Trial Outcomes & Findings for Study Evaluating the Effect of Fluticasone Furoate/ Vilanterol (FF/VI) Inhalation Powder Compared With Vilanterol (VI) Inhalation Powder on Bone Mineral Density (BMD) in Subjects With Chronic Obstructive Pulmonary Disease (COPD). (NCT NCT01957150)

NCT ID: NCT01957150

Last Updated: 2019-04-10

Results Overview

BMD analysis performed on log (BMD ratio to baseline) using a repeated measures model with covariates of treatment group, age, gender, baseline BMI, visit, log baseline BMD, log baseline BMD by visit and treatment group by visit interactions. These estimates were then converted into annual changes and averaged to calculate the overall treatment estimates and difference which were used for testing non-inferiority. The analysis shown is for the "While on Treatment" estimand of the difference in percentage change from baseline per annum between FF/VI ± BMD medication/SCS (systemic corticosteroids) and VI ± BMD medication/SCS. Baseline is defined as the measurement performed at Visit 1. Percentage change is calculated as (BMD value post-Baseline divided by Baseline value) -1 multiplied by 100.

• Recruitment status: COMPLETED
• Study phase: PHASE4
• Target enrollment: 283 participants
• Primary outcome timeframe: Baseline (Visit 1) and 26, 52, 78, 104, 130 and 156 Weeks
• Results posted on: 2019-04-10

Participant Flow

The study was conducted on participants with chronic obstructive pulmonary disease (COPD) in five countries to assess the long-term safety effects of Fluticasone Furoate (FF) component of the FF/Vilanterol (VI) inhalation powder.

A total of 482 participants were screened of which 199 were screen failures. A total of 283 participants were randomized in a 1:1 ratio to receive either VI or FF/VI.

Participant milestones

Measure	Participants Administered VI Following run-in period of 14 to 21 days, eligible participants were administered VI 25 microgram (mcg) once daily via ELLIPTA inhaler for 156 weeks.	Participants Administered FF/VI Following run-in period of 14 to 21 days, eligible participants were administered FF 100 mcg along with VI 25 mcg once daily via ELLIPTA inhaler for 156 weeks.
Overall Study STARTED	142	141
Overall Study COMPLETED	87	83
Overall Study NOT COMPLETED	55	58

Reasons for withdrawal

Measure	Participants Administered VI Following run-in period of 14 to 21 days, eligible participants were administered VI 25 microgram (mcg) once daily via ELLIPTA inhaler for 156 weeks.	Participants Administered FF/VI Following run-in period of 14 to 21 days, eligible participants were administered FF 100 mcg along with VI 25 mcg once daily via ELLIPTA inhaler for 156 weeks.
Overall Study Adverse Event	23	20
Overall Study Withdrawal by Subject	13	17
Overall Study Physician Decision	3	6
Overall Study Lost to Follow-up	4	4
Overall Study Protocol Violation	1	0
Overall Study Lack of Efficacy	11	11

Baseline Characteristics

Study Evaluating the Effect of Fluticasone Furoate/ Vilanterol (FF/VI) Inhalation Powder Compared With Vilanterol (VI) Inhalation Powder on Bone Mineral Density (BMD) in Subjects With Chronic Obstructive Pulmonary Disease (COPD).

Baseline characteristics by cohort

Measure	Participants Administered VI n=142 Participants Following run-in period of 14 to 21 days, eligible participants were administered VI 25 microgram (mcg) once daily via ELLIPTA inhaler for 156 weeks.	Participants Administered FF/VI n=141 Participants Following run-in period of 14 to 21 days, eligible participants were administered FF 100 mcg along with VI 25 mcg once daily via ELLIPTA inhaler for 156 weeks.	Total n=283 Participants Total of all reporting groups
Age, Continuous	66.0 Years STANDARD_DEVIATION 8.19 • n=5 Participants	64.4 Years STANDARD_DEVIATION 9.04 • n=7 Participants	65.2 Years STANDARD_DEVIATION 8.65 • n=5 Participants
Sex: Female, Male Female	70 Participants n=5 Participants	71 Participants n=7 Participants	141 Participants n=5 Participants
Sex: Female, Male Male	72 Participants n=5 Participants	70 Participants n=7 Participants	142 Participants n=5 Participants
Race/Ethnicity, Customized Central/South Asian Heritage	0 Count of participants n=5 Participants	1 Count of participants n=7 Participants	1 Count of participants n=5 Participants
Race/Ethnicity, Customized Black or African American	1 Count of participants n=5 Participants	1 Count of participants n=7 Participants	2 Count of participants n=5 Participants
Race/Ethnicity, Customized White	141 Count of participants n=5 Participants	139 Count of participants n=7 Participants	280 Count of participants n=5 Participants

PRIMARY outcome

Timeframe: Baseline (Visit 1) and 26, 52, 78, 104, 130 and 156 Weeks

Population: Safety Population. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).All randomized participants who received at least one dose of study treatment were included in Safety Population.

BMD analysis performed on log (BMD ratio to baseline) using a repeated measures model with covariates of treatment group, age, gender, baseline BMI, visit, log baseline BMD, log baseline BMD by visit and treatment group by visit interactions. These estimates were then converted into annual changes and averaged to calculate the overall treatment estimates and difference which were used for testing non-inferiority. The analysis shown is for the "While on Treatment" estimand of the difference in percentage change from baseline per annum between FF/VI ± BMD medication/SCS (systemic corticosteroids) and VI ± BMD medication/SCS. Baseline is defined as the measurement performed at Visit 1. Percentage change is calculated as (BMD value post-Baseline divided by Baseline value) -1 multiplied by 100.

Outcome measures

Measure	Participants Administered VI n=132 Participants Following run-in period of 14 to 21 days, eligible participants were administered VI 25 microgram (mcg) once daily via ELLIPTA inhaler for 156 weeks.	Participants Administered FF/VI n=130 Participants Following run-in period of 14 to 21 days, eligible participants were administered FF 100 mcg along with VI 25 mcg once daily via ELLIPTA inhaler for 156 weeks.
Percentage Change From Baseline in Bone Mineral Density (BMD) Measured at Total Hip % change by Week 52, n = 104, 121	0.35 Percentage change Interval -0.21 to 0.91	-0.43 Percentage change Interval -0.96 to 0.1
Percentage Change From Baseline in Bone Mineral Density (BMD) Measured at Total Hip Overall % change per year, n = 132, 130	0.18 Percentage change Interval -0.18 to 0.55	-0.27 Percentage change Interval -0.63 to 0.09
Percentage Change From Baseline in Bone Mineral Density (BMD) Measured at Total Hip % change by Week 26, n= 130, 130	0.37 Percentage change Interval -0.07 to 0.82	0.31 Percentage change Interval -0.13 to 0.76
Percentage Change From Baseline in Bone Mineral Density (BMD) Measured at Total Hip % change by Week 78, n = 97, 102	0.22 Percentage change Interval -0.41 to 0.85	-0.68 Percentage change Interval -1.29 to -0.07
Percentage Change From Baseline in Bone Mineral Density (BMD) Measured at Total Hip % change by Week 104, n = 94, 96	-0.16 Percentage change Interval -0.84 to 0.52	-1.02 Percentage change Interval -1.68 to -0.36
Percentage Change From Baseline in Bone Mineral Density (BMD) Measured at Total Hip % change by Week 130, n = 88, 84	0.00 Percentage change Interval -0.73 to 0.75	-1.02 Percentage change Interval -1.75 to -0.29
Percentage Change From Baseline in Bone Mineral Density (BMD) Measured at Total Hip % change by Week 156, n = 76, 75	-0.16 Percentage change Interval -1.02 to 0.71	-1.29 Percentage change Interval -2.13 to -0.45

SECONDARY outcome

Timeframe: Baseline (Visit 1) and 26, 52, 78, 104, 130 and 156 Weeks

Population: Safety Population. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).

BMD analysis performed on log (BMD ratio to baseline) using separate repeated measures models for each gender with covariates of treatment group, age, baseline BMI, visit, log baseline BMD, log baseline BMD by visit and treatment group by visit interactions. These estimates were then converted into annual changes and averaged to calculate the overall treatment estimates and difference which were used for testing non-inferiority. The analysis shown is for the "While on Treatment" estimand of the difference in percentage change from baseline per annum between FF/VI ± BMD medication/SCS (systemic corticosteroids) and VI ± BMD medication/SCS. Baseline is defined as the measurement performed at Visit 1. Percentage change is calculated as (BMD value post-Baseline divided by Baseline value) -1 multiplied by 100.

Outcome measures

Measure	Participants Administered VI n=67 Participants Following run-in period of 14 to 21 days, eligible participants were administered VI 25 microgram (mcg) once daily via ELLIPTA inhaler for 156 weeks.	Participants Administered FF/VI n=63 Participants Following run-in period of 14 to 21 days, eligible participants were administered FF 100 mcg along with VI 25 mcg once daily via ELLIPTA inhaler for 156 weeks.
Percentage Change From Baseline in BMD Measurements at Total Hip by Gender (Male Participants) Overall Week % change per year, n = 67, 63	0.27 Percent change Interval -0.23 to 0.77	-0.20 Percent change Interval -0.7 to 0.31
Percentage Change From Baseline in BMD Measurements at Total Hip by Gender (Male Participants) % change by Week 26, n = 66, 63	0.45 Percent change Interval -0.06 to 0.97	0.44 Percent change Interval -0.09 to 0.97
Percentage Change From Baseline in BMD Measurements at Total Hip by Gender (Male Participants) % change by Week 52, n = 52, 56	0.48 Percent change Interval -0.31 to 1.27	-0.43 Percent change Interval -1.19 to 0.33
Percentage Change From Baseline in BMD Measurements at Total Hip by Gender (Male Participants) % change by Week 78, n = 51, 46	0.06 Percent change Interval -0.81 to 0.95	-0.68 Percent change Interval -1.56 to 0.21
Percentage Change From Baseline in BMD Measurements at Total Hip by Gender (Male Participants) % change by Week 104, n = 50, 43	0.07 Percent change Interval -0.86 to 1.0	-0.68 Percent change Interval -1.62 to 0.27
Percentage Change From Baseline in BMD Measurements at Total Hip by Gender (Male Participants) % change by Week 130, n = 44, 39	0.37 Percent change Interval -0.75 to 1.5	-0.89 Percent change Interval -2.02 to 0.26
Percentage Change From Baseline in BMD Measurements at Total Hip by Gender (Male Participants) % change by Week 156, n = 40, 35	0.05 Percent change Interval -1.26 to 1.37	-1.39 Percent change Interval -2.71 to -0.05

SECONDARY outcome

Timeframe: Baseline (Visit 1) and 26, 52, 78, 104, 130 and 156 Weeks

Population: Safety Population. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).

BMD analysis performed on log (BMD ratio to baseline) using separate repeated measures models for each gender with covariates of treatment group, age, baseline BMI, visit, log baseline BMD, log baseline BMD by visit and treatment group by visit interactions. These estimates were then converted into annual changes and averaged to calculate the overall treatment estimates and difference which were used for testing non-inferiority. The analysis shown is for the "While on Treatment" estimand of the difference in percentage change from baseline per annum between FF/VI ± BMD medication/SCS (systemic corticosteroids) and VI ± BMD medication/SCS. Baseline is defined as the measurement performed at Visit 1. Percentage change is calculated as (BMD value post-Baseline divided by Baseline value) -1 multiplied by 100.

Outcome measures

Measure	Participants Administered VI n=65 Participants Following run-in period of 14 to 21 days, eligible participants were administered VI 25 microgram (mcg) once daily via ELLIPTA inhaler for 156 weeks.	Participants Administered FF/VI n=67 Participants Following run-in period of 14 to 21 days, eligible participants were administered FF 100 mcg along with VI 25 mcg once daily via ELLIPTA inhaler for 156 weeks.
Percentage Change From Baseline in BMD Measurements at Total Hip by Gender (Female Participants) OverallWeek % change per year, n = 65, 67	0.09 Percent change Interval -0.46 to 0.64	-0.31 Percent change Interval -0.84 to 0.22
Percentage Change From Baseline in BMD Measurements at Total Hip by Gender (Female Participants) % change by Week 26, n = 64, 67	0.28 Percent change Interval -0.45 to 1.02	0.20 Percent change Interval -0.51 to 0.92
Percentage Change From Baseline in BMD Measurements at Total Hip by Gender (Female Participants) % change by Week 52, n = 52, 65	0.13 Percent change Interval -0.67 to 0.94	-0.42 Percent change Interval -1.16 to 0.33
Percentage Change From Baseline in BMD Measurements at Total Hip by Gender (Female Participants) % change by Week 78, n = 46, 56	0.37 Percent change Interval -0.54 to 1.28	-0.63 Percent change Interval -1.48 to 0.23
Percentage Change From Baseline in BMD Measurements at Total Hip by Gender (Female Participants) % change by Week 104, n = 44, 53	-0.40 Percent change Interval -1.4 to 0.61	-1.26 Percent change Interval -2.19 to -0.32
Percentage Change From Baseline in BMD Measurements at Total Hip by Gender (Female Participants) % change by Week 130, n = 44, 45	-0.18 Percent change Interval -1.12 to 0.77	-0.99 Percent change Interval -1.9 to -0.08
Percentage Change From Baseline in BMD Measurements at Total Hip by Gender (Female Participants) % change by Week 156, n = 36, 40	-0.42 Percent change Interval -1.56 to 0.73	-1.19 Percent change Interval -2.27 to -0.11

SECONDARY outcome

Timeframe: Baseline (Visit 1) and 26, 52, 78, 104, 130 and 156 Weeks

Population: Safety Population. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).

BMD analysis performed on log (BMD ratio to baseline) using separate repeated measures models for each gender with covariates of treatment group, age, baseline BMI, visit, log baseline BMD, log baseline BMD by visit and treatment group by visit interactions. These estimates were then converted into annual changes and averaged to calculate the overall treatment estimates and difference which were used for testing non-inferiority. The analysis shown is for the "While on Treatment" estimand of the difference in percentage change from baseline per annum between FF/VI ± BMD medication/SCS (systemic corticosteroids) and VI ± BMD medication/SCS. Baseline is defined as the measurement performed at Visit 1. Percentage change is calculated as (BMD value post-Baseline divided by Baseline value) -1 multiplied by 100.

Outcome measures

Measure	Participants Administered VI n=69 Participants Following run-in period of 14 to 21 days, eligible participants were administered VI 25 microgram (mcg) once daily via ELLIPTA inhaler for 156 weeks.	Participants Administered FF/VI n=64 Participants Following run-in period of 14 to 21 days, eligible participants were administered FF 100 mcg along with VI 25 mcg once daily via ELLIPTA inhaler for 156 weeks.
Percentage Change From Baseline in BMD Measurements at Lumbar Spine (L1 to L4) by Gender (Male Participants) Overall, male % change per year, n = 69, 64	1.41 Percent change Interval 0.79 to 2.04	0.38 Percent change Interval -0.26 to 1.02
Percentage Change From Baseline in BMD Measurements at Lumbar Spine (L1 to L4) by Gender (Male Participants) % change by Week 26, n = 67, 64	1.03 Percent change Interval 0.26 to 1.8	0.42 Percent change Interval -0.36 to 1.21
Percentage Change From Baseline in BMD Measurements at Lumbar Spine (L1 to L4) by Gender (Male Participants) % change by Week 52, n = 53, 56	1.91 Percent change Interval 0.89 to 2.94	0.11 Percent change Interval -0.88 to 1.11
Percentage Change From Baseline in BMD Measurements at Lumbar Spine (L1 to L4) by Gender (Male Participants) % change by Week 78, n = 52, 45	2.09 Percent change Interval 0.84 to 3.35	0.64 Percent change Interval -0.67 to 1.97
Percentage Change From Baseline in BMD Measurements at Lumbar Spine (L1 to L4) by Gender (Male Participants) % change by Week 104, n = 52, 43	2.72 Percent change Interval 1.48 to 3.98	0.42 Percent change Interval -0.88 to 1.75
Percentage Change From Baseline in BMD Measurements at Lumbar Spine (L1 to L4) by Gender (Male Participants) % change by Week 130, n = 47, 38	1.95 Percent change Interval 0.76 to 3.16	0.47 Percent change Interval -0.82 to 1.78
Percentage Change From Baseline in BMD Measurements at Lumbar Spine (L1 to L4) by Gender (Male Participants) % change by Week 156, n = 43, 35	2.96 Percent change Interval 1.68 to 4.25	1.49 Percent change Interval 0.13 to 2.86

SECONDARY outcome

Timeframe: Baseline (Visit 1) and 26, 52, 78, 104, 130 and 156 Weeks

Population: Safety Population. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).

BMD analysis performed on log (BMD ratio to baseline) using separate repeated measures models for each gender with covariates of treatment group, age, baseline BMI, visit, log baseline BMD, log baseline BMD by visit and treatment group by visit interactions. These estimates were then converted into annual changes and averaged to calculate the overall treatment estimates and difference which were used for testing non-inferiority. The analysis shown is for the "While on Treatment" estimand of the difference in percentage change from baseline per annum between FF/VI ± BMD medication/SCS (systemic corticosteroids) and VI ± BMD medication/SCS. Baseline is defined as the measurement performed at Visit 1. Percentage change is calculated as (BMD value post-Baseline divided by Baseline value) -1 multiplied by 100.

Outcome measures

Measure	Participants Administered VI n=66 Participants Following run-in period of 14 to 21 days, eligible participants were administered VI 25 microgram (mcg) once daily via ELLIPTA inhaler for 156 weeks.	Participants Administered FF/VI n=68 Participants Following run-in period of 14 to 21 days, eligible participants were administered FF 100 mcg along with VI 25 mcg once daily via ELLIPTA inhaler for 156 weeks.
Percentage Change From Baseline in BMD Measurements at Lumbar Spine (L1 to L4) by Gender (Female Participants) % change by Week 26, n = 66, 68	0.10 Percent change Interval -0.67 to 0.88	-0.19 Percent change Interval -0.95 to 0.58
Percentage Change From Baseline in BMD Measurements at Lumbar Spine (L1 to L4) by Gender (Female Participants) % change by Week 78, n = 46, 57	0.33 Percent change Interval -0.6 to 1.26	0.25 Percent change Interval -0.61 to 1.11
Percentage Change From Baseline in BMD Measurements at Lumbar Spine (L1 to L4) by Gender (Female Participants) Overall Week % change per year, n = 66, 68	0.17 Percent change Interval -0.42 to 0.77	0.12 Percent change Interval -0.45 to 0.7
Percentage Change From Baseline in BMD Measurements at Lumbar Spine (L1 to L4) by Gender (Female Participants) % change by Week 52, n = 51, 66	-0.48 Percent change Interval -1.44 to 0.48	0.57 Percent change Interval -0.31 to 1.46
Percentage Change From Baseline in BMD Measurements at Lumbar Spine (L1 to L4) by Gender (Female Participants) % change by Week 104, n = 43, 54	0.65 Percent change Interval -0.5 to 1.8	0.64 Percent change Interval -0.41 to 1.7
Percentage Change From Baseline in BMD Measurements at Lumbar Spine (L1 to L4) by Gender (Female Participants) % change by Week 130, n = 44, 49	1.33 Percent change Interval 0.01 to 2.67	0.10 Percent change Interval -1.12 to 1.33
Percentage Change From Baseline in BMD Measurements at Lumbar Spine (L1 to L4) by Gender (Female Participants) % change by Week 156, n = 36, 42	0.80 Percent change Interval -0.74 to 2.36	0.10 Percent change Interval -1.32 to 1.53

SECONDARY outcome

Timeframe: Baseline (Visit 1) and 26, 52, 78, 104, 130 and 156 Weeks

Population: Safety Population. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).

BMD analysis performed on log (BMD ratio to baseline) using a repeated measures model with covariates of treatment group, age, gender, baseline BMI, visit, log baseline BMD, log baseline BMD by visit and treatment group by visit interactions. These estimates were then converted into annual changes and averaged to calculate the overall treatment estimates and difference which were used for testing non-inferiority. The analysis shown is for the "While on Treatment" estimand of the difference in percentage change from baseline per annum between FF/VI ± BMD medication/SCS (systemic corticosteroids) and VI ± BMD medication/SCS. Baseline is defined as the measurement performed at Visit 1. Percentage change is calculated as (BMD value post-Baseline divided by Baseline value) -1 multiplied by 100.

Outcome measures

Measure	Participants Administered VI n=135 Participants Following run-in period of 14 to 21 days, eligible participants were administered VI 25 microgram (mcg) once daily via ELLIPTA inhaler for 156 weeks.	Participants Administered FF/VI n=132 Participants Following run-in period of 14 to 21 days, eligible participants were administered FF 100 mcg along with VI 25 mcg once daily via ELLIPTA inhaler for 156 weeks.
Percentage Change From Baseline in BMD Measurements at Lumbar Spine (L1 to L4) % change by Week 104, n = 95, 97	1.66 Percentage Change Interval 0.82 to 2.51	0.61 Percentage Change Interval -0.22 to 1.44
Percentage Change From Baseline in BMD Measurements at Lumbar Spine (L1 to L4) Overall week % change per year, n=135, 132	0.79 Percentage Change Interval 0.36 to 1.22	0.28 Percentage Change Interval -0.15 to 0.71
Percentage Change From Baseline in BMD Measurements at Lumbar Spine (L1 to L4) % change by Week 26, n = 133, 132	0.55 Percentage Change Interval 0.01 to 1.1	0.13 Percentage Change Interval -0.41 to 0.68
Percentage Change From Baseline in BMD Measurements at Lumbar Spine (L1 to L4) % change by Week 52, n = 104, 122	0.71 Percentage Change Interval 0.01 to 1.42	0.40 Percentage Change Interval -0.26 to 1.07
Percentage Change From Baseline in BMD Measurements at Lumbar Spine (L1 to L4) % change by Week 78, n= 98, 102	1.20 Percentage Change Interval 0.43 to 1.99	0.45 Percentage Change Interval -0.31 to 1.21
Percentage Change From Baseline in BMD Measurements at Lumbar Spine (L1 to L4) % change by Week 130, n = 91, 87	1.70 Percentage Change Interval 0.8 to 2.61	0.30 Percentage Change Interval -0.6 to 1.2
Percentage Change From Baseline in BMD Measurements at Lumbar Spine (L1 to L4) % change by Week 156, n = 79, 77	1.84 Percentage Change Interval 0.86 to 2.84	0.83 Percentage Change Interval -0.14 to 1.81

Adverse Events

Participants Administered VI

Serious events: 42 serious events

Other events: 102 other events

Deaths: 6 deaths

Participants Administered FF/VI

Serious events: 41 serious events

Other events: 116 other events

Deaths: 4 deaths

Serious adverse events

Measure	Participants Administered VI n=142 participants at risk Following run-in period of 14 to 21 days, eligible participants were administered VI 25 microgram (mcg) once daily via ELLIPTA inhaler for 156 weeks.	Participants Administered FF/VI n=141 participants at risk Following run-in period of 14 to 21 days, eligible participants were administered FF 100 mcg along with VI 25 mcg once daily via ELLIPTA inhaler for 156 weeks.
Respiratory, thoracic and mediastinal disorders Chronic obstructive pulmonary disease	7.0% 10/142 • Number of events 13 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.	4.3% 6/141 • Number of events 10 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.
Respiratory, thoracic and mediastinal disorders Acute respiratory failure	0.70% 1/142 • Number of events 1 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.	2.1% 3/141 • Number of events 3 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.
Respiratory, thoracic and mediastinal disorders Hypoxia	1.4% 2/142 • Number of events 2 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.	0.71% 1/141 • Number of events 1 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.
Respiratory, thoracic and mediastinal disorders Respiratory failure	0.70% 1/142 • Number of events 1 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.	0.71% 1/141 • Number of events 1 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.
Respiratory, thoracic and mediastinal disorders Chronic respiratory failure	0.00% 0/142 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.	0.71% 1/141 • Number of events 1 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.
Respiratory, thoracic and mediastinal disorders Haemoptysis	0.00% 0/142 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.	0.71% 1/141 • Number of events 1 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.
Respiratory, thoracic and mediastinal disorders Pneumothorax	0.00% 0/142 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.	0.71% 1/141 • Number of events 1 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.
Respiratory, thoracic and mediastinal disorders Pneumothorax spontaneous	0.00% 0/142 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.	0.71% 1/141 • Number of events 1 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.
Infections and infestations Pneumonia	2.8% 4/142 • Number of events 4 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.	7.8% 11/141 • Number of events 15 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.
Infections and infestations Sepsis	0.00% 0/142 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.	1.4% 2/141 • Number of events 2 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.
Infections and infestations Abdominal wall abscess	0.70% 1/142 • Number of events 1 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.	0.00% 0/141 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.
Infections and infestations Abscess limb	0.70% 1/142 • Number of events 1 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.	0.00% 0/141 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.
Infections and infestations Bacteraemia	0.70% 1/142 • Number of events 1 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.	0.00% 0/141 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.
Infections and infestations Cellulitis	0.70% 1/142 • Number of events 1 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.	0.00% 0/141 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.
Infections and infestations Erysipelas	0.00% 0/142 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.	0.71% 1/141 • Number of events 1 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.
Infections and infestations Pyelonephritis	0.70% 1/142 • Number of events 1 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.	0.00% 0/141 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.
Infections and infestations Urosepsis	0.70% 1/142 • Number of events 1 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.	0.00% 0/141 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.
Cardiac disorders Atrial fibrillation	1.4% 2/142 • Number of events 2 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.	0.00% 0/141 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.
Cardiac disorders Myocardial infarction	0.70% 1/142 • Number of events 1 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.	0.71% 1/141 • Number of events 1 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.
Cardiac disorders Acute myocardial infarction	0.70% 1/142 • Number of events 1 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.	0.00% 0/141 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.
Cardiac disorders Angina pectoris	0.70% 1/142 • Number of events 1 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.	0.00% 0/141 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.
Cardiac disorders Angina unstable	0.70% 1/142 • Number of events 1 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.	0.00% 0/141 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.
Cardiac disorders Aortic valve stenosis	0.70% 1/142 • Number of events 1 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.	0.00% 0/141 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.
Cardiac disorders Atrial flutter	0.70% 1/142 • Number of events 1 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.	0.00% 0/141 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.
Cardiac disorders Cardiac asthma	0.00% 0/142 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.	0.71% 1/141 • Number of events 1 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.
Cardiac disorders Cardiac failure congestive	0.70% 1/142 • Number of events 1 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.	0.00% 0/141 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.
Cardiac disorders Ischaemic cardiomyopathy	0.00% 0/142 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.	0.71% 1/141 • Number of events 1 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.
Cardiac disorders Myocardial ischaemia	0.70% 1/142 • Number of events 2 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.	0.00% 0/141 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.
Cardiac disorders Sinus node dysfunction	0.70% 1/142 • Number of events 1 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.	0.00% 0/141 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.
Injury, poisoning and procedural complications Femoral neck fracture	0.00% 0/142 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.	1.4% 2/141 • Number of events 2 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.
Injury, poisoning and procedural complications Hip fracture	0.70% 1/142 • Number of events 1 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.	0.71% 1/141 • Number of events 1 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.
Injury, poisoning and procedural complications Fall	0.00% 0/142 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.	0.71% 1/141 • Number of events 1 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.
Injury, poisoning and procedural complications Femur fracture	0.00% 0/142 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.	0.71% 1/141 • Number of events 1 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.
Injury, poisoning and procedural complications Lumbar vertebral fracture	0.00% 0/142 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.	0.71% 1/141 • Number of events 1 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.
Injury, poisoning and procedural complications Procedural pain	0.70% 1/142 • Number of events 1 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.	0.00% 0/141 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.
Injury, poisoning and procedural complications Radius fracture	0.00% 0/142 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.	0.71% 1/141 • Number of events 1 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.
Injury, poisoning and procedural complications Spinal compression fracture	0.70% 1/142 • Number of events 1 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.	0.00% 0/141 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.
Injury, poisoning and procedural complications Thermal burn	0.00% 0/142 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.	0.71% 1/141 • Number of events 1 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.
Nervous system disorders Cerebrovascular accident	0.70% 1/142 • Number of events 1 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.	0.71% 1/141 • Number of events 1 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.
Nervous system disorders Brain injury	0.00% 0/142 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.	0.71% 1/141 • Number of events 1 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.
Nervous system disorders Carotid artery stenosis	0.70% 1/142 • Number of events 1 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.	0.00% 0/141 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.
Nervous system disorders Carpal tunnel syndrome	0.00% 0/142 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.	0.71% 1/141 • Number of events 1 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.
Nervous system disorders Cerebral haemorrhage	0.00% 0/142 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.	0.71% 1/141 • Number of events 1 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.
Nervous system disorders Dementia	0.70% 1/142 • Number of events 1 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.	0.00% 0/141 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.
Nervous system disorders Hepatic encephalopathy	0.70% 1/142 • Number of events 1 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.	0.00% 0/141 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.
Nervous system disorders Ischaemic stroke	0.00% 0/142 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.	0.71% 1/141 • Number of events 1 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.
Nervous system disorders Myoclonus	0.00% 0/142 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.	0.71% 1/141 • Number of events 1 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.
Nervous system disorders Transient ischaemic attack	0.70% 1/142 • Number of events 1 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.	0.00% 0/141 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Prostate cancer	0.70% 1/142 • Number of events 1 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.	0.71% 1/141 • Number of events 1 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Bladder cancer	0.00% 0/142 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.	0.71% 1/141 • Number of events 1 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Bladder cancer stage 0, with cancer in situ	0.00% 0/142 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.	0.71% 1/141 • Number of events 1 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Breast cancer	0.00% 0/142 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.	0.71% 1/141 • Number of events 1 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Lung neoplasm malignant	0.70% 1/142 • Number of events 1 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.	0.00% 0/141 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Non-small cell lung cancer	0.70% 1/142 • Number of events 1 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.	0.00% 0/141 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Oesophageal adenocarcinoma	0.00% 0/142 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.	0.71% 1/141 • Number of events 1 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Oesophageal carcinoma	0.70% 1/142 • Number of events 1 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.	0.00% 0/141 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.
Gastrointestinal disorders Colitis ischaemic	0.00% 0/142 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.	0.71% 1/141 • Number of events 1 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.
Gastrointestinal disorders Duodenal ulcer	0.70% 1/142 • Number of events 1 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.	0.00% 0/141 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.
Gastrointestinal disorders Gastrointestinal haemorrhage	0.70% 1/142 • Number of events 1 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.	0.00% 0/141 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.
Gastrointestinal disorders Ileus	0.00% 0/142 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.	0.71% 1/141 • Number of events 1 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.
Gastrointestinal disorders Inguinal hernia	0.70% 1/142 • Number of events 1 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.	0.00% 0/141 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.
Gastrointestinal disorders Intestinal obstruction	0.70% 1/142 • Number of events 1 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.	0.00% 0/141 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.
Gastrointestinal disorders Intestinal perforation	0.70% 1/142 • Number of events 1 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.	0.00% 0/141 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.
Gastrointestinal disorders Large intestine polyp	0.00% 0/142 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.	0.71% 1/141 • Number of events 1 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.
General disorders Death	0.70% 1/142 • Number of events 1 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.	0.71% 1/141 • Number of events 1 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.
General disorders Chest pain	0.70% 1/142 • Number of events 1 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.	0.00% 0/141 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.
General disorders Non-cardiac chest pain	0.70% 1/142 • Number of events 1 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.	0.00% 0/141 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.
General disorders Pain	0.70% 1/142 • Number of events 1 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.	0.00% 0/141 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.
Vascular disorders Aortic aneurysm	0.70% 1/142 • Number of events 1 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.	0.00% 0/141 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.
Vascular disorders Aortic dissection	0.70% 1/142 • Number of events 1 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.	0.00% 0/141 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.
Vascular disorders Hypertension	0.00% 0/142 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.	0.71% 1/141 • Number of events 1 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.
Vascular disorders Hypotension	0.00% 0/142 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.	0.71% 1/141 • Number of events 1 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.
Vascular disorders Intermittent claudication	0.00% 0/142 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.	0.71% 1/141 • Number of events 1 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.
Psychiatric disorders Confusional state	0.00% 0/142 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.	0.71% 1/141 • Number of events 1 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.
Psychiatric disorders Depression	0.70% 1/142 • Number of events 1 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.	0.00% 0/141 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.
Psychiatric disorders Mental status changes	0.00% 0/142 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.	0.71% 1/141 • Number of events 1 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.
Psychiatric disorders Substance abuse	0.00% 0/142 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.	0.71% 1/141 • Number of events 1 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.
Psychiatric disorders Suicide attempt	0.00% 0/142 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.	0.71% 1/141 • Number of events 1 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.
Renal and urinary disorders Acute kidney injury	0.00% 0/142 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.	0.71% 1/141 • Number of events 1 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.
Renal and urinary disorders Calculus bladder	0.70% 1/142 • Number of events 1 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.	0.00% 0/141 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.
Renal and urinary disorders Urinary tract obstruction	0.00% 0/142 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.	0.71% 1/141 • Number of events 1 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.
Renal and urinary disorders Vesical fistula	0.70% 1/142 • Number of events 1 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.	0.00% 0/141 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.
Ear and labyrinth disorders Vertigo	0.00% 0/142 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.	0.71% 1/141 • Number of events 1 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.
Ear and labyrinth disorders Vestibular disorder	0.70% 1/142 • Number of events 1 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.	0.00% 0/141 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.
Immune system disorders Contrast media reaction	0.70% 1/142 • Number of events 1 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.	0.00% 0/141 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.
Immune system disorders Drug hypersensitivity	0.70% 1/142 • Number of events 1 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.	0.00% 0/141 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.
Metabolism and nutrition disorders Dehydration	0.00% 0/142 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.	0.71% 1/141 • Number of events 1 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.
Metabolism and nutrition disorders Metabolic acidosis	0.70% 1/142 • Number of events 1 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.	0.00% 0/141 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.
Reproductive system and breast disorders Benign prostatic hyperplasia	0.00% 0/142 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.	0.71% 1/141 • Number of events 1 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.
Reproductive system and breast disorders Rectocele	0.00% 0/142 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.	0.71% 1/141 • Number of events 1 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.
Hepatobiliary disorders Hepatitis cholestatic	0.70% 1/142 • Number of events 1 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.	0.00% 0/141 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.

Other adverse events

Measure	Participants Administered VI n=142 participants at risk Following run-in period of 14 to 21 days, eligible participants were administered VI 25 microgram (mcg) once daily via ELLIPTA inhaler for 156 weeks.	Participants Administered FF/VI n=141 participants at risk Following run-in period of 14 to 21 days, eligible participants were administered FF 100 mcg along with VI 25 mcg once daily via ELLIPTA inhaler for 156 weeks.
Infections and infestations Nasopharyngitis	21.8% 31/142 • Number of events 57 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.	28.4% 40/141 • Number of events 75 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.
Infections and infestations Bronchitis	11.3% 16/142 • Number of events 23 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.	7.8% 11/141 • Number of events 12 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.
Infections and infestations Influenza	3.5% 5/142 • Number of events 5 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.	14.2% 20/141 • Number of events 30 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.
Infections and infestations Upper respiratory tract infection	9.2% 13/142 • Number of events 18 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.	8.5% 12/141 • Number of events 20 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.
Infections and infestations Urinary tract infection	8.5% 12/142 • Number of events 18 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.	8.5% 12/141 • Number of events 24 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.
Infections and infestations Sinusitis	2.1% 3/142 • Number of events 3 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.	9.2% 13/141 • Number of events 17 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.
Infections and infestations Pneumonia	3.5% 5/142 • Number of events 5 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.	5.7% 8/141 • Number of events 8 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.
Infections and infestations Oral candidiasis	2.8% 4/142 • Number of events 5 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.	5.0% 7/141 • Number of events 13 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.
Infections and infestations Cystitis	3.5% 5/142 • Number of events 6 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.	3.5% 5/141 • Number of events 7 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.
Infections and infestations Pharyngitis	2.8% 4/142 • Number of events 5 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.	3.5% 5/141 • Number of events 8 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.
Infections and infestations Herpes zoster	0.00% 0/142 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.	4.3% 6/141 • Number of events 7 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.
Musculoskeletal and connective tissue disorders Back pain	9.2% 13/142 • Number of events 27 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.	14.2% 20/141 • Number of events 28 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.
Musculoskeletal and connective tissue disorders Pain in extremity	4.2% 6/142 • Number of events 6 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.	7.1% 10/141 • Number of events 13 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.
Musculoskeletal and connective tissue disorders Osteoarthritis	6.3% 9/142 • Number of events 14 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.	4.3% 6/141 • Number of events 7 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.
Musculoskeletal and connective tissue disorders Musculoskeletal pain	4.2% 6/142 • Number of events 6 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.	2.8% 4/141 • Number of events 6 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.
Musculoskeletal and connective tissue disorders Muscle spasms	2.8% 4/142 • Number of events 4 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.	3.5% 5/141 • Number of events 5 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.
Musculoskeletal and connective tissue disorders Osteoporosis	2.8% 4/142 • Number of events 4 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.	3.5% 5/141 • Number of events 5 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.
Musculoskeletal and connective tissue disorders Arthritis	3.5% 5/142 • Number of events 5 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.	1.4% 2/141 • Number of events 2 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.
Respiratory, thoracic and mediastinal disorders Cough	10.6% 15/142 • Number of events 15 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.	9.2% 13/141 • Number of events 15 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.
Musculoskeletal and connective tissue disorders Arthralgia	9.9% 14/142 • Number of events 15 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.	9.2% 13/141 • Number of events 19 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.
Respiratory, thoracic and mediastinal disorders Oropharyngeal pain	5.6% 8/142 • Number of events 8 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.	8.5% 12/141 • Number of events 17 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.
Respiratory, thoracic and mediastinal disorders Dyspnoea	3.5% 5/142 • Number of events 6 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.	4.3% 6/141 • Number of events 6 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.
Gastrointestinal disorders Diarrhoea	7.7% 11/142 • Number of events 12 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.	6.4% 9/141 • Number of events 9 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.
Gastrointestinal disorders Abdominal pain upper	2.8% 4/142 • Number of events 5 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.	5.0% 7/141 • Number of events 10 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.
Gastrointestinal disorders Constipation	2.1% 3/142 • Number of events 4 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.	4.3% 6/141 • Number of events 7 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.
Gastrointestinal disorders Gastrooesophageal reflux disease	3.5% 5/142 • Number of events 5 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.	2.8% 4/141 • Number of events 5 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.
Gastrointestinal disorders Toothache	2.1% 3/142 • Number of events 3 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.	3.5% 5/141 • Number of events 8 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.
Gastrointestinal disorders Vomiting	1.4% 2/142 • Number of events 2 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.	3.5% 5/141 • Number of events 5 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.
Nervous system disorders Headache	11.3% 16/142 • Number of events 24 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.	18.4% 26/141 • Number of events 44 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.
Vascular disorders Hypertension	7.7% 11/142 • Number of events 12 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.	7.1% 10/141 • Number of events 10 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.
Psychiatric disorders Insomnia	0.70% 1/142 • Number of events 1 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.	4.3% 6/141 • Number of events 10 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.
Psychiatric disorders Anxiety	3.5% 5/142 • Number of events 5 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.	0.00% 0/141 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.
Psychiatric disorders Depression	0.00% 0/142 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.	3.5% 5/141 • Number of events 5 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.
Injury, poisoning and procedural complications Contusion	4.2% 6/142 • Number of events 7 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.	1.4% 2/141 • Number of events 3 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.
Injury, poisoning and procedural complications Procedural pain	4.2% 6/142 • Number of events 7 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.	0.71% 1/141 • Number of events 1 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.
Skin and subcutaneous tissue disorders Eczema	3.5% 5/142 • Number of events 6 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.	3.5% 5/141 • Number of events 5 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.
Eye disorders Cataract	2.1% 3/142 • Number of events 3 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.	4.3% 6/141 • Number of events 9 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.
General disorders Chest pain	3.5% 5/142 • Number of events 6 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.	2.8% 4/141 • Number of events 4 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.
Immune system disorders Seasonal allergy	3.5% 5/142 • Number of events 6 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.	1.4% 2/141 • Number of events 2 • Serious adverse events and non-serious adverse events were collected from randomization of the study until 159 weeks. Safety Population. The non-serious AEs are reported using a frequency threshold of \>3%.

Additional Information

GSK Response Center

GlaxoSmithKline

Phone: 866-435-7343

Email: GSKClinicalSupportHD@gsk.com

Results disclosure agreements

• Principal investigator is a sponsor employee GSK agreements may vary with individual investigators, but will not prohibit any investigator from publishing. GSK supports the publication of results from all centers of a multi-center trial but requests that reports based on single-site data not precede the primary publication of the entire clinical trial.
• Publication restrictions are in place

Restriction type: OTHER