs in the morning.
Trough FVC Response on Day 170	0.116 Litres Standard Error 0.018	0.163 Litres Standard Error 0.018	0.202 Litres Standard Error 0.018	0.266 Litres Standard Error 0.018	0.274 Litres Standard Error 0.018

SECONDARY outcome

Timeframe: 1 h and 10 min prior to dose on the first day of randomized treatment (baseline) and on day 365

Population: FAS (day 365). Since it is possible for the patient to meet the data criterion for only a subset of the primary endpoints, it is possible that the number of patients used in the FAS analysis for different endpoints will vary.

Trough FVC was defined as the FVC value at the end of the dosing interval (24 hours), calculated as the mean of the pre-dose measurements.

Trough FVC response was defined as trough FVC minus baseline FVC. Baseline was defined as the mean of the 2 pre-dose measurements performed 1 h and 10 min prior to administration of the first dose at visit 2 (day 1).

Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures (MMRM) model in each treatment group.

The adjusted means (SE) were obtained from fitting an Mixed effect model repeated measures (MMRM) including fixed effects of treatment, planned test day, treatment-by-test day interaction, baseline and baseline-by-test day interaction, patient as random effect, and spatial power covariance structure for within-patient errors and Kenward-Roger approximation for denominator degrees of freedom.

Outcome measures

Measure	Olodaterol (5 μg) n=503 Participants Oral inhalation of Olodaterol 5 μg (2.5 μg per actuation), 2 puffs in the morning.	Tiotropium (2.5 μg) n=499 Participants Oral inhalation of Tiotropium 2.5 μg (1.25 μg per actuation), 2 puffs in the morning.	Tiotropium (5 μg) n=498 Participants Oral inhalation of Tiotropium 5 μg (2.5 μg per actuation), 2 puffs in the morning.	Tio+Olo FDC (2.5/5 μg) n=500 Participants Oral inhalation of FDC of Tiotropium 2.5 μg and Olodaterol 5 μg (Tiotropium: 1.25 μg per actuation and Olodaterol: 2.5 μg per actuation), 2 puffs in the morning.	Tio+Olo FDC (5/5 μg) n=497 Participants Oral inhalation of FDC of Tiotropium 5 μg and Olodaterol 5 μg (Tiotropium and Olodaterol: 2.5 μg per actuation), 2 puffs in the morning.
Trough FVC Response on Day 365	0.028 Litres Standard Error 0.019	0.096 Litres Standard Error 0.019	0.097 Litres Standard Error 0.019	0.198 Litres Standard Error 0.019	0.184 Litres Standard Error 0.019

SECONDARY outcome

Timeframe: 1 hour (h) and 10 minutes (min) prior to dose to on the first day of randomized treatment and on Day 169 and 5 min, 15 min, 30 min, 1 h, 2 h, 3 h, 4 h, 5 h, 6 h, 8 h, 10 h, 12 h post-dose on Day 169

Population: 12 hr PFT set: All patients who have given Informed Consent for the 12-hour PFT testing and had any spirometry measurement after 3-hour and before or at 12-hours post-dose on Days 169 and 170.

FEV1 AUC(0-12h) was calculated as the area under the FEV1- time curve from 0 to 12 h post-dose using the trapezoidal rule, divided by the duration (12 h) to report in litres.

FEV1 AUC(0-12h) response was defined as FEV1 AUC(0-12h) minus baseline FEV1. Baseline was defined as the mean of the 2 pre-dose measurements performed 1 h and 10 min prior to administration of the first dose at visit 2 (day 1).

The adjusted mean (SE) were obtained from fitting an ANCOVA model with categorical effect of treatment and baseline as covariate.

Number of participants analyzed are the number of patients contributing to the ANCOVA model in each treatment group.

Outcome measures

Measure	Olodaterol (5 μg) n=194 Participants Oral inhalation of Olodaterol 5 μg (2.5 μg per actuation), 2 puffs in the morning.	Tiotropium (2.5 μg) n=185 Participants Oral inhalation of Tiotropium 2.5 μg (1.25 μg per actuation), 2 puffs in the morning.	Tiotropium (5 μg) n=160 Participants Oral inhalation of Tiotropium 5 μg (2.5 μg per actuation), 2 puffs in the morning.	Tio+Olo FDC (2.5/5 μg) n=178 Participants Oral inhalation of FDC of Tiotropium 2.5 μg and Olodaterol 5 μg (Tiotropium: 1.25 μg per actuation and Olodaterol: 2.5 μg per actuation), 2 puffs in the morning.	Tio+Olo FDC (5/5 μg) n=167 Participants Oral inhalation of FDC of Tiotropium 5 μg and Olodaterol 5 μg (Tiotropium and Olodaterol: 2.5 μg per actuation), 2 puffs in the morning.
FEV1 AUC(0-12h) Response in Sub-set of Patients With 12-hour Pulmonary Function Test (PFT) on Day 169 From the Two Twin Trials, Present 1237.6 (NCT01431287) and 1237.5 (NCT01431274)	0.131 Litres Standard Error 0.015	0.109 Litres Standard Error 0.016	0.127 Litres Standard Error 0.017	0.202 Litres Standard Error 0.016	0.250 Litres Standard Error 0.016

SECONDARY outcome

Timeframe: 1 hour (h) and 10 minutes (min) prior to dose to on the first day of randomized treatment and on Day 169 and 5 min, 15 min, 30 min, 1 h, 2 h, 3 h, 4 h, 5 h, 6 h, 8 h, 10 h, 12 h, 23 h, 23 h and 50 min post-dose on Day 169

Population: 12-hr PFT set

FEV1 AUC(0-24h) was calculated as the area under the FEV1- time curve from 0 to 24 h post-dose using the trapezoidal rule, divided by the duration (24 h) to report in litres. FEV1 AUC(0-24h) response was defined as FEV1 AUC(0-24h) minus baseline FEV1. Baseline was defined as the mean of the 2 pre-dose measurements performed 1 h and 10 min prior to administration of the first dose at visit 2 (day 1).

