Trial Outcomes & Findings for Study to Assess the Efficacy and Safety of Simtuzumab (GS-6624) in Adults With Idiopathic Pulmonary Fibrosis (IPF) (NCT NCT01769196)

Last Updated: 2017-05-30

Results Overview

Progression free survival (PFS) was defined as the categorical decrease in forced vital capacity (FVC) % predicted (≥ 10% relative decrease in FVC and ≥ 5% absolute decrease in FVC from baseline) with confirmation at a consecutive visit at least 2 weeks later using the same criteria.

Recruitment status

TERMINATED

Study phase

PHASE2

Target enrollment

544 participants

Primary outcome timeframe

Up to 148 weeks

Results posted on

2017-05-30

Participant Flow

Participants were enrolled at study sites in North America, Europe, and Asia Pacific. The first participant was screened on 31 January 2013. The last study visit occurred on 23 February 2016.

1250 participants were screened.

Participant milestones

Participant milestones
Measure	Simtuzumab Simtuzumab 125 mg/mL administered subcutaneously once a week	Simtuzumab Placebo Simtuzumab placebo administered subcutaneously once a week
Overall Study STARTED	272	272
Overall Study COMPLETED	0	0
Overall Study NOT COMPLETED	272	272

Reasons for withdrawal

Reasons for withdrawal
Measure	Simtuzumab Simtuzumab 125 mg/mL administered subcutaneously once a week	Simtuzumab Placebo Simtuzumab placebo administered subcutaneously once a week
Overall Study Adverse Event	24	20
Overall Study Death	21	26
Overall Study Investigator Discretion	7	3
Overall Study Lack of Efficacy	3	2
Overall Study Progressive disease	11	6
Overall Study Protocol defined criteria for withdrawal	9	11
Overall Study Protocol Violation	0	3
Overall Study Study terminated by sponsor	160	161
Overall Study Participant never dosed with study drug	1	0
Overall Study Withdrew consent	36	40

Baseline Characteristics

Study to Assess the Efficacy and Safety of Simtuzumab (GS-6624) in Adults With Idiopathic Pulmonary Fibrosis (IPF)

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Simtuzumab n=272 Participants Simtuzumab 125 mg/mL administered subcutaneously once a week	Simtuzumab Placebo n=272 Participants Simtuzumab placebo administered subcutaneously once a week	Total n=544 Participants Total of all reporting groups
Age, Continuous	67.7 years STANDARD_DEVIATION 7.60 • n=5 Participants	68.5 years STANDARD_DEVIATION 7.07 • n=7 Participants	68.1 years STANDARD_DEVIATION 7.34 • n=5 Participants
Sex: Female, Male Female	45 Participants n=5 Participants	47 Participants n=7 Participants	92 Participants n=5 Participants
Sex: Female, Male Male	227 Participants n=5 Participants	225 Participants n=7 Participants	452 Participants n=5 Participants
Race/Ethnicity, Customized Asian	35 Participants n=5 Participants	36 Participants n=7 Participants	71 Participants n=5 Participants
Race/Ethnicity, Customized Black	3 Participants n=5 Participants	3 Participants n=7 Participants	6 Participants n=5 Participants
Race/Ethnicity, Customized White	231 Participants n=5 Participants	229 Participants n=7 Participants	460 Participants n=5 Participants
Race/Ethnicity, Customized Other	3 Participants n=5 Participants	4 Participants n=7 Participants	7 Participants n=5 Participants
Race/Ethnicity, Customized Hispanic or Latino	5 Participants n=5 Participants	7 Participants n=7 Participants	12 Participants n=5 Participants
Race/Ethnicity, Customized Not Hispanic or Latino	267 Participants n=5 Participants	264 Participants n=7 Participants	531 Participants n=5 Participants
Race/Ethnicity, Customized Not Permitted	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants
Region of Enrollment United States	102 Participants n=5 Participants	106 Participants n=7 Participants	208 Participants n=5 Participants
Region of Enrollment Korea, Republic of	34 Participants n=5 Participants	35 Participants n=7 Participants	69 Participants n=5 Participants
Region of Enrollment Spain	11 Participants n=5 Participants	13 Participants n=7 Participants	24 Participants n=5 Participants
Region of Enrollment Canada	10 Participants n=5 Participants	14 Participants n=7 Participants	24 Participants n=5 Participants
Region of Enrollment Czech Republic	6 Participants n=5 Participants	6 Participants n=7 Participants	12 Participants n=5 Participants
Region of Enrollment Belgium	10 Participants n=5 Participants	4 Participants n=7 Participants	14 Participants n=5 Participants
Region of Enrollment United Kingdom	12 Participants n=5 Participants	21 Participants n=7 Participants	33 Participants n=5 Participants
Region of Enrollment Poland	15 Participants n=5 Participants	13 Participants n=7 Participants	28 Participants n=5 Participants
Region of Enrollment Italy	8 Participants n=5 Participants	6 Participants n=7 Participants	14 Participants n=5 Participants
Region of Enrollment Israel	7 Participants n=5 Participants	5 Participants n=7 Participants	12 Participants n=5 Participants
Region of Enrollment Australia	11 Participants n=5 Participants	18 Participants n=7 Participants	29 Participants n=5 Participants
Region of Enrollment France	24 Participants n=5 Participants	12 Participants n=7 Participants	36 Participants n=5 Participants
Region of Enrollment Germany	22 Participants n=5 Participants	18 Participants n=7 Participants	40 Participants n=5 Participants
Region of Enrollment Switzerland	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants
Forced vital capacity (FVC) Percent Predicted	61.4 FVC % predicted STANDARD_DEVIATION 12.17 • n=5 Participants	62.3 FVC % predicted STANDARD_DEVIATION 12.22 • n=7 Participants	61.8 FVC % predicted STANDARD_DEVIATION 12.19 • n=5 Participants
FVC % Predicted Category Mild	37 Participants n=5 Participants	46 Participants n=7 Participants	83 Participants n=5 Participants
FVC % Predicted Category Moderate	152 Participants n=5 Participants	150 Participants n=7 Participants	302 Participants n=5 Participants
FVC % Predicted Category Severe	83 Participants n=5 Participants	76 Participants n=7 Participants	159 Participants n=5 Participants
Baseline Serum LOXL2	89.8 pg/mL STANDARD_DEVIATION 70.06 • n=5 Participants	86.7 pg/mL STANDARD_DEVIATION 51.99 • n=7 Participants	88.2 pg/mL STANDARD_DEVIATION 61.48 • n=5 Participants

PRIMARY outcome

Timeframe: Up to 148 weeks

Population: ITT Analysis Set

Outcome measures

Outcome measures
Measure	Simtuzumab n=272 Participants Simtuzumab 125 mg/mL administered subcutaneously once a week	Simtuzumab Placebo n=272 Participants Simtuzumab placebo administered subcutaneously once a week
Progression Free Survival	12.6 months Interval 11.3 to 14.4	15.4 months Interval 12.6 to 19.1

PRIMARY outcome

Timeframe: Up to 148 weeks

Population: Participants in the ITT Analysis Set with serum LOXL2 (sLOXL2) ≥ 50th percentile in peripheral blood were analyzed.

Outcome measures

Outcome measures
Measure	Simtuzumab n=137 Participants Simtuzumab 125 mg/mL administered subcutaneously once a week	Simtuzumab Placebo n=140 Participants Simtuzumab placebo administered subcutaneously once a week
PFS Among the Participants With sLOXL2 ≥ 50th Percentile	11.7 months Interval 9.9 to 15.9	14.3 months Interval 10.4 to 19.1

PRIMARY outcome

Timeframe: Up to 148 weeks

Population: Participants in the ITT Analysis Set with sLOXL2 ≥ 75th percentile in peripheral blood were analyzed.

Outcome measures

Outcome measures
Measure	Simtuzumab n=68 Participants Simtuzumab 125 mg/mL administered subcutaneously once a week	Simtuzumab Placebo n=71 Participants Simtuzumab placebo administered subcutaneously once a week
PFS Among the Participants With sLOXL2 ≥ 75th Percentile	11.6 months Interval 9.0 to 15.0	16.9 months Interval 7.7 to 21.7

SECONDARY outcome

Timeframe: Up to 151 weeks

Population: ITT Analysis Set

Overall survival was defined as the time from randomization date to death that occurred prior to the last dose date plus 30 days.

Outcome measures

Outcome measures
Measure	Simtuzumab n=272 Participants Simtuzumab 125 mg/mL administered subcutaneously once a week	Simtuzumab Placebo n=272 Participants Simtuzumab placebo administered subcutaneously once a week
Overall Survival (OS)	NA months NA = Not reached due to insufficient number of events	NA months NA = Not reached due to insufficient number of events

SECONDARY outcome

Timeframe: Up to 151 weeks

Population: Participants in the ITT Analysis Set with sLOXL2 ≥ 50th percentile in peripheral blood were analyzed.

Outcome measures

Outcome measures
Measure	Simtuzumab n=137 Participants Simtuzumab 125 mg/mL administered subcutaneously once a week	Simtuzumab Placebo n=140 Participants Simtuzumab placebo administered subcutaneously once a week
Overall Survival Among the Participants With sLOXL2 ≥ 50th Percentile	NA months NA = Not reached due to insufficient number of events	NA months NA = Not reached due to insufficient number of events

SECONDARY outcome

Timeframe: Up to 151 weeks

Population: Participants in the ITT Analysis Set with sLOXL2 ≥ 75th percentile in peripheral blood were analyzed.

Outcome measures

Outcome measures
Measure	Simtuzumab n=68 Participants Simtuzumab 125 mg/mL administered subcutaneously once a week	Simtuzumab Placebo n=71 Participants Simtuzumab placebo administered subcutaneously once a week
Overall Survival Among the Participants With sLOXL2 ≥ 75th Percentile	NA months Interval 19.2 to NA = Not reached due to insufficient number of events	NA months NA = Not reached due to insufficient number of events

SECONDARY outcome

Timeframe: Weeks 54, 106, and 130

Population: Participants in the ITT Analysis Set with available data were analyzed. Any participant with available outcome data on baseline or post-baseline was included in the MMRM model, thus all 272 participants in each of the two treatment groups were included in this analysis.

* FVC was defined as the volume of air (liters) that can forcibly be blown out after taking a full breath. FVC % predicted was defined as FVC % of the participant divided by the average FVC % in the population for any person of similar age, sex, and body composition. * Adjusted means were from mixed model repeated measures (MMRM) model with baseline FVC % predicted, sLOXL2 level, concomitant pirfenidone/nintedanib use (never vs. ever), treatment, visