Trial Outcomes & Findings for A Non-inferiority Study to Evaluate the Efficacy, Safety, and Tolerability of Fluticasone Propionate/Salmeterol (FSC) 250/50 Microgram (mcg) Through a Capsule-Based Inhaler and a Multi-Dose Inhaler Administered Twice Daily (BID) in Adults With Chronic Obstructive Pulmonary Disease (COPD) (NCT NCT01978145)

NCT ID: NCT01978145

Last Updated: 2017-08-22

Results Overview

Pulmonary function was measured by FEV1, defined as the maximal amount of air that can be forcefully exhaled in one second. The trough FEV1 is defined as morning prebronchodilator and predose (12 hours after the last evening dose Day 84). Trough FEV1 was measured electronically by spirometer in the morning, before using the bronchodilator and predose, at Week 12 (Day 85) of each Treatment Period. Baseline was defined as the value obtained predose (0 minutes) on day 1 in each treatment period. Change from Baseline within each period was calculated as trough FEV1 at Day 85 minus the period specific Baseline value. The change from Baseline in trough FEV1 was analyzed using mixed model for repeated measures analysis, having fixed effect participant level Baseline, adjusted period-specific Baseline, treatment group, period, visit, visit by treatment, visit by participant level Baseline, visit by adjusted period-specific Baseline, with participant as random effect.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

665 participants

Primary outcome timeframe

Baseline and Day 85 of each treatment period

Results posted on

2017-08-22

Participant Flow

A Total of 665 participants (par.) were enrolled into the study, 185 participants were screen failures and 53 participants were run-in failures. A total of 427 participants were randomized and 426 participants were included in Intent-to-Treat (ITT) Population.

Participant milestones

Participant milestones
Measure	Sequence 1: Pl MD DPI/FSC CB DPI Then FSC MD DPI/Pl CB DPI Participants self administered one inhalation of matching Placebo (Pl) via a multi-dose dry powder inhaler (MD DPI) followed by one inhalation of single capsule containing Fluticasone propionate and salmeterol combination (FSC) (250/50 microgram \[mcg\]) via a capsule-based unit dose (CB) DPI in the morning and evening in the Treatment Period 1 for 12 weeks. After washout period of 4 weeks, participants self administered one inhalation of FSC (250/50 mcg) via the MD DPI and one inhalation of of matching Placebo via the capsule-based unit dose DPI in the morning and evening in Treatment Period 2 for 12 weeks. Salbutamol/albuterol was provided to use as rescue medication	Sequence 2: FSC MD DPI/Pl CB DPI Then Pl MD DPI/FSC CB DPI Participants self administered one inhalation of FSC (250/50 mcg) via a MD DPI and one inhalation of Placebo via a CB DPI in the morning and evening in Treatment Period 1 for 12 weeks. After washout period of 4 weeks, participants self admnistered one inhalation of matching Placebo via a MD DPI and one inhalation of FSC (250/50 mcg) via a CB DPI in the morning and evening in Treatment Period 2 for 12 weeks. Salbutamol/albuterol was provided to use as rescue medication.
Treatment Period 1 STARTED	214	212
Treatment Period 1 COMPLETED	205	196
Treatment Period 1 NOT COMPLETED	9	16
Washout Period 1 STARTED	205	196
Washout Period 1 COMPLETED	204	193
Washout Period 1 NOT COMPLETED	1	3
Treatment Period 2 STARTED	204	193
Treatment Period 2 COMPLETED	185	179
Treatment Period 2 NOT COMPLETED	19	14

Reasons for withdrawal

Reasons for withdrawal
Measure	Sequence 1: Pl MD DPI/FSC CB DPI Then FSC MD DPI/Pl CB DPI Participants self administered one inhalation of matching Placebo (Pl) via a multi-dose dry powder inhaler (MD DPI) followed by one inhalation of single capsule containing Fluticasone propionate and salmeterol combination (FSC) (250/50 microgram \[mcg\]) via a capsule-based unit dose (CB) DPI in the morning and evening in the Treatment Period 1 for 12 weeks. After washout period of 4 weeks, participants self administered one inhalation of FSC (250/50 mcg) via the MD DPI and one inhalation of of matching Placebo via the capsule-based unit dose DPI in the morning and evening in Treatment Period 2 for 12 weeks. Salbutamol/albuterol was provided to use as rescue medication	Sequence 2: FSC MD DPI/Pl CB DPI Then Pl MD DPI/FSC CB DPI Participants self administered one inhalation of FSC (250/50 mcg) via a MD DPI and one inhalation of Placebo via a CB DPI in the morning and evening in Treatment Period 1 for 12 weeks. After washout period of 4 weeks, participants self admnistered one inhalation of matching Placebo via a MD DPI and one inhalation of FSC (250/50 mcg) via a CB DPI in the morning and evening in Treatment Period 2 for 12 weeks. Salbutamol/albuterol was provided to use as rescue medication.
Treatment Period 1 Adverse Event	1	9
Treatment Period 1 Physician Decision	1	0
Treatment Period 1 Withdrawal by Subject	5	4
Treatment Period 1 Par. reached defined stopping criteria	2	3
Washout Period 1 Adverse Event	0	1
Washout Period 1 Withdrawal by Subject	1	1
Washout Period 1 Par. reached defined stopping criteria	0	1
Treatment Period 2 Adverse Event	3	3
Treatment Period 2 Protocol Violation	0	1
Treatment Period 2 Lost to Follow-up	1	1
Treatment Period 2 Withdrawal by Subject	7	4
Treatment Period 2 Par. reached defined stopping criteria	8	5

Baseline Characteristics

A Non-inferiority Study to Evaluate the Efficacy, Safety, and Tolerability of Fluticasone Propionate/Salmeterol (FSC) 250/50 Microgram (mcg) Through a Capsule-Based Inhaler and a Multi-Dose Inhaler Administered Twice Daily (BID) in Adults With Chronic Obstructive Pulmonary Disease (COPD)

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Overall Study n=426 Participants All participants received one of the following 2 treatments in each of the two 12-week treatment periods separated by a 4-week washout period. One inhalation of FSC (250/50 mcg) self administered twice daily (BID) (morning and evening) via MD DPI plus one inhalation of Placebo self administered BID (morning and evening) via CB DPI or one inhalation of Placebo self administered BID (morning and evening) via MD DPI plus one inhalation of FSC (250/50 mcg) self administered BID (morning and evening) via CB DPI . Salbutamol/albuterol was provided to use as rescue medication.
Age, Continuous	62.7 Years STANDARD_DEVIATION 8.43 • n=5 Participants
Sex: Female, Male Female	87 Participants n=5 Participants
Sex: Female, Male Male	339 Participants n=5 Participants
Race/Ethnicity, Customized American Indian or Alaskan Native	27 Participants n=5 Participants
Race/Ethnicity, Customized White	390 Participants n=5 Participants
Race/Ethnicity, Customized Mixed American Indian or Alaskan Native and White	9 Participants n=5 Participants

PRIMARY outcome

Timeframe: Baseline and Day 85 of each treatment period

Population: Intent-to-Treat (ITT) Population: all participants randomly assigned to treatment who received at least one dose of randomized study treatment in the treatment period. Only those participants available at the specified time points were analyzed.

Outcome measures

Outcome measures
Measure	FSC Capsule-Based Unit Dose DPI n=383 Participants Participants received one inhalation of Placebo self administered BID (morning and evening) via MD DPI plus one inhalation of FSC (250/50 mcg) self administered BID (morning and evening) via CB DPI in either of two treatment periods for 12 weeks. Treatment periods were separated by washout period of 4 weeks. Salbutamol/albuterol was provided to use as rescue medication	FSC Multi-Dose DPI n=380 Participants Participants received one inhalation of FSC (250/50 mcg) self administered BID (morning and evening) via MD DPI plus one inhalation of Placebo self administered BID (morning and evening) via CB DPI in either of two treatment periods for 12 weeks. Treatment periods were separated by washout period of 4 weeks. Salbutamol/albuterol was provided to use as rescue medication
Change From Baseline in Trough Morning Forced Expiratory Volume in 1 Second (FEV1) at Day 85	0.116 Liters (L) Standard Error 0.0116	0.091 Liters (L) Standard Error 0.0116

SECONDARY outcome

Timeframe: Baseline and Days 28 and 56 of each treatment period

Population: Intent-to-Treat (ITT) Population. Only those participants available at the specified time points were analyzed (represented by n=X, X in the category titles).

Pulmonary function was measured by FEV1, defined as the maximal amount of air that can be forcefully exhaled in one second. The trough FEV1 at Days 28 and 56 is defined as morning prebronchodilator and predose (12 hours after the last evening dose Days 27 and 55). Trough FEV1 was measured electronically by spirometer in the morning, before using the bronchodilator and predose, at Days 28 and 56 of each Treatment Period. Baseline was defined as the value obtained predose (0 minutes) on day 1 in each treatment period. Change from Baseline within each period was calculated as trough FEV1 at Day 85 minus the period specific Baseline value. The change from Baseline in trough FEV1 was analyzed using mixed model for repeated measures analysis, having fixed effect participant level Baseline, adjusted period-specific Baseline, treatment group, period, visit, visit by treatment, visit by participant level Baseline, visit by adjusted period-specific Baseline, with participant as random effect.

Outcome measures

Outcome measures
Measure	FSC Capsule-Based Unit Dose DPI n=426 Participants Participants received one inhalation of Placebo self administered BID (morning and evening) via MD DPI plus one inhalation of FSC (250/50 mcg) self administered BID (morning and evening) via CB DPI in either of two treatment periods for 12 weeks. Treatment periods were separated by washout period of 4 weeks. Salbutamol/albuterol was provided to use as rescue medication	FSC Multi-Dose DPI n=426 Participants Participants received one inhalation of FSC (250/50 mcg) self administered BID (morning and evening) via MD DPI plus one inhalation of Placebo self administered BID (morning and evening) via CB DPI in either of two treatment periods for 12 weeks. Treatment periods were separated by washout period of 4 weeks. Salbutamol/albuterol was provided to use as rescue medication
Change From Baseline in Trough Morning Forced Expiratory Volume in 1 Second (FEV1) at Day 28 and 56 Day 28, n=400, 403	0.108 Liters (L) Standard Error 0.0116	0.104 Liters (L) Standard Error 0.0116
Change From Baseline in Trough Morning Forced Expiratory Volume in 1 Second (FEV1) at Day 28 and 56 Day 56, n= 395, 396	0.135 Liters (L) Standard Error 0.0121	0.115 Liters (L) Standard Error 0.0121

SECONDARY outcome

Timeframe: Day 85 of each treatment period

Population: ITT population. Only those participants available at the specified time points were analyzed.

Pulmonary function was measured by FEV1, defined as the maximal amount of air that can be forcefully exhaled in one second. FEV1. The FEV1 was measured on Day 85 of each treatment period at time 0 (predose),15 minutes, 30 minutes, 1, 2, 4, 6, and 10 hours post morning dosing for determination of AUC 0 to10 hours. The AUC was analyzed using a mixed effects analysis of covariance (ANCOVA) with participant-level Baseline (Day 1 trough FEV1), adjusted period-specific Baseline (Day 1 trough FEV1), treatment group and period as fixed effects and participant as a random effect.

Outcome measures

Outcome measures
Measure	FSC Capsule-Based Unit Dose DPI n=371 Participants Participants received one inhalation of Placebo self administered BID (morning and evening) via MD DPI plus one inhalation of FSC (250/50 mcg) self administered BID (morning and evening) via CB DPI in either of two treatment periods for 12 weeks. Treatment periods were separated by washout period of 4 weeks. Salbutamol/albuterol was provided to use as rescue medication	FSC Multi-Dose DPI n=370 Participants Participants received one inhalation of FSC (250/50 mcg) self administered BID (morning and evening) via MD DPI plus one inhalation of Placebo self administered BID (morning and evening) via CB DPI in either of two treatment periods for 12 weeks. Treatment periods were separated by washout period of 4 weeks. Salbutamol/albuterol was provided to use as rescue medication
FEV1 Area Under the Curve From 0 to 10 Hours (AUC [0-10]) on Day 85 of Each Treatment Period	13.382 Liter*hours Standard Error 0.1298	13.216 Liter*hours Standard Error 0.1298

SECONDARY outcome

Timeframe: Baseline, and Days 28, 56 and 85

Population: ITT population. Only those participants available at the specified time points were analyzed (n=X, X in the category title).

Baseline Dysponea Index (BDI) and Transition Dyspnoea Index (TDI) are interview-based measurements of breathlessness due to COPD related daily living activities. Scores depend on ratings for 3 categories: functional impairment, magnitude of task and magnitude of effort. BDI was collected at Day 1 and TDI at Days 28, 56 and 85 of each treatment (trt) period. Each BDI scale has 5 possible scores ranging from 0 to 4, with 0 (worst) to 12 (best) as the total range. Each TDI scale has 7 possible scores ranging from -3 to +3, with -9 (worst) to +9 (best) as the total range. TDI focal score \>=1 is considered to be a clinically meaningful change. Change from Baseline was calculated as TDI minus BDI values. Analysis was performed using MMRM by par. level BDI focal score, adjusted period-specific BDI focal score, trt group, trt period, visit, visit\*trt group, visit\*par. level BDI focal score, visit\*adjusted period-specific BDI focal score as a fixed effect and with par. as a random effect.

Outcome measures

Outcome measures
Measure	FSC Capsule-Based Unit Dose DPI n=426 Participants Participants received one inhalation of Placebo self administered BID (morning and evening) via MD DPI plus one inhalation of FSC (250/50 mcg) self administered BID (morning and evening) via CB DPI in either of two treatment periods for 12 weeks. Treatment periods were separated by washout period of 4 weeks. Salbutamol/albuterol was provided to use as rescue medication	FSC Multi-Dose DPI n=426 Participants Participants received one inhalation of FSC (250/50 mcg) self administered BID (morning and evening) via MD DPI plus one inhalation of Placebo self administered BID (morning and evening) via CB DPI in either of two treatment periods for 12 weeks. Treatment periods were separated by washout period of 4 weeks. Salbutamol/albuterol was provided to use as rescue medication
Change From Baseline in Transition Dyspnoea Index (TDI) Focal Score at Days 28, 56 and 85 Day 28, n=396, 402	1.982 Scores on a scale Standard Error 0.1214	1.984 Scores on a scale Standard Error 0.1206
Change From Baseline in Transition Dyspnoea Index (TDI) Focal Score at Days 28, 56 and 85 Day 56, n=391, 394	1.968 Scores on a scale Standard Error 0.1231	2.037 Scores on a scale Standard Error 0.1226
Change From Baseline in Transition Dyspnoea Index (TDI) Focal Score at Days 28, 56 and 85 Day 85, n=380, 380	1.941 Scores on a scale Standard Error 0.1231	2.074 Scores on a scale Standard Error 0.1229

SECONDARY outcome

Timeframe: Baseline and Week 12 of each treatment period

Population: ITT population. Only those participants available at the specified time points were analyzed.

The SGRQ-C is a 40-item COPD-specific questionnaire designed to measure the effect of COPD and its treatment on the participant's health-related quality of life (HRQoL). The SGRQ-C includes 14 questions with a total of 40 items grouped into three components (symptoms, activity, and impacts). Each questionnaire response has a unique empirically derived weight. The lowest possible weight is zero and the highest is 100. Higher scores indicate greater impairment of HRQoL. HRQoL of participants was assessed using the SGRQ-C at Baseline (Day 1) and Week 12 of each treatment period. Change from Baseline was calculated as value at Week 12 minus the period specific Baseline value. Change from Baseline in SGRQ total score at Week 12 was analyzed using a mixed effects ANCOVA model, with participant-level Baseline SGRQ total score, adjusted treatment period-specific Baseline SGRQ total score, treatment group, and treatment period as fixed effects and participant as a random effect.

Outcome measures

Outcome measures
Measure	FSC Capsule-Based Unit Dose DPI n=375 Participants Participants received one inhalation of Placebo self administered BID (morning and evening) via MD DPI plus one inhalation of FSC (250/50 mcg) self administered BID (morning and evening) via CB DPI in either of two treatment periods for 12 weeks. Treatment periods were separated by washout period of 4 weeks. Salbutamol/albuterol was provided to use as rescue medication	FSC Multi-Dose DPI n=373 Participants Participants received one inhalation of FSC (250/50 mcg) self administered BID (morning and evening) via MD DPI plus one inhalation of Placebo self administered BID (morning and evening) via CB DPI in either of two treatment periods for 12 weeks. Treatment periods were separated by washout period of 4 weeks. Salbutamol/albuterol was provided to use as rescue medication
Change From Baseline in St George's Respiratory Questionnaire-COPD (SGRQ C) Score at Week 12	-3.48 Scores on a scale Standard Error 0.418	-3.72 Scores on a scale Standard Error 0.419

SECONDARY outcome

Timeframe: Baseline and Week 12 of each treatment period

Population: ITT population. Only those participants available at the specified time points were analyzed.

The CAT is a participant-completed instrument designed to provide a simple and reliable measure of health status in COPD for the assessment and long-term follow-up of the individual participant. The CAT consists of eight items, each formatted on a semantic differential scale. Participants rated their experience on a 6-point scale for each question, ranging from 0 to 5 with a maximum total score of 40. Higher scores indicate greater disease impact. CAT of each participant was assessed at Baseline (Day 1) and Week 12 (Day 85) of each treatment period. Change from Baseline within each period was calculated as values at Week 12 minus period specific Baseline value. The change from Baseline in CAT overall score at Week 12 was analyzed using a mixed effects ANCOVA model, with participant-level Baseline CAT overall score, adjusted treatment period specific Baseline CAT overall score, treatment group, treatment period as fixed effects and participant as a random effect.

Outcome measures

Outcome measures
Measure	FSC Capsule-Based Unit Dose DPI n=384 Participants Participants received one inhalation of Placebo self administered BID (morning and evening) via MD DPI plus one inhalation of FSC (250/50 mcg) self administered BID (morning and evening) via CB DPI in either of two treatment periods for 12 weeks. Treatment periods were separated by washout period of 4 weeks. Salbutamol/albuterol was provided to use as rescue medication	FSC Multi-Dose DPI n=380 Participants Participants received one inhalation of FSC (250/50 mcg) self administered BID (morning and evening) via MD DPI plus one inhalation of Placebo self administered BID (morning and evening) via CB DPI in either of two treatment periods for 12 weeks. Treatment periods were separated by washout period of 4 weeks. Salbutamol/albuterol was provided to use as rescue medication
Change From Baseline in COPD Assessment Test (CAT) Scores at Week 12	-2.3 Scores on a scale Standard Error 0.26	-1.7 Scores on a scale Standard Error 0.26

Adverse Events

FSC Capsule-Based Unit Dose DPI

Serious events: 6 serious events

Other events: 20 other events

Deaths: 0 deaths

FSC Multi-Dose DPI

Serious events: 17 serious events

Other events: 19 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Other adverse events
Measure	FSC Capsule-Based Unit Dose DPI n=426 participants at risk Participants received one inhalation of Placebo self administered BID (morning and evening) via MD DPI plus one inhalation of FSC (250/50 mcg) self administered BID (morning and evening) via CB DPI in either of two treatment periods for 12 weeks. Treatment periods were separated by washout period of 4 weeks. Salbutamol/albuterol was provided to use as rescue medication	FSC Multi-Dose DPI n=426 participants at risk Participants received one inhalation of FSC (250/50 mcg) self administered BID (morning and evening) via MD DPI plus one inhalation of Placebo self administered BID (morning and evening) via CB DPI in either of two treatment periods for 12 weeks. Treatment periods were separated by washout period of 4 weeks. Salbutamol/albuterol was provided to use as rescue medication
Nervous system disorders Headache	4.7% 20/426 • On treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of administration of the study drug until the follow-up contact (up to Week 28). SAEs and non-serious AEs were collected in members of the Safety Population, comprised of all participants randomized to treatment, who had received at least one dose of study medication.	4.5% 19/426 • On treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of administration of the study drug until the follow-up contact (up to Week 28). SAEs and non-serious AEs were collected in members of the Safety Population, comprised of all participants randomized to treatment, who had received at least one dose of study medication.

Additional Information

GSK Response Center

GlaxoSmithKline

Phone: 866-435-7343

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

Measure	FSC Capsule-Based Unit Dose DPI n=426 participants at risk Participants received one inhalation of Placebo self administered BID (morning and evening) via MD DPI plus one inhalation of FSC (250/50 mcg) self administered BID (morning and evening) via CB DPI in either of two treatment periods for 12 weeks. Treatment periods were separated by washout period of 4 weeks. Salbutamol/albuterol was provided to use as rescue medication	FSC Multi-Dose DPI n=426 participants at risk Participants received one inhalation of FSC (250/50 mcg) self administered BID (morning and evening) via MD DPI plus one inhalation of Placebo self administered BID (morning and evening) via CB DPI in either of two treatment periods for 12 weeks. Treatment periods were separated by washout period of 4 weeks. Salbutamol/albuterol was provided to use as rescue medication
Respiratory, thoracic and mediastinal disorders Chronic obstructive pulmonary disease	0.23% 1/426 • On treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of administration of the study drug until the follow-up contact (up to Week 28). SAEs and non-serious AEs were collected in members of the Safety Population, comprised of all participants randomized to treatment, who had received at least one dose of study medication.	1.2% 5/426 • On treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of administration of the study drug until the follow-up contact (up to Week 28). SAEs and non-serious AEs were collected in members of the Safety Population, comprised of all participants randomized to treatment, who had received at least one dose of study medication.
Respiratory, thoracic and mediastinal disorders Epistaxis	0.23% 1/426 • On treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of administration of the study drug until the follow-up contact (up to Week 28). SAEs and non-serious AEs were collected in members of the Safety Population, comprised of all participants randomized to treatment, who had received at least one dose of study medication.	0.00% 0/426 • On treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of administration of the study drug until the follow-up contact (up to Week 28). SAEs and non-serious AEs were collected in members of the Safety Population, comprised of all participants randomized to treatment, who had received at least one dose of study medication.
Respiratory, thoracic and mediastinal disorders Pickwickian syndrome	0.00% 0/426 • On treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of administration of the study drug until the follow-up contact (up to Week 28). SAEs and non-serious AEs were collected in members of the Safety Population, comprised of all participants randomized to treatment, who had received at least one dose of study medication.	0.23% 1/426 • On treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of administration of the study drug until the follow-up contact (up to Week 28). SAEs and non-serious AEs were collected in members of the Safety Population, comprised of all participants randomized to treatment, who had received at least one dose of study medication.
Respiratory, thoracic and mediastinal disorders Pneumothorax	0.23% 1/426 • On treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of administration of the study drug until the follow-up contact (up to Week 28). SAEs and non-serious AEs were collected in members of the Safety Population, comprised of all participants randomized to treatment, who had received at least one dose of study medication.	0.00% 0/426 • On treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of administration of the study drug until the follow-up contact (up to Week 28). SAEs and non-serious AEs were collected in members of the Safety Population, comprised of all participants randomized to treatment, who had received at least one dose of study medication.
Respiratory, thoracic and mediastinal disorders Pulmonary embolism	0.23% 1/426 • On treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of administration of the study drug until the follow-up contact (up to Week 28). SAEs and non-serious AEs were collected in members of the Safety Population, comprised of all participants randomized to treatment, who had received at least one dose of study medication.	0.00% 0/426 • On treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of administration of the study drug until the follow-up contact (up to Week 28). SAEs and non-serious AEs were collected in members of the Safety Population, comprised of all participants randomized to treatment, who had received at least one dose of study medication.
Infections and infestations Pneumonia	0.00% 0/426 • On treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of administration of the study drug until the follow-up contact (up to Week 28). SAEs and non-serious AEs were collected in members of the Safety Population, comprised of all participants randomized to treatment, who had received at least one dose of study medication.	0.94% 4/426 • On treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of administration of the study drug until the follow-up contact (up to Week 28). SAEs and non-serious AEs were collected in members of the Safety Population, comprised of all participants randomized to treatment, who had received at least one dose of study medication.
Infections and infestations Gangrene	0.00% 0/426 • On treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of administration of the study drug until the follow-up contact (up to Week 28). SAEs and non-serious AEs were collected in members of the Safety Population, comprised of all participants randomized to treatment, who had received at least one dose of study medication.	0.23% 1/426 • On treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of administration of the study drug until the follow-up contact (up to Week 28). SAEs and non-serious AEs were collected in members of the Safety Population, comprised of all participants randomized to treatment, who had received at least one dose of study medication.
Infections and infestations Lobar pneumonia	0.00% 0/426 • On treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of administration of the study drug until the follow-up contact (up to Week 28). SAEs and non-serious AEs were collected in members of the Safety Population, comprised of all participants randomized to treatment, who had received at least one dose of study medication.	0.23% 1/426 • On treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of administration of the study drug until the follow-up contact (up to Week 28). SAEs and non-serious AEs were collected in members of the Safety Population, comprised of all participants randomized to treatment, who had received at least one dose of study medication.
Infections and infestations Septic shock	0.00% 0/426 • On treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of administration of the study drug until the follow-up contact (up to Week 28). SAEs and non-serious AEs were collected in members of the Safety Population, comprised of all participants randomized to treatment, who had received at least one dose of study medication.	0.23% 1/426 • On treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of administration of the study drug until the follow-up contact (up to Week 28). SAEs and non-serious AEs were collected in members of the Safety Population, comprised of all participants randomized to treatment, who had received at least one dose of study medication.
Injury, poisoning and procedural complications Lower limb fracture	0.00% 0/426 • On treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of administration of the study drug until the follow-up contact (up to Week 28). SAEs and non-serious AEs were collected in members of the Safety Population, comprised of all participants randomized to treatment, who had received at least one dose of study medication.	0.23% 1/426 • On treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of administration of the study drug until the follow-up contact (up to Week 28). SAEs and non-serious AEs were collected in members of the Safety Population, comprised of all participants randomized to treatment, who had received at least one dose of study medication.
Injury, poisoning and procedural complications Rib fracture	0.23% 1/426 • On treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of administration of the study drug until the follow-up contact (up to Week 28). SAEs and non-serious AEs were collected in members of the Safety Population, comprised of all participants randomized to treatment, who had received at least one dose of study medication.	0.00% 0/426 • On treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of administration of the study drug until the follow-up contact (up to Week 28). SAEs and non-serious AEs were collected in members of the Safety Population, comprised of all participants randomized to treatment, who had received at least one dose of study medication.
Injury, poisoning and procedural complications Thermal burn	0.00% 0/426 • On treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of administration of the study drug until the follow-up contact (up to Week 28). SAEs and non-serious AEs were collected in members of the Safety Population, comprised of all participants randomized to treatment, who had received at least one dose of study medication.	0.23% 1/426 • On treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of administration of the study drug until the follow-up contact (up to Week 28). SAEs and non-serious AEs were collected in members of the Safety Population, comprised of all participants randomized to treatment, who had received at least one dose of study medication.
Cardiac disorders Atrial fibrillation	0.00% 0/426 • On treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of administration of the study drug until the follow-up contact (up to Week 28). SAEs and non-serious AEs were collected in members of the Safety Population, comprised of all participants randomized to treatment, who had received at least one dose of study medication.	0.23% 1/426 • On treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of administration of the study drug until the follow-up contact (up to Week 28). SAEs and non-serious AEs were collected in members of the Safety Population, comprised of all participants randomized to treatment, who had received at least one dose of study medication.
Gastrointestinal disorders Lower gastrointestinal haemorrhage	0.00% 0/426 • On treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of administration of the study drug until the follow-up contact (up to Week 28). SAEs and non-serious AEs were collected in members of the Safety Population, comprised of all participants randomized to treatment, who had received at least one dose of study medication.	0.23% 1/426 • On treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of administration of the study drug until the follow-up contact (up to Week 28). SAEs and non-serious AEs were collected in members of the Safety Population, comprised of all participants randomized to treatment, who had received at least one dose of study medication.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Rectosigmoid cancer stage II	0.00% 0/426 • On treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of administration of the study drug until the follow-up contact (up to Week 28). SAEs and non-serious AEs were collected in members of the Safety Population, comprised of all participants randomized to treatment, who had received at least one dose of study medication.	0.23% 1/426 • On treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of administration of the study drug until the follow-up contact (up to Week 28). SAEs and non-serious AEs were collected in members of the Safety Population, comprised of all participants randomized to treatment, who had received at least one dose of study medication.
Nervous system disorders Ischaemic stroke	0.00% 0/426 • On treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of administration of the study drug until the follow-up contact (up to Week 28). SAEs and non-serious AEs were collected in members of the Safety Population, comprised of all participants randomized to treatment, who had received at least one dose of study medication.	0.23% 1/426 • On treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of administration of the study drug until the follow-up contact (up to Week 28). SAEs and non-serious AEs were collected in members of the Safety Population, comprised of all participants randomized to treatment, who had received at least one dose of study medication.
Renal and urinary disorders Renal colic	0.23% 1/426 • On treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of administration of the study drug until the follow-up contact (up to Week 28). SAEs and non-serious AEs were collected in members of the Safety Population, comprised of all participants randomized to treatment, who had received at least one dose of study medication.	0.00% 0/426 • On treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of administration of the study drug until the follow-up contact (up to Week 28). SAEs and non-serious AEs were collected in members of the Safety Population, comprised of all participants randomized to treatment, who had received at least one dose of study medication.
Vascular disorders Venous thrombosis limb	0.00% 0/426 • On treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of administration of the study drug until the follow-up contact (up to Week 28). SAEs and non-serious AEs were collected in members of the Safety Population, comprised of all participants randomized to treatment, who had received at least one dose of study medication.	0.23% 1/426 • On treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of administration of the study drug until the follow-up contact (up to Week 28). SAEs and non-serious AEs were collected in members of the Safety Population, comprised of all participants randomized to treatment, who had received at least one dose of study medication.