The adjusted mean (SE) were obtained from fitting an ANCOVA model with categorical effect of treatment and baseline as covariate.

Number of participants analyzed are the number of patients contributing to the ANCOVA model in each treatment group.

Outcome measures

Measure	Olodaterol (5 μg) n=194 Participants Oral inhalation of Olodaterol 5 μg (2.5 μg per actuation), 2 puffs in the morning.	Tiotropium (2.5 μg) n=185 Participants Oral inhalation of Tiotropium 2.5 μg (1.25 μg per actuation), 2 puffs in the morning.	Tiotropium (5 μg) n=160 Participants Oral inhalation of Tiotropium 5 μg (2.5 μg per actuation), 2 puffs in the morning.	Tio+Olo FDC (2.5/5 μg) n=178 Participants Oral inhalation of FDC of Tiotropium 2.5 μg and Olodaterol 5 μg (Tiotropium: 1.25 μg per actuation and Olodaterol: 2.5 μg per actuation), 2 puffs in the morning.	Tio+Olo FDC (5/5 μg) n=167 Participants Oral inhalation of FDC of Tiotropium 5 μg and Olodaterol 5 μg (Tiotropium and Olodaterol: 2.5 μg per actuation), 2 puffs in the morning.
FEV1 AUC(0-24h) Response in Sub-set of Patients With 12-hour PFTs on Day 169 From the Two Twin Trials, Present 1237.6 (NCT01431287) and 1237.5 (NCT01431274)	0.108 Litres Standard Error 0.014	0.083 Litres Standard Error 0.015	0.100 Litres Standard Error 0.016	0.159 Litres Standard Error 0.015	0.206 Litres Standard Error 0.015

SECONDARY outcome

Timeframe: 1 hour (h) and 10 minutes (min) prior to dose to on the first day of randomized treatment and on Day 169 and 5 min, 15 min, 30 min, 1 h, 2 h, 3 h, 4 h, 5 h, 6 h, 8 h, 10 h, 12 h post-dose on Day 169

Population: 12-hr PFT set

FVC AUC(0-12h) was calculated as the area under the FVC- time curve from 0 to 12 h post-dose using the trapezoidal rule, divided by the duration (12 h) to report in litres.

FVC AUC(0-12h) response was defined as FVC AUC(0-12h) minus baseline FVC. Baseline was defined as the mean of the 2 pre-dose measurements performed 1 h and 10 min prior to administration of the first dose at visit 2 (day 1).

The adjusted mean (SE) were obtained from fitting an ANCOVA model with categorical effect of treatment and baseline as covariate. Number of participants analyzed are the number of patients contributing to the ANCOVA model in each treatment group.

Outcome measures

Measure	Olodaterol (5 μg) n=194 Participants Oral inhalation of Olodaterol 5 μg (2.5 μg per actuation), 2 puffs in the morning.	Tiotropium (2.5 μg) n=185 Participants Oral inhalation of Tiotropium 2.5 μg (1.25 μg per actuation), 2 puffs in the morning.	Tiotropium (5 μg) n=160 Participants Oral inhalation of Tiotropium 5 μg (2.5 μg per actuation), 2 puffs in the morning.	Tio+Olo FDC (2.5/5 μg) n=178 Participants Oral inhalation of FDC of Tiotropium 2.5 μg and Olodaterol 5 μg (Tiotropium: 1.25 μg per actuation and Olodaterol: 2.5 μg per actuation), 2 puffs in the morning.	Tio+Olo FDC (5/5 μg) n=167 Participants Oral inhalation of FDC of Tiotropium 5 μg and Olodaterol 5 μg (Tiotropium and Olodaterol: 2.5 μg per actuation), 2 puffs in the morning.
FVC AUC(0-12h) Response in Sub-set of Patients With 12-hour PFTs on Day 169 From Two Twin Trials, Present 1237.6 (NCT01431287) and 1237.5 (NCT01431274)	0.227 Litres Standard Error 0.029	0.180 Litres Standard Error 0.030	0.248 Litres Standard Error 0.032	0.356 Litres Standard Error 0.030	0.388 Litres Standard Error 0.031

SECONDARY outcome

Timeframe: 1 hour (h) and 10 minutes (min) prior to dose to on the first day of randomized treatment and on Day 169 and 5 min, 15 min, 30 min, 1 h, 2 h, 3 h, 4 h, 5 h, 6 h, 8 h, 10 h, 12 h, 23 h, 23 h and 50 min post-dose on Day 169

Population: 12-hr PFT set

FVC AUC(0-24h) was calculated as the area under the FVC- time curve from 0 to 24 h post-dose using the trapezoidal rule, divided by the duration (24 h) to report in litres.

FVC AUC(0-24h) response was defined as FVC AUC(0-24h) minus baseline FVC. Baseline was defined as the mean of the 2 pre-dose measurements performed 1 h and 10 min prior to administration of the first dose at visit 2 (day 1).

The adjusted mean (SE) were obtained from fitting an ANCOVA model with categorical effect of treatment and baseline as covariate.

Number of participants analyzed are the number of patients contributing to the ANCOVA model in each treatment group.

Outcome measures

Measure	Olodaterol (5 μg) n=194 Participants Oral inhalation of Olodaterol 5 μg (2.5 μg per actuation), 2 puffs in the morning.	Tiotropium (2.5 μg) n=185 Participants Oral inhalation of Tiotropium 2.5 μg (1.25 μg per actuation), 2 puffs in the morning.	Tiotropium (5 μg) n=160 Participants Oral inhalation of Tiotropium 5 μg (2.5 μg per actuation), 2 puffs in the morning.	Tio+Olo FDC (2.5/5 μg) n=178 Participants Oral inhalation of FDC of Tiotropium 2.5 μg and Olodaterol 5 μg (Tiotropium: 1.25 μg per actuation and Olodaterol: 2.5 μg per actuation), 2 puffs in the morning.	Tio+Olo FDC (5/5 μg) n=167 Participants Oral inhalation of FDC of Tiotropium 5 μg and Olodaterol 5 μg (Tiotropium and Olodaterol: 2.5 μg per actuation), 2 puffs in the morning.
FVC AUC(0-24h) Response in Sub-set of Patients With 12-hour PFTs on Day 169 From the Two Twin Trials, Present 1237.6 (NCT01431287) and 1237.5 (NCT01431274)	0.192 Litres Standard Error 0.028	0.141 Litres Standard Error 0.028	0.203 Litres Standard Error 0.030	0.297 Litres Standard Error 0.029	0.329 Litres Standard Error 0.030

SECONDARY outcome

Timeframe: Day 85

Population: FAS (day 85). Since it is possible for the patient to meet the data criterion for only a subset of the primary endpoints, it is possible that the number of patients used in the FAS analysis for different endpoints will vary.

The SGRQ is designed to measure health impairment in patients with COPD. It is divided into 2 parts: part 1 produces the symptoms score, and part 2 the activity and impacts scores. A total score is also produced. Each subscale score is the sum of the weights for the items in the subscale as a percent of the sum of the weights for a patient in the worst possible condition. The total score uses the same calculation except that the weights are summed over the entire questionnaire. The individual subscales as well as the total score can range from 0 to 100 with a lower score denoting a better health status.

Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures model (MMRM) in each treatment group.

Outcome measures

Measure	Olodaterol (5 μg) n=954 Participants Oral inhalation of Olodaterol 5 μg (2.5 μg per actuation), 2 puffs in the morning.	Tiotropium (2.5 μg) n=960 Participants Oral inhalation of Tiotropium 2.5 μg (1.25 μg per actuation), 2 puffs in the morning.	Tiotropium (5 μg) n=955 Participants Oral inhalation of Tiotropium 5 μg (2.5 μg per actuation), 2 puffs in the morning.	Tio+Olo FDC (2.5/5 μg) n=990 Participants Oral inhalation of FDC of Tiotropium 2.5 μg and Olodaterol 5 μg (Tiotropium: 1.25 μg per actuation and Olodaterol: 2.5 μg per actuation), 2 puffs in the morning.	Tio+Olo FDC (5/5 μg) n=979 Participants Oral inhalation of FDC of Tiotropium 5 μg and Olodaterol 5 μg (Tiotropium and Olodaterol: 2.5 μg per actuation), 2 puffs in the morning.
Saint George's Respiratory Questionnaire (SGRQ) Total Score on Day 85 From the Two Twin Trials, Present 1237.6 (NCT01431287) and 1237.5 (NCT01431274)	38.832 points on a scale Standard Error 0.398	37.821 points on a scale Standard Error 0.397	37.822 points on a scale Standard Error 0.399	37.304 points on a scale Standard Error 0.392	36.691 points on a scale Standard Error 0.394

SECONDARY outcome

Timeframe: Day 365

Population: FAS (day 365). Since it is possible for the patient to meet the data criterion for only a subset of the primary endpoints, it is possible that the number of patients used in the FAS analysis for different endpoints will vary.

The SGRQ is designed to measure health impairment in patients with COPD. It is divided into 2 parts: part 1 produces the symptoms score, and part 2 the activity and impacts scores. A total score is also produced. Each subscale score is the sum of the weights for the items in the subscale as a percent of the sum of the weights for a patient in the worst possible condition. The total score uses the same calculation except that the weights are summed over the entire questionnaire. The individual subscales as well as the total score can range from 0 to 100 with a lower score denoting a better health status.

Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures model (MMRM) in each treatment group.

Outcome measures

Measure	Olodaterol (5 μg) n=954 Participants Oral inhalation of Olodaterol 5 μg (2.5 μg per actuation), 2 puffs in the morning.	Tiotropium (2.5 μg) n=960 Participants Oral inhalation of Tiotropium 2.5 μg (1.25 μg per actuation), 2 puffs in the morning.	Tiotropium (5 μg) n=955 Participants Oral inhalation of Tiotropium 5 μg (2.5 μg per actuation), 2 puffs in the morning.	Tio+Olo FDC (2.5/5 μg) n=990 Participants Oral inhalation of FDC of Tiotropium 2.5 μg and Olodaterol 5 μg (Tiotropium: 1.25 μg per actuation and Olodaterol: 2.5 μg per actuation), 2 puffs in the morning.	Tio+Olo FDC (5/5 μg) n=979 Participants Oral inhalation of FDC of Tiotropium 5 μg and Olodaterol 5 μg (Tiotropium and Olodaterol: 2.5 μg per actuation), 2 puffs in the morning.
Saint George's Respiratory Questionnaire (SGRQ) Total Score on Day 365 From the Two Twin Trials, Present 1237.6 (NCT01431287) and 1237.5 (NCT01431274)	38.989 points on a scale Standard Error 0.414	37.609 points on a scale Standard Error 0.409	37.581 points on a scale Standard Error 0.411	37.553 points on a scale Standard Error 0.403	37.138 points on a scale Standard Error 0.404

SECONDARY outcome

Timeframe: Day 43

Population: FAS (day 43). Since it is possible for the patient to meet the data criterion for only a subset of the primary endpoints, it is possible that the number of patients used in the FAS analysis for different endpoints will vary.

Mahler TDI focal score on Day 43 From the two twin trials, present 1237.6 (NCT01431287) and 1237.5 (NCT01431274).

The Mahler Dyspnoea questionnaire is an instrument which measures change from the baseline state The TDI focal score was used to measure the effect of Tio+Olo FDC on patients' dyspnoea after 24 weeks of treatment (Day 169). The focal score is the sum of the subscale scores for Functional Impairment, Magnitude of Effort and Magnitude of Task. Scores for each subscale range from -3 to 3 so that the Focal score ranges from -9 to 9. For all subscale scores and the Focal score a higher value indicates a better outcome.

Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures model (MMRM) in each treatment group.

Outcome measures

Measure	Olodaterol (5 μg) n=984 Participants Oral inhalation of Olodaterol 5 μg (2.5 μg per actuation), 2 puffs in the morning.	Tiotropium (2.5 μg) n=982 Participants Oral inhalation of Tiotropium 2.5 μg (1.25 μg per actuation), 2 puffs in the morning.	Tiotropium (5 μg) n=978 Participants Oral inhalation of Tiotropium 5 μg (2.5 μg per actuation), 2 puffs in the morning.	Tio+Olo FDC (2.5/5 μg) n=992 Participants Oral inhalation of FDC of Tiotropium 2.5 μg and Olodaterol 5 μg (Tiotropium: 1.25 μg per actuation and Olodaterol: 2.5 μg per actuation), 2 puffs in the morning.	Tio+Olo FDC (5/5 μg) n=992 Participants Oral inhalation of FDC of Tiotropium 5 μg and Olodaterol 5 μg (Tiotropium and Olodaterol: 2.5 μg per actuation), 2 puffs in the morning.
Mahler Transitional Dyspnoea Index (TDI) Focal Score on Day 43 From the Two Twin Trials, Present 1237.6 (NCT01431287) and 1237.5 (NCT01431274)	1.453 points on a scale Standard Error 0.096	1.430 points on a scale Standard Error 0.097	1.408 points on a scale Standard Error 0.097	1.876 points on a scale Standard Error 0.096	2.048 points on a scale Standard Error 0.096

SECONDARY outcome

Timeframe: Day 85

Population: FAS (day 85). Since it is possible for the patient to meet the data criterion for only a subset of the primary endpoints, it is possible that the number of patients used in the FAS analysis for different endpoints will vary.

Mahler TDI focal score on Day 85 From the two twin trials, present 1237.6 (NCT01431287) and 1237.5 (NCT01431274).

The Mahler Dyspnoea questionnaire is an instrument which measures change from the baseline state The TDI focal score was used to measure the effect of Tio+Olo FDC on patients' dyspnoea after 24 weeks of treatment (Day 169). The focal score is the sum of the subscale scores for Functional Impairment, Magnitude of Effort and Magnitude of Task. Scores for each subscale range from -3 to 3 so that the Focal score ranges from -9 to 9. For all subscale scores and the Focal score a higher value indicates a better outcome.

Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures model (MMRM) in each treatment group.

Outcome measures

Measure	Olodaterol (5 μg) n=984 Participants Oral inhalation of Olodaterol 5 μg (2.5 μg per actuation), 2 puffs in the morning.	Tiotropium (2.5 μg) n=982 Participants Oral inhalation of Tiotropium 2.5 μg (1.25 μg per actuation), 2 puffs in the morning.	Tiotropium (5 μg) n=978 Participants Oral inhalation of Tiotropium 5 μg (2.5 μg per actuation), 2 puffs in the morning.	Tio+Olo FDC (2.5/5 μg) n=992 Participants Oral inhalation of FDC of Tiotropium 2.5 μg and Olodaterol 5 μg (Tiotropium: 1.25 μg per actuation and Olodaterol: 2.5 μg per actuation), 2 puffs in the morning.	Tio+Olo FDC (5/5 μg) n=992 Participants Oral inhalation of FDC of Tiotropium 5 μg and Olodaterol 5 μg (Tiotropium and Olodaterol: 2.5 μg per actuation), 2 puffs in the morning.
Mahler Transitional Dyspnoea Index (TDI) Focal Score on Day 85 From the Two Twin Trials, Present 1237.6 (NCT01431287) and 1237.5 (NCT01431274)	1.506 points on a scale Standard Error 0.097	1.698 points on a scale Standard Error 0.097	1.702 points on a scale Standard Error 0.097	1.925 points on a scale Standard Error 0.096	2.136 points on a scale Standard Error 0.096

SECONDARY outcome

Timeframe: Day 365

Population: FAS (day 365). Since it is possible for the patient to meet the data criterion for only a subset of the primary endpoints, it is possible that the number of patients used in the FAS analysis for different endpoints will vary.

Mahler TDI focal score on Day 365 From the two twin trials, present 1237.6 (NCT01431287) and 1237.5 (NCT01431274).

The Mahler Dyspnoea questionnaire is an instrument which measures change from the baseline state The TDI focal score was used to measure the effect of Tio+Olo FDC on patients' dyspnoea after 24 weeks of treatment (Day 169). The focal score is the sum of the subscale scores for Functional Impairment, Magnitude of Effort and Magnitude of Task. Scores for each subscale range from -3 to 3 so that the Focal score ranges from -9 to 9. For all subscale scores and the Focal score a higher value indicates a better outcome.

Number of participants analyzed are the number of patients contributing to the mixed effect repeated measures model (MMRM) in each treatment group.

Outcome measures

Measure	Olodaterol (5 μg) n=984 Participants Oral inhalation of Olodaterol 5 μg (2.5 μg per actuation), 2 puffs in the morning.	Tiotropium (2.5 μg) n=982 Participants Oral inhalation of Tiotropium 2.5 μg (1.25 μg per actuation), 2 puffs in the morning.	Tiotropium (5 μg) n=978 Participants Oral inhalation of Tiotropium 5 μg (2.5 μg per actuation), 2 puffs in the morning.	Tio+Olo FDC (2.5/5 μg) n=992 Participants Oral inhalation of FDC of Tiotropium 2.5 μg and Olodaterol 5 μg (Tiotropium: 1.25 μg per actuation and Olodaterol: 2.5 μg per actuation), 2 puffs in the morning.	Tio+Olo FDC (5/5 μg) n=992 Participants Oral inhalation of FDC of Tiotropium 5 μg and Olodaterol 5 μg (Tiotropium and Olodaterol: 2.5 μg per actuation), 2 puffs in the morning.
Mahler Transitional Dyspnoea Index (TDI) Focal Score on Day 365 From the Two Twin Trials, Present 1237.6 (NCT01431287) and 1237.5 (NCT01431274)	1.411 points on a scale Standard Error 0.101	1.450 points on a scale Standard Error 0.100	1.736 points on a scale Standard Error 0.101	1.782 points on a scale Standard Error 0.099	2.058 points on a scale Standard Error 0.099

Adverse Events

Olodaterol (5 μg)

Serious events: 106 serious events

Other events: 246 other events

Deaths: 0 deaths

Tiotropium (2.5 μg)

Serious events: 90 serious events

Other events: 228 other events

Deaths: 0 deaths

Tiotropium (5 μg)

Serious events: 93 serious events

Other events: 216 other events

Deaths: 0 deaths

Tio+Olo FDC (2.5/5 μg)

Serious events: 87 serious events

Other events: 223 other events

Deaths: 0 deaths

Tio+Olo FDC (5/5 μg)

Serious events: 82 serious events

Other events: 214 other events

Deaths: 0 deaths

Serious adverse events

Measure	Olodaterol (5 μg) n=510 participants at risk Oral inhalation of Olodaterol 5 μg (2.5 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.	Tiotropium (2.5 μg) n=507 participants at risk Oral inhalation of Tiotropium 2.5 μg (1.25 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.	Tiotropium (5 μg) n=506 participants at risk Oral inhalation of Tiotropium 5 μg (2.5 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.	Tio+Olo FDC (2.5/5 μg) n=508 participants at risk Oral inhalation of fixed dose combination (FDC) of Tiotropium 2.5 μg and Olodaterol 5 μg (Tiotropium: 1.25 μg per actuation and Olodaterol: 2.5 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.	Tio+Olo FDC (5/5 μg) n=507 participants at risk Oral inhalation of FDC of Tiotropium 5 μg and Olodaterol 5 μg (Tiotropium and Olodaterol: 2.5 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.
Musculoskeletal and connective tissue disorders Periarthritis	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Blood and lymphatic system disorders Anaemia	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Blood and lymphatic system disorders Haemorrhagic anaemia	0.20% 1/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Blood and lymphatic system disorders Iron deficiency anaemia	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Cardiac disorders Acute coronary syndrome	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Cardiac disorders Acute myocardial infarction	0.39% 2/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Cardiac disorders Angina pectoris	0.59% 3/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Cardiac disorders Angina unstable	0.20% 1/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Cardiac disorders Aortic valve stenosis	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.39% 2/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Cardiac disorders Atrial fibrillation	0.20% 1/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Cardiac disorders Atrial flutter	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Cardiac disorders Cardiac arrest	0.20% 1/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.39% 2/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Cardiac disorders Cardiac disorder	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Cardiac disorders Cardiac failure	0.39% 2/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.40% 2/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Cardiac disorders Cardiac failure acute	0.20% 1/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Cardiac disorders Cardiac failure congestive	0.20% 1/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.39% 2/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Cardiac disorders Cardio-respiratory arrest	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Cardiac disorders Coronary artery disease	0.39% 2/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.59% 3/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.39% 2/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Cardiac disorders Extrasystoles	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Cardiac disorders Ischaemic cardiomyopathy	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Cardiac disorders Left ventricular dysfunction	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Cardiac disorders Myocardial infarction	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.39% 2/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Cardiac disorders Myocardial ischaemia	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Cardiac disorders Palpitations	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Cardiac disorders Supraventricular tachycardia	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Cardiac disorders Tachyarrhythmia	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Cardiac disorders Ventricular fibrillation	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Cardiac disorders Ventricular tachycardia	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Congenital, familial and genetic disorders Malformation biliary	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Ear and labyrinth disorders Vertigo	0.20% 1/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Eye disorders Age-related macular degeneration	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Eye disorders Cataract	0.20% 1/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Eye disorders Lacrimation increased	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Eye disorders Macular degeneration	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Eye disorders Retinal tear	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Eye disorders Vision blurred	0.20% 1/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Gastrointestinal disorders Abdominal pain	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Gastrointestinal disorders Abdominal pain upper	0.20% 1/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Gastrointestinal disorders Colitis	0.20% 1/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Gastrointestinal disorders Colitis ischaemic	0.20% 1/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Gastrointestinal disorders Colitis ulcerative	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Gastrointestinal disorders Crohn's disease	0.20% 1/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Gastrointestinal disorders Diarrhoea	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Gastrointestinal disorders Diverticulum intestinal	0.20% 1/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Gastrointestinal disorders Duodenal ulcer haemorrhage	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Gastrointestinal disorders Duodenal ulcer perforation	0.20% 1/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Gastrointestinal disorders Dysphagia	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Gastrointestinal disorders Enteritis	0.20% 1/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Gastrointestinal disorders Gastritis	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.39% 2/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Gastrointestinal disorders Gastrointestinal haemorrhage	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Gastrointestinal disorders Gastrooesophageal reflux disease	0.20% 1/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Gastrointestinal disorders Ileus	0.20% 1/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Gastrointestinal disorders Inguinal hernia	0.59% 3/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Gastrointestinal disorders Inguinal hernia strangulated	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Gastrointestinal disorders Melaena	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Gastrointestinal disorders Mesenteric artery stenosis	0.20% 1/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Gastrointestinal disorders Oesophageal achalasia	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Gastrointestinal disorders Oesophageal stenosis	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Gastrointestinal disorders Oral pain	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Gastrointestinal disorders Pancreatitis acute	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Gastrointestinal disorders Proctalgia	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Gastrointestinal disorders Small intestinal obstruction	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Gastrointestinal disorders Upper gastrointestinal haemorrhage	0.20% 1/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
General disorders Chest discomfort	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
General disorders Chest pain	0.20% 1/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.39% 2/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
General disorders Death	0.20% 1/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
General disorders Device dislocation	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
General disorders Drowning	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
General disorders Generalised oedema	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
General disorders Medical device complication	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
General disorders Multi-organ failure	0.20% 1/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
General disorders Non-cardiac chest pain	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.39% 2/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
General disorders Oedema peripheral	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.39% 2/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
General disorders Pyrexia	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
General disorders Sudden death	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Hepatobiliary disorders Bile duct stone	0.20% 1/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Hepatobiliary disorders Biliary colic	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Hepatobiliary disorders Cholecystitis	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Hepatobiliary disorders Cholecystitis acute	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.39% 2/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Hepatobiliary disorders Cholelithiasis	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Immune system disorders Anti-neutrophil cytoplasmic antibody positive vasculitis	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Infections and infestations Abscess	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Infections and infestations Anal abscess	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Infections and infestations Appendicitis perforated	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Infections and infestations Biliary sepsis	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Infections and infestations Bronchitis	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.39% 2/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Infections and infestations Bronchopneumonia	0.39% 2/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Infections and infestations Cellulitis	0.39% 2/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Infections and infestations Cellulitis pharyngeal	0.20% 1/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Infections and infestations Dermatitis infected	0.20% 1/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Infections and infestations Diverticulitis	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Infections and infestations Escherichia bacteraemia	0.20% 1/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Infections and infestations Gastroenteritis	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.40% 2/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Infections and infestations Gastroenteritis viral	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Infections and infestations Graft infection	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Infections and infestations H1N1 influenza	0.20% 1/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Infections and infestations Hepatitis B	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Infections and infestations Infection	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Infections and infestations Infective exacerbation of chronic obstructive airways disease	0.39% 2/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Infections and infestations Influenza	0.39% 2/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Infections and infestations Lobar pneumonia	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Infections and infestations Lower respiratory tract infection	0.20% 1/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Infections and infestations Lung infection	0.20% 1/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Infections and infestations Ophthalmic herpes zoster	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Infections and infestations Pelvic abscess	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Infections and infestations Pneumococcal sepsis	0.20% 1/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Infections and infestations Pneumonia	1.2% 6/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	1.2% 6/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.40% 2/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	1.8% 9/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	1.8% 9/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Infections and infestations Post procedural infection	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Infections and infestations Postoperative abscess	0.20% 1/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Infections and infestations Pyelonephritis	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Infections and infestations Respiratory tract infection	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Infections and infestations Sepsis	0.20% 1/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Infections and infestations Septic shock	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Infections and infestations Sinusitis	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Infections and infestations Superinfection	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Infections and infestations Urinary tract infection	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Infections and infestations Urosepsis	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Injury, poisoning and procedural complications Abdominal injury	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Injury, poisoning and procedural complications Acetabulum fracture	0.20% 1/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Injury, poisoning and procedural complications Avulsion fracture	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Injury, poisoning and procedural complications Clavicle fracture	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Injury, poisoning and procedural complications Contusion	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Injury, poisoning and procedural complications Fall	0.59% 3/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.39% 2/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Injury, poisoning and procedural complications Femoral neck fracture	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Injury, poisoning and procedural complications Femur fracture	0.20% 1/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Injury, poisoning and procedural complications Head injury	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Injury, poisoning and procedural complications Hip fracture	0.20% 1/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Injury, poisoning and procedural complications Humerus fracture	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Injury, poisoning and procedural complications Injury	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Injury, poisoning and procedural complications Joint dislocation	0.20% 1/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Injury, poisoning and procedural complications Liver contusion	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Injury, poisoning and procedural complications Lumbar vertebral fracture	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Injury, poisoning and procedural complications Meniscus injury	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Injury, poisoning and procedural complications Patella fracture	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Injury, poisoning and procedural complications Rib fracture	0.20% 1/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.39% 2/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Injury, poisoning and procedural complications Skull fractured base	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Injury, poisoning and procedural complications Spinal compression fracture	0.20% 1/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Injury, poisoning and procedural complications Stab wound	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Injury, poisoning and procedural complications Subdural haematoma	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Injury, poisoning and procedural complications Tendon rupture	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Injury, poisoning and procedural complications Thoracic vertebral fracture	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Injury, poisoning and procedural complications Traumatic haematoma	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Injury, poisoning and procedural complications Vascular pseudoaneurysm	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Investigations Blood glucose increased	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Investigations Blood pressure decreased	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Investigations Troponin T increased	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Metabolism and nutrition disorders Dehydration	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.39% 2/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Metabolism and nutrition disorders Diabetes mellitus	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Metabolism and nutrition disorders Diabetic ketoacidosis	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Metabolism and nutrition disorders Gout	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Metabolism and nutrition disorders Hypokalaemia	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Musculoskeletal and connective tissue disorders Arthralgia	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Musculoskeletal and connective tissue disorders Back pain	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Musculoskeletal and connective tissue disorders Bone deformity	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Musculoskeletal and connective tissue disorders Flank pain	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Musculoskeletal and connective tissue disorders Foot deformity	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Musculoskeletal and connective tissue disorders Intervertebral disc degeneration	0.20% 1/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Musculoskeletal and connective tissue disorders Intervertebral disc protrusion	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Musculoskeletal and connective tissue disorders Lumbar spinal stenosis	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.39% 2/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Musculoskeletal and connective tissue disorders Monarthritis	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Musculoskeletal and connective tissue disorders Musculoskeletal pain	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Musculoskeletal and connective tissue disorders Osteoarthritis	0.39% 2/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.39% 2/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Musculoskeletal and connective tissue disorders Spinal column stenosis	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.59% 3/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Musculoskeletal and connective tissue disorders Spinal osteoarthritis	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Musculoskeletal and connective tissue disorders Spondylolisthesis	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Musculoskeletal and connective tissue disorders Synovial cyst	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Adenocarcinoma of colon	0.20% 1/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Basal cell carcinoma	0.20% 1/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Bladder cancer	0.20% 1/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Bladder neoplasm	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Bronchial carcinoma	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Colon adenoma	0.20% 1/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Colon cancer	0.39% 2/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Endometrial cancer	0.20% 1/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Gastric cancer	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Hepatic cancer	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.39% 2/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Lung adenocarcinoma	0.20% 1/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Lung adenocarcinoma metastatic	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Lung cancer metastatic	0.39% 2/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Lung neoplasm	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Lung neoplasm malignant	0.20% 1/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.40% 2/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.39% 2/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Metastases to adrenals	0.20% 1/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Metastases to central nervous system	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Metastases to liver	0.39% 2/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Neoplasm prostate	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Neuroendocrine carcinoma	0.20% 1/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Non-small cell lung cancer	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Oesophageal carcinoma	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Oesophageal squamous cell carcinoma	0.20% 1/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Oropharyngeal cancer	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Pancreatic carcinoma	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Penile cancer	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Prostate cancer	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.39% 2/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Prostate cancer metastatic	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Rectal cancer	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Renal cancer	0.20% 1/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Renal cancer metastatic	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Small cell lung cancer	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Squamous cell carcinoma of lung	0.20% 1/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Squamous cell carcinoma of skin	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Squamous cell carcinoma of the tongue	0.20% 1/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Sweat gland tumour	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Transitional cell carcinoma	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Nervous system disorders Acute polyneuropathy	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Nervous system disorders Carotid artery aneurysm	0.20% 1/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Nervous system disorders Carotid artery stenosis	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Nervous system disorders Cerebellar haemorrhage	0.20% 1/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Nervous system disorders Cerebral haemorrhage	0.20% 1/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Nervous system disorders Cerebral infarction	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.39% 2/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Nervous system disorders Cerebrovascular accident	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.40% 2/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.39% 2/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Nervous system disorders Cerebrovascular disorder	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Nervous system disorders Convulsion	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Nervous system disorders Dizziness	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Nervous system disorders Epilepsy	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Nervous system disorders Haemorrhage intracranial	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Nervous system disorders Headache	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Nervous system disorders Hypoxic-ischaemic encephalopathy	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Nervous system disorders Nervous system disorder	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Nervous system disorders Neuromyopathy	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Nervous system disorders Presyncope	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Nervous system disorders Spondylitic myelopathy	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Nervous system disorders Subarachnoid haemorrhage	0.20% 1/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Nervous system disorders Syncope	0.20% 1/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Nervous system disorders Thrombotic cerebral infarction	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Nervous system disorders Transient ischaemic attack	0.39% 2/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Nervous system disorders Tremor	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Psychiatric disorders Acute stress disorder	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Psychiatric disorders Aggression	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Psychiatric disorders Bipolar I disorder	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Psychiatric disorders Confusional state	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Psychiatric disorders Conversion disorder	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Psychiatric disorders Delirium	0.20% 1/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Psychiatric disorders Depression	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Psychiatric disorders Major depression	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Renal and urinary disorders Dysuria	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Renal and urinary disorders Haematuria	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Renal and urinary disorders Nephritis	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Renal and urinary disorders Renal colic	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Renal and urinary disorders Renal failure	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Renal and urinary disorders Renal failure acute	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Renal and urinary disorders Renal vasculitis	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Reproductive system and breast disorders Benign prostatic hyperplasia	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.79% 4/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Reproductive system and breast disorders Vaginal prolapse	0.20% 1/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Respiratory, thoracic and mediastinal disorders Acute respiratory failure	0.39% 2/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.39% 2/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.39% 2/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Respiratory, thoracic and mediastinal disorders Analgesic asthma syndrome	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Respiratory, thoracic and mediastinal disorders Atelectasis	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Respiratory, thoracic and mediastinal disorders Bronchiectasis	0.20% 1/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Respiratory, thoracic and mediastinal disorders Bullous lung disease	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Respiratory, thoracic and mediastinal disorders Chronic obstructive pulmonary disease	8.0% 41/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	7.3% 37/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	6.5% 33/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	5.9% 30/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	6.5% 33/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Respiratory, thoracic and mediastinal disorders Dysphonia	0.20% 1/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Respiratory, thoracic and mediastinal disorders Dyspnoea	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.39% 2/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.40% 2/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.39% 2/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Respiratory, thoracic and mediastinal disorders Emphysema	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Respiratory, thoracic and mediastinal disorders Epistaxis	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Respiratory, thoracic and mediastinal disorders Haemoptysis	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Respiratory, thoracic and mediastinal disorders Hydrothorax	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Respiratory, thoracic and mediastinal disorders Hypercapnia	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Respiratory, thoracic and mediastinal disorders Hypoxia	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Respiratory, thoracic and mediastinal disorders Interstitial lung disease	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Respiratory, thoracic and mediastinal disorders Nasal polyps	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Respiratory, thoracic and mediastinal disorders Nasal turbinate hypertrophy	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Respiratory, thoracic and mediastinal disorders Paranasal sinus discomfort	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Respiratory, thoracic and mediastinal disorders Pleural effusion	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Respiratory, thoracic and mediastinal disorders Pneumonia aspiration	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Respiratory, thoracic and mediastinal disorders Pneumothorax	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.59% 3/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Respiratory, thoracic and mediastinal disorders Pneumothorax spontaneous	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Respiratory, thoracic and mediastinal disorders Pulmonary embolism	0.39% 2/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.39% 2/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.59% 3/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Respiratory, thoracic and mediastinal disorders Pulmonary granuloma	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Respiratory, thoracic and mediastinal disorders Pulmonary hypertension	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Respiratory, thoracic and mediastinal disorders Pulmonary infarction	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Respiratory, thoracic and mediastinal disorders Pulmonary mass	0.20% 1/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Respiratory, thoracic and mediastinal disorders Pulmonary oedema	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Respiratory, thoracic and mediastinal disorders Respiratory failure	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.59% 3/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.59% 3/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Respiratory, thoracic and mediastinal disorders Rhonchi	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Respiratory, thoracic and mediastinal disorders Vocal cord polyp	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Skin and subcutaneous tissue disorders Eczema	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Vascular disorders Aneurysm	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Vascular disorders Aortic aneurysm	0.20% 1/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Vascular disorders Aortic aneurysm rupture	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Vascular disorders Arteritis	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Vascular disorders Deep vein thrombosis	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Vascular disorders Haemorrhage	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Vascular disorders Hypertension	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Vascular disorders Hypertensive crisis	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Vascular disorders Hypotension	0.20% 1/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Vascular disorders Intermittent claudication	0.20% 1/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Vascular disorders Leriche syndrome	0.20% 1/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Vascular disorders Peripheral arterial occlusive disease	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Vascular disorders Peripheral artery aneurysm	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Vascular disorders Peripheral artery stenosis	0.00% 0/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.20% 1/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Vascular disorders Shock	0.20% 1/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Vascular disorders Thrombophlebitis	0.20% 1/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	0.00% 0/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)

Other adverse events

Measure	Olodaterol (5 μg) n=510 participants at risk Oral inhalation of Olodaterol 5 μg (2.5 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.	Tiotropium (2.5 μg) n=507 participants at risk Oral inhalation of Tiotropium 2.5 μg (1.25 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.	Tiotropium (5 μg) n=506 participants at risk Oral inhalation of Tiotropium 5 μg (2.5 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.	Tio+Olo FDC (2.5/5 μg) n=508 participants at risk Oral inhalation of fixed dose combination (FDC) of Tiotropium 2.5 μg and Olodaterol 5 μg (Tiotropium: 1.25 μg per actuation and Olodaterol: 2.5 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.	Tio+Olo FDC (5/5 μg) n=507 participants at risk Oral inhalation of FDC of Tiotropium 5 μg and Olodaterol 5 μg (Tiotropium and Olodaterol: 2.5 μg per actuation) , 2 puffs from the RESPIMAT inhaler, once daily, in the morning.
Infections and infestations Nasopharyngitis	12.9% 66/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	11.6% 59/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	10.7% 54/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	13.8% 70/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	12.0% 61/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Infections and infestations Upper respiratory tract infection	6.3% 32/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	6.1% 31/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	5.3% 27/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	5.7% 29/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	5.7% 29/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Respiratory, thoracic and mediastinal disorders Chronic obstructive pulmonary disease	28.8% 147/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	28.8% 146/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	26.1% 132/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	23.2% 118/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	25.4% 129/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Respiratory, thoracic and mediastinal disorders Cough	3.3% 17/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	5.3% 27/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	4.9% 25/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	5.7% 29/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	4.7% 24/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Respiratory, thoracic and mediastinal disorders Dyspnoea	3.9% 20/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	4.3% 22/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	5.3% 27/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	4.1% 21/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	3.9% 20/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)
Vascular disorders Hypertension	5.1% 26/510 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	2.0% 10/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	2.0% 10/506 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	3.7% 19/508 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)	2.4% 12/507 • All Adverse events with an onset after the first dose of study medication up to a period of 21 days after the last dose of study medication were assigned to the treatment period for evaluation (Up to 459 days)

Additional Information

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• Principal investigator is a sponsor employee Boehringer Ingelheim (BI) acknowledges that investigators have the right to publish the study results. Investigators shall provide BI with a copy of any publication or presentation for review prior to any submission. Such review will be done with regard to proprietary information, information related to patentable inventions, medical, scientific, and statistical accuracy within 60 days. BI may request a delay of the publication in order to protect BI's intellectual property rights.
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