Trial Outcomes & Findings for A Study to Compare the Lung Effect of Indacaterol and Tiotropium in Chronic Obstructive Pulmonary Disease (COPD) (NCT NCT00900731)

Last Updated: 2011-08-19

Results Overview

Spirometry was conducted according to internationally accepted standards. Trough FEV1 was defined as the average of the 23 hour 10 minute and 23 hour 45 minute post-dose FEV1 readings. Mixed model used baseline FEV1, FEV1 prior to and 10-15 minutes post inhalation of salbutamol/albuterol, FEV1 prior to and 1 hour post inhalation of ipratropium, and inhaled corticosteroid use at baseline as covariates.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

1598 participants

Primary outcome timeframe

End of treatment (Week 12)

Results posted on

2011-08-19

Participant Flow

1598 participants were randomized. 3 participants in the Indacaterol group and 2 participants in the Tiotropium group did not receive study medication.

Participant milestones

Participant milestones
Measure	Indacaterol 150 µg Participants received indacaterol 150 μg delivered via a single-dose dry-powder inhaler (SDDPI) plus placebo to tiotropium delivered via the manufacturer's proprietary inhalation device (HandiHaler®) once daily in the morning. Participants were permitted to take salbutamol/albuterol as a rescue medication.	Tiotropium 18 µg Participants received tiotropium 18 μg delivered via the manufacturer's proprietary inhalation device (HandiHaler®) plus placebo to indacaterol delivered via a single-dose dry-powder inhaler (SDDPI) once daily in the morning. Participants were permitted to take salbutamol/albuterol as a rescue medication.
Overall Study STARTED	797	801
Overall Study Safety Set: Received Study Drug	794	799
Overall Study COMPLETED	737	740
Overall Study NOT COMPLETED	60	61

Reasons for withdrawal

Reasons for withdrawal
Measure	Indacaterol 150 µg Participants received indacaterol 150 μg delivered via a single-dose dry-powder inhaler (SDDPI) plus placebo to tiotropium delivered via the manufacturer's proprietary inhalation device (HandiHaler®) once daily in the morning. Participants were permitted to take salbutamol/albuterol as a rescue medication.	Tiotropium 18 µg Participants received tiotropium 18 μg delivered via the manufacturer's proprietary inhalation device (HandiHaler®) plus placebo to indacaterol delivered via a single-dose dry-powder inhaler (SDDPI) once daily in the morning. Participants were permitted to take salbutamol/albuterol as a rescue medication.
Overall Study Adverse Event	31	27
Overall Study Withdrawal by Subject	8	7
Overall Study Protocol Deviation	8	11
Overall Study Administrative Problems	5	4
Overall Study Abnormal Test Procedure Result(s)	3	0
Overall Study Abnormal Laboratory Value(s)	2	4
Overall Study Lost to Follow-up	2	3
Overall Study Lack of Efficacy	1	3
Overall Study Death	0	2

Baseline Characteristics

A Study to Compare the Lung Effect of Indacaterol and Tiotropium in Chronic Obstructive Pulmonary Disease (COPD)

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Indacaterol 150 µg n=794 Participants Participants received indacaterol 150 μg delivered via a single-dose dry-powder inhaler (SDDPI) plus placebo to tiotropium delivered via the manufacturer's proprietary inhalation device (HandiHaler®) once daily in the morning. Participants were permitted to take salbutamol/albuterol as a rescue medication.	Tiotropium 18 µg n=799 Participants Participants received tiotropium 18 μg delivered via the manufacturer's proprietary inhalation device (HandiHaler®) plus placebo to indacaterol delivered via a single-dose dry-powder inhaler (SDDPI) once daily in the morning. Participants were permitted to take salbutamol/albuterol as a rescue medication.	Total n=1593 Participants Total of all reporting groups
Age Continuous	63.6 years STANDARD_DEVIATION 8.60 • n=5 Participants	63.4 years STANDARD_DEVIATION 8.29 • n=7 Participants	63.5 years STANDARD_DEVIATION 8.45 • n=5 Participants
Sex: Female, Male Female	239 Participants n=5 Participants	261 Participants n=7 Participants	500 Participants n=5 Participants
Sex: Female, Male Male	555 Participants n=5 Participants	538 Participants n=7 Participants	1093 Participants n=5 Participants

PRIMARY outcome

Timeframe: End of treatment (Week 12)

Population: Per-protocol population included all participants who received at least one dose of study medication without any major protocol deviations. The endpoint was analyzed only for those participants who had data for this outcome measure. Missing data were imputed using last observation carried forward.

Outcome measures

Outcome measures
Measure	Indacaterol 150 µg n=562 Participants Participants received indacaterol 150 μg delivered via a single-dose dry-powder inhaler (SDDPI) plus placebo to tiotropium delivered via the manufacturer's proprietary inhalation device (HandiHaler®) once daily in the morning. Participants were permitted to take salbutamol/albuterol as a rescue medication.	Tiotropium 18 µg n=595 Participants Participants received tiotropium 18 μg delivered via the manufacturer's proprietary inhalation device (HandiHaler®) plus placebo to indacaterol delivered via a single-dose dry-powder inhaler (SDDPI) once daily in the morning. Participants were permitted to take salbutamol/albuterol as a rescue medication.
Trough Forced Expiratory Volume in 1 Second (FEV1) at End of Treatment (Week 12)	1.44 Liters Standard Error 0.010	1.43 Liters Standard Error 0.010

SECONDARY outcome

Timeframe: 5 minutes to 4 hours post-dose at the end of treatment (week 12)

Population: Full analysis set included all participants who received at least one dose of study medication. The endpoint was analyzed only for those participants who had data at week 12 for this outcome measure.

Spirometry was conducted according to internationally accepted standards. FEV1 was measured at 5 and 30 minutes; and 1, 2, and 4 hours post-dose on Week 12. Standardized FEV1 AUC (5 minutes-4 hour) post-dose at week 12 was calculated based on the trapezoidal rule, and was adjusted for the area per time unit by using the scheduled time of measurements for FEV1. Mixed model used baseline FEV1, FEV1 prior to and 10-15 minutes post inhalation of salbutamol/albuterol, FEV1 prior to and 1 hour post inhalation of ipratropium, and inhaled corticosteroid use at baseline as covariates.

Outcome measures

Outcome measures
Measure	Indacaterol 150 µg n=685 Participants Participants received indacaterol 150 μg delivered via a single-dose dry-powder inhaler (SDDPI) plus placebo to tiotropium delivered via the manufacturer's proprietary inhalation device (HandiHaler®) once daily in the morning. Participants were permitted to take salbutamol/albuterol as a rescue medication.	Tiotropium 18 µg n=692 Participants Participants received tiotropium 18 μg delivered via the manufacturer's proprietary inhalation device (HandiHaler®) plus placebo to indacaterol delivered via a single-dose dry-powder inhaler (SDDPI) once daily in the morning. Participants were permitted to take salbutamol/albuterol as a rescue medication.
Forced Expiratory Volume in 1 Second (FEV1) Standardized (With Respect to Time) Area Under the Curve (AUC) From 5 Minutes to 4 Hours Post-dose at the End of Treatment (Week 12)	1.51 Liter Standard Error 0.010	1.52 Liter Standard Error 0.010

SECONDARY outcome

Timeframe: 12 weeks

Population: Full Analysis Set included all randomized participants who received at least one dose of study drug. The endpoint was analyzed only for those participants who had data at week 12 for this outcome measure. Missing data were imputed using Last Observation Carried Forward.

TDI focal score is based on three domains: functional impairment, magnitude of task and magnitude of effort. Each domain is scored from -3 (major deterioration) to 3 (major improvement) to give an overall TDI focal score of -9 to 9 with a negative score indicating a deterioration from baseline. A 1 unit difference in the TDI focal score is clinically significant. Mixed model used baseline dyspnea index, FEV1 prior to and 10-15 minutes post inhalation of salbutamol/albuterol, FEV1 prior to and 1 hour post inhalation of ipratropium, and inhaled corticosteroid use at baseline as covariates.

Outcome measures

Outcome measures
Measure	Indacaterol 150 µg n=729 Participants Participants received indacaterol 150 μg delivered via a single-dose dry-powder inhaler (SDDPI) plus placebo to tiotropium delivered via the manufacturer's proprietary inhalation device (HandiHaler®) once daily in the morning. Participants were permitted to take salbutamol/albuterol as a rescue medication.	Tiotropium 18 µg n=737 Participants Participants received tiotropium 18 μg delivered via the manufacturer's proprietary inhalation device (HandiHaler®) plus placebo to indacaterol delivered via a single-dose dry-powder inhaler (SDDPI) once daily in the morning. Participants were permitted to take salbutamol/albuterol as a rescue medication.
Transition Dyspnea Index (TDI) Focal Score After 12 Weeks of Treatment	2.01 Score on a scale Standard Error 0.178	1.43 Score on a scale Standard Error 0.178

SECONDARY outcome

Timeframe: 12 weeks

SGRQ is a health related quality of life questionnaire consisting of 50 items in three domains: symptoms (frequency and severity), activity (that cause or are limited by breathlessness) and impacts (social functioning \& psychological disturbances resulting from airway disease). The total score is 0 to 100 with a higher score indicating greater impairment of health status. Mixed model used baseline SGRQ, FEV1 prior to and 10-15 minutes post inhalation of salbutamol/albuterol, FEV1 prior to and 1 hour post inhalation of ipratropium, and inhaled corticosteroid use at baseline as covariates.

Outcome measures

Outcome measures
Measure	Indacaterol 150 µg n=743 Participants Participants received indacaterol 150 μg delivered via a single-dose dry-powder inhaler (SDDPI) plus placebo to tiotropium delivered via the manufacturer's proprietary inhalation device (HandiHaler®) once daily in the morning. Participants were permitted to take salbutamol/albuterol as a rescue medication.	Tiotropium 18 µg n=753 Participants Participants received tiotropium 18 μg delivered via the manufacturer's proprietary inhalation device (HandiHaler®) plus placebo to indacaterol delivered via a single-dose dry-powder inhaler (SDDPI) once daily in the morning. Participants were permitted to take salbutamol/albuterol as a rescue medication.
Quality of Life Assessment With St. George's Respiratory Questionnaire (SGRQ) Total Score After 12 Weeks of Treatment	37.1 Score on a scale Standard Error 0.56	39.2 Score on a scale Standard Error 0.55

SECONDARY outcome

Timeframe: Baseline, up to 12 weeks

Population: Full analysis set included all participants who received at least 1 dose of study medication. The endpoint was analyzed only for those participants who had data at baseline and at week 12 for this outcome measure.

Participants recorded the number of puffs of rescue medication taken in the previous 12 hours each morning and evening in an electronic diary. The number of puffs per day over the 12 weeks of treatment was divided by the number of days to derive the mean number per day of puffs of rescue medication for each participant. Mixed model used baseline number of puffs per day of rescue medication, FEV1 prior to and 10-15 minutes post inhalation of salbutamol/albuterol, FEV1 prior to and 1 hour post inhalation of ipratropium, and inhaled corticosteroid use at baseline as covariates.

Outcome measures

Outcome measures
Measure	Indacaterol 150 µg n=740 Participants Participants received indacaterol 150 μg delivered via a single-dose dry-powder inhaler (SDDPI) plus placebo to tiotropium delivered via the manufacturer's proprietary inhalation device (HandiHaler®) once daily in the morning. Participants were permitted to take salbutamol/albuterol as a rescue medication.	Tiotropium 18 µg n=747 Participants Participants received tiotropium 18 μg delivered via the manufacturer's proprietary inhalation device (HandiHaler®) plus placebo to indacaterol delivered via a single-dose dry-powder inhaler (SDDPI) once daily in the morning. Participants were permitted to take salbutamol/albuterol as a rescue medication.
Change From Baseline in the Mean Number of Puffs Per Day of Rescue Medication Over the Study Duration (From Day 1 to Week 12)	-1.40 Puffs Standard Error 0.097	-0.85 Puffs Standard Error 0.097

SECONDARY outcome

Timeframe: Baseline, up to 12 weeks

Participants recorded the number of puffs of rescue medication taken in the previous 12 hours each evening in an electronic diary. The number of daytime puffs per day over the 12 weeks of treatment was divided by the number of days to derive the mean number per day of daytime puffs of rescue medication for each participant. Mixed model used baseline number of daytime puffs per day of rescue medication, FEV1 prior to and 10-15 minutes post inhalation of salbutamol/albuterol, FEV1 prior to and 1 hour post inhalation of ipratropium, and inhaled corticosteroid use at baseline as covariates.

Outcome measures

Outcome measures
Measure	Indacaterol 150 µg n=722 Participants Participants received indacaterol 150 μg delivered via a single-dose dry-powder inhaler (SDDPI) plus placebo to tiotropium delivered via the manufacturer's proprietary inhalation device (HandiHaler®) once daily in the morning. Participants were permitted to take salbutamol/albuterol as a rescue medication.	Tiotropium 18 µg n=732 Participants Participants received tiotropium 18 μg delivered via the manufacturer's proprietary inhalation device (HandiHaler®) plus placebo to indacaterol delivered via a single-dose dry-powder inhaler (SDDPI) once daily in the morning. Participants were permitted to take salbutamol/albuterol as a rescue medication.
Change From Baseline in the Mean Number Per Day of Daytime Puffs of Rescue Medication Over the Study Duration (From Day 1 to Week 12)	-0.90 Puffs Standard Error 0.063	-0.59 Puffs Standard Error 0.063

SECONDARY outcome

Timeframe: Baseline, up to 12 weeks

Participants recorded the number of puffs of rescue medication taken in the previous 12 hours each morning in an electronic diary. The number of nighttime puffs per day over the 12 weeks of treatment was divided by the number of days to derive the mean number per day of nighttime puffs of rescue medication for each participant. Mixed model used baseline number of nighttime puffs per day of rescue medication, FEV1 prior to and 10-15 minutes post inhalation of salbutamol/albuterol, FEV1 prior to and 1 hour post inhalation of ipratropium, and inhaled corticosteroid use at baseline as covariates.

Outcome measures

Outcome measures
Measure	Indacaterol 150 µg n=729 Participants Participants received indacaterol 150 μg delivered via a single-dose dry-powder inhaler (SDDPI) plus placebo to tiotropium delivered via the manufacturer's proprietary inhalation device (HandiHaler®) once daily in the morning. Participants were permitted to take salbutamol/albuterol as a rescue medication.	Tiotropium 18 µg n=742 Participants Participants received tiotropium 18 μg delivered via the manufacturer's proprietary inhalation device (HandiHaler®) plus placebo to indacaterol delivered via a single-dose dry-powder inhaler (SDDPI) once daily in the morning. Participants were permitted to take salbutamol/albuterol as a rescue medication.
Change From Baseline in the Mean Number Per Day of Nighttime Puffs of Rescue Medication Over the Study Duration (From Day 1 to Week 12)	-0.52 Puffs Standard Error 0.043	-0.28 Puffs Standard Error 0.042

SECONDARY outcome

Timeframe: Up to 12 weeks

Population: Full analysis set included all participants who received at least one dose of study medication. The endpoint was analyzed only for those participants who had data for this outcome measure.

A day with no rescue medication was defined as any day in the diary that the participant used no puffs of rescue medication. The percentage of days with no rescue medication was calculated by dividing the number of days with no rescue medication over the 12 week treatment period by the number of evaluable days and multiplying by 100. Mixed model used baseline percentage of days with no rescue medication, FEV1 prior to and 10-15 minutes post inhalation of salbutamol/albuterol, FEV1 prior to and 1 hour post inhalation of ipratropium, and inhaled corticosteroid use at baseline as covariates.

Outcome measures

Outcome measures
Measure	Indacaterol 150 µg n=725 Participants Participants received indacaterol 150 μg delivered via a single-dose dry-powder inhaler (SDDPI) plus placebo to tiotropium delivered via the manufacturer's proprietary inhalation device (HandiHaler®) once daily in the morning. Participants were permitted to take salbutamol/albuterol as a rescue medication.	Tiotropium 18 µg n=738 Participants Participants received tiotropium 18 μg delivered via the manufacturer's proprietary inhalation device (HandiHaler®) plus placebo to indacaterol delivered via a single-dose dry-powder inhaler (SDDPI) once daily in the morning. Participants were permitted to take salbutamol/albuterol as a rescue medication.
Percentage of Days With no Rescue Medication Use During the 12 Weeks of Treatment	46.1 Percentage of days Standard Error 1.65	41.4 Percentage of days Standard Error 1.64

Adverse Events

Indacaterol 150 μg

Serious events: 22 serious events

Other events: 80 other events

Deaths: 0 deaths

Tiotropium 18 μg

Serious events: 30 serious events

Other events: 61 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Other adverse events
Measure	Indacaterol 150 μg n=794 participants at risk Participants received indacaterol 150 μg delivered via a single-dose dry-powder inhaler (SDDPI) plus placebo to tiotropium delivered via the manufacturer's proprietary inhalation device (HandiHaler®) once daily in the morning. Participants were permitted to take salbutamol/albuterol as a rescue medication.	Tiotropium 18 μg n=799 participants at risk Participants received tiotropium 18 μg delivered via the manufacturer's proprietary inhalation device (HandiHaler®) plus placebo to indacaterol delivered via a single-dose dry-powder inhaler (SDDPI) once daily in the morning. Participants were permitted to take salbutamol/albuterol as a rescue medication.
Respiratory, thoracic and mediastinal disorders Chronic obstructive pulmonary disease	10.1% 80/794 • 12 weeks Safety set consisting of all participants who received at least one dose of study drug.	7.6% 61/799 • 12 weeks Safety set consisting of all participants who received at least one dose of study drug.

Additional Information

Study Director

Novartis Pharmaceuticals

Phone: 862 778-8300

Results disclosure agreements

Principal investigator is a sponsor employee The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (ie, data from all sites) in the clinical trial.
Publication restrictions are in place

Restriction type: OTHER

Measure	Indacaterol 150 μg n=794 participants at risk Participants received indacaterol 150 μg delivered via a single-dose dry-powder inhaler (SDDPI) plus placebo to tiotropium delivered via the manufacturer's proprietary inhalation device (HandiHaler®) once daily in the morning. Participants were permitted to take salbutamol/albuterol as a rescue medication.	Tiotropium 18 μg n=799 participants at risk Participants received tiotropium 18 μg delivered via the manufacturer's proprietary inhalation device (HandiHaler®) plus placebo to indacaterol delivered via a single-dose dry-powder inhaler (SDDPI) once daily in the morning. Participants were permitted to take salbutamol/albuterol as a rescue medication.
Nervous system disorders Cerebrovascular accident	0.00% 0/794 • 12 weeks Safety set consisting of all participants who received at least one dose of study drug.	0.25% 2/799 • 12 weeks Safety set consisting of all participants who received at least one dose of study drug.
Nervous system disorders Cerebrovascular insufficiency	0.13% 1/794 • 12 weeks Safety set consisting of all participants who received at least one dose of study drug.	0.00% 0/799 • 12 weeks Safety set consisting of all participants who received at least one dose of study drug.
Nervous system disorders Epilepsy	0.00% 0/794 • 12 weeks Safety set consisting of all participants who received at least one dose of study drug.	0.13% 1/799 • 12 weeks Safety set consisting of all participants who received at least one dose of study drug.
Nervous system disorders Syncope	0.13% 1/794 • 12 weeks Safety set consisting of all participants who received at least one dose of study drug.	0.00% 0/799 • 12 weeks Safety set consisting of all participants who received at least one dose of study drug.
Nervous system disorders Vagus nerve paralysis	0.00% 0/794 • 12 weeks Safety set consisting of all participants who received at least one dose of study drug.	0.13% 1/799 • 12 weeks Safety set consisting of all participants who received at least one dose of study drug.
Psychiatric disorders Alcohol withdrawal syndrome	0.13% 1/794 • 12 weeks Safety set consisting of all participants who received at least one dose of study drug.	0.00% 0/799 • 12 weeks Safety set consisting of all participants who received at least one dose of study drug.
Psychiatric disorders Mental status changes	0.00% 0/794 • 12 weeks Safety set consisting of all participants who received at least one dose of study drug.	0.13% 1/799 • 12 weeks Safety set consisting of all participants who received at least one dose of study drug.
Renal and urinary disorders Nephrotic syndrome	0.00% 0/794 • 12 weeks Safety set consisting of all participants who received at least one dose of study drug.	0.13% 1/799 • 12 weeks Safety set consisting of all participants who received at least one dose of study drug.
Respiratory, thoracic and mediastinal disorders Chronic obstructive pulmonary disease	0.88% 7/794 • 12 weeks Safety set consisting of all participants who received at least one dose of study drug.	0.75% 6/799 • 12 weeks Safety set consisting of all participants who received at least one dose of study drug.
Respiratory, thoracic and mediastinal disorders Dyspnoea	0.13% 1/794 • 12 weeks Safety set consisting of all participants who received at least one dose of study drug.	0.38% 3/799 • 12 weeks Safety set consisting of all participants who received at least one dose of study drug.
Respiratory, thoracic and mediastinal disorders Hypoxia	0.13% 1/794 • 12 weeks Safety set consisting of all participants who received at least one dose of study drug.	0.00% 0/799 • 12 weeks Safety set consisting of all participants who received at least one dose of study drug.
Respiratory, thoracic and mediastinal disorders Pleural effusion	0.13% 1/794 • 12 weeks Safety set consisting of all participants who received at least one dose of study drug.	0.13% 1/799 • 12 weeks Safety set consisting of all participants who received at least one dose of study drug.
Respiratory, thoracic and mediastinal disorders Pleurisy	0.00% 0/794 • 12 weeks Safety set consisting of all participants who received at least one dose of study drug.	0.13% 1/799 • 12 weeks Safety set consisting of all participants who received at least one dose of study drug.
Respiratory, thoracic and mediastinal disorders Pulmonary haemorrhage	0.13% 1/794 • 12 weeks Safety set consisting of all participants who received at least one dose of study drug.	0.00% 0/799 • 12 weeks Safety set consisting of all participants who received at least one dose of study drug.
Respiratory, thoracic and mediastinal disorders Respiratory distress	0.00% 0/794 • 12 weeks Safety set consisting of all participants who received at least one dose of study drug.	0.13% 1/799 • 12 weeks Safety set consisting of all participants who received at least one dose of study drug.
Vascular disorders Hypertension	0.00% 0/794 • 12 weeks Safety set consisting of all participants who received at least one dose of study drug.	0.13% 1/799 • 12 weeks Safety set consisting of all participants who received at least one dose of study drug.
Vascular disorders Peripheral arterial occlusive disease	0.00% 0/794 • 12 weeks Safety set consisting of all participants who received at least one dose of study drug.	0.13% 1/799 • 12 weeks Safety set consisting of all participants who received at least one dose of study drug.
Vascular disorders Peripheral vascular disorder	0.00% 0/794 • 12 weeks Safety set consisting of all participants who received at least one dose of study drug.	0.13% 1/799 • 12 weeks Safety set consisting of all participants who received at least one dose of study drug.
Cardiac disorders Acute coronary syndrome	0.13% 1/794 • 12 weeks Safety set consisting of all participants who received at least one dose of study drug.	0.00% 0/799 • 12 weeks Safety set consisting of all participants who received at least one dose of study drug.
Cardiac disorders Angina pectoris	0.13% 1/794 • 12 weeks Safety set consisting of all participants who received at least one dose of study drug.	0.00% 0/799 • 12 weeks Safety set consisting of all participants who received at least one dose of study drug.
Cardiac disorders Arrhythmia	0.00% 0/794 • 12 weeks Safety set consisting of all participants who received at least one dose of study drug.	0.25% 2/799 • 12 weeks Safety set consisting of all participants who received at least one dose of study drug.
Cardiac disorders Atrial fibrillation	0.00% 0/794 • 12 weeks Safety set consisting of all participants who received at least one dose of study drug.	0.13% 1/799 • 12 weeks Safety set consisting of all participants who received at least one dose of study drug.
Cardiac disorders Cardiac arrest	0.00% 0/794 • 12 weeks Safety set consisting of all participants who received at least one dose of study drug.	0.13% 1/799 • 12 weeks Safety set consisting of all participants who received at least one dose of study drug.
Cardiac disorders Cardiac failure congestive	0.00% 0/794 • 12 weeks Safety set consisting of all participants who received at least one dose of study drug.	0.13% 1/799 • 12 weeks Safety set consisting of all participants who received at least one dose of study drug.
Cardiac disorders Coronary artery disease	0.25% 2/794 • 12 weeks Safety set consisting of all participants who received at least one dose of study drug.	0.13% 1/799 • 12 weeks Safety set consisting of all participants who received at least one dose of study drug.
Cardiac disorders Myocardial infarction	0.13% 1/794 • 12 weeks Safety set consisting of all participants who received at least one dose of study drug.	0.00% 0/799 • 12 weeks Safety set consisting of all participants who received at least one dose of study drug.
Cardiac disorders Myocardial ischaemia	0.13% 1/794 • 12 weeks Safety set consisting of all participants who received at least one dose of study drug.	0.00% 0/799 • 12 weeks Safety set consisting of all participants who received at least one dose of study drug.
Eye disorders Diabetic eye disease	0.00% 0/794 • 12 weeks Safety set consisting of all participants who received at least one dose of study drug.	0.13% 1/799 • 12 weeks Safety set consisting of all participants who received at least one dose of study drug.
Gastrointestinal disorders Abdominal pain	0.13% 1/794 • 12 weeks Safety set consisting of all participants who received at least one dose of study drug.	0.00% 0/799 • 12 weeks Safety set consisting of all participants who received at least one dose of study drug.
Gastrointestinal disorders Flatulence	0.13% 1/794 • 12 weeks Safety set consisting of all participants who received at least one dose of study drug.	0.00% 0/799 • 12 weeks Safety set consisting of all participants who received at least one dose of study drug.
Gastrointestinal disorders Gastrooesophageal reflux disease	0.13% 1/794 • 12 weeks Safety set consisting of all participants who received at least one dose of study drug.	0.00% 0/799 • 12 weeks Safety set consisting of all participants who received at least one dose of study drug.
Gastrointestinal disorders Melaena	0.00% 0/794 • 12 weeks Safety set consisting of all participants who received at least one dose of study drug.	0.13% 1/799 • 12 weeks Safety set consisting of all participants who received at least one dose of study drug.
Gastrointestinal disorders Subileus	0.13% 1/794 • 12 weeks Safety set consisting of all participants who received at least one dose of study drug.	0.00% 0/799 • 12 weeks Safety set consisting of all participants who received at least one dose of study drug.
Gastrointestinal disorders Vomiting	0.00% 0/794 • 12 weeks Safety set consisting of all participants who received at least one dose of study drug.	0.13% 1/799 • 12 weeks Safety set consisting of all participants who received at least one dose of study drug.
General disorders Non-cardiac chest pain	0.00% 0/794 • 12 weeks Safety set consisting of all participants who received at least one dose of study drug.	0.13% 1/799 • 12 weeks Safety set consisting of all participants who received at least one dose of study drug.
Immune system disorders Hypersensitivity	0.13% 1/794 • 12 weeks Safety set consisting of all participants who received at least one dose of study drug.	0.00% 0/799 • 12 weeks Safety set consisting of all participants who received at least one dose of study drug.
Infections and infestations Acute sinusitis	0.13% 1/794 • 12 weeks Safety set consisting of all participants who received at least one dose of study drug.	0.00% 0/799 • 12 weeks Safety set consisting of all participants who received at least one dose of study drug.
Infections and infestations Appendicitis	0.13% 1/794 • 12 weeks Safety set consisting of all participants who received at least one dose of study drug.	0.00% 0/799 • 12 weeks Safety set consisting of all participants who received at least one dose of study drug.
Infections and infestations Ear infection	0.00% 0/794 • 12 weeks Safety set consisting of all participants who received at least one dose of study drug.	0.13% 1/799 • 12 weeks Safety set consisting of all participants who received at least one dose of study drug.
Infections and infestations H1N1 influenza	0.25% 2/794 • 12 weeks Safety set consisting of all participants who received at least one dose of study drug.	0.00% 0/799 • 12 weeks Safety set consisting of all participants who received at least one dose of study drug.
Infections and infestations Influenza	0.00% 0/794 • 12 weeks Safety set consisting of all participants who received at least one dose of study drug.	0.13% 1/799 • 12 weeks Safety set consisting of all participants who received at least one dose of study drug.
Infections and infestations Lobar pneumonia	0.00% 0/794 • 12 weeks Safety set consisting of all participants who received at least one dose of study drug.	0.25% 2/799 • 12 weeks Safety set consisting of all participants who received at least one dose of study drug.
Infections and infestations Lower respiratory tract infection	0.13% 1/794 • 12 weeks Safety set consisting of all participants who received at least one dose of study drug.	0.00% 0/799 • 12 weeks Safety set consisting of all participants who received at least one dose of study drug.
Infections and infestations Pneumococcal sepsis	0.00% 0/794 • 12 weeks Safety set consisting of all participants who received at least one dose of study drug.	0.13% 1/799 • 12 weeks Safety set consisting of all participants who received at least one dose of study drug.
Infections and infestations Pneumonia	0.38% 3/794 • 12 weeks Safety set consisting of all participants who received at least one dose of study drug.	0.25% 2/799 • 12 weeks Safety set consisting of all participants who received at least one dose of study drug.
Infections and infestations Septic shock	0.00% 0/794 • 12 weeks Safety set consisting of all participants who received at least one dose of study drug.	0.13% 1/799 • 12 weeks Safety set consisting of all participants who received at least one dose of study drug.
Infections and infestations Urinary tract infection	0.00% 0/794 • 12 weeks Safety set consisting of all participants who received at least one dose of study drug.	0.13% 1/799 • 12 weeks Safety set consisting of all participants who received at least one dose of study drug.
Infections and infestations Viral upper respiratory tract infection	0.00% 0/794 • 12 weeks Safety set consisting of all participants who received at least one dose of study drug.	0.13% 1/799 • 12 weeks Safety set consisting of all participants who received at least one dose of study drug.
Injury, poisoning and procedural complications Anaesthetic complication pulmonary	0.13% 1/794 • 12 weeks Safety set consisting of all participants who received at least one dose of study drug.	0.00% 0/799 • 12 weeks Safety set consisting of all participants who received at least one dose of study drug.
Injury, poisoning and procedural complications Drug toxicity	0.13% 1/794 • 12 weeks Safety set consisting of all participants who received at least one dose of study drug.	0.00% 0/799 • 12 weeks Safety set consisting of all participants who received at least one dose of study drug.
Injury, poisoning and procedural complications Fall	0.13% 1/794 • 12 weeks Safety set consisting of all participants who received at least one dose of study drug.	0.13% 1/799 • 12 weeks Safety set consisting of all participants who received at least one dose of study drug.
Injury, poisoning and procedural complications Foot fracture	0.13% 1/794 • 12 weeks Safety set consisting of all participants who received at least one dose of study drug.	0.00% 0/799 • 12 weeks Safety set consisting of all participants who received at least one dose of study drug.
Injury, poisoning and procedural complications Humerus fracture	0.00% 0/794 • 12 weeks Safety set consisting of all participants who received at least one dose of study drug.	0.13% 1/799 • 12 weeks Safety set consisting of all participants who received at least one dose of study drug.
Injury, poisoning and procedural complications Lumbar vertebral fracture	0.13% 1/794 • 12 weeks Safety set consisting of all participants who received at least one dose of study drug.	0.00% 0/799 • 12 weeks Safety set consisting of all participants who received at least one dose of study drug.
Injury, poisoning and procedural complications Overdose	0.00% 0/794 • 12 weeks Safety set consisting of all participants who received at least one dose of study drug.	0.13% 1/799 • 12 weeks Safety set consisting of all participants who received at least one dose of study drug.
Injury, poisoning and procedural complications Rib fracture	0.00% 0/794 • 12 weeks Safety set consisting of all participants who received at least one dose of study drug.	0.13% 1/799 • 12 weeks Safety set consisting of all participants who received at least one dose of study drug.
Investigations Fibrin D dimer increased	0.00% 0/794 • 12 weeks Safety set consisting of all participants who received at least one dose of study drug.	0.13% 1/799 • 12 weeks Safety set consisting of all participants who received at least one dose of study drug.
Investigations Troponin increased	0.13% 1/794 • 12 weeks Safety set consisting of all participants who received at least one dose of study drug.	0.00% 0/799 • 12 weeks Safety set consisting of all participants who received at least one dose of study drug.
Metabolism and nutrition disorders Metabolic disorder	0.00% 0/794 • 12 weeks Safety set consisting of all participants who received at least one dose of study drug.	0.13% 1/799 • 12 weeks Safety set consisting of all participants who received at least one dose of study drug.
Musculoskeletal and connective tissue disorders Bursitis	0.00% 0/794 • 12 weeks Safety set consisting of all participants who received at least one dose of study drug.	0.13% 1/799 • 12 weeks Safety set consisting of all participants who received at least one dose of study drug.
Musculoskeletal and connective tissue disorders Costochondritis	0.00% 0/794 • 12 weeks Safety set consisting of all participants who received at least one dose of study drug.	0.13% 1/799 • 12 weeks Safety set consisting of all participants who received at least one dose of study drug.
Musculoskeletal and connective tissue disorders Rheumatoid nodule	0.13% 1/794 • 12 weeks Safety set consisting of all participants who received at least one dose of study drug.	0.00% 0/799 • 12 weeks Safety set consisting of all participants who received at least one dose of study drug.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Colon cancer	0.00% 0/794 • 12 weeks Safety set consisting of all participants who received at least one dose of study drug.	0.13% 1/799 • 12 weeks Safety set consisting of all participants who received at least one dose of study drug.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Gallbladder cancer	0.00% 0/794 • 12 weeks Safety set consisting of all participants who received at least one dose of study drug.	0.13% 1/799 • 12 weeks Safety set consisting of all participants who received at least one dose of study drug.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Lung adenocarcinoma	0.13% 1/794 • 12 weeks Safety set consisting of all participants who received at least one dose of study drug.	0.00% 0/799 • 12 weeks Safety set consisting of all participants who received at least one dose of study drug.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Lung neoplasm malignant	0.00% 0/794 • 12 weeks Safety set consisting of all participants who received at least one dose of study drug.	0.13% 1/799 • 12 weeks Safety set consisting of all participants who received at least one dose of study drug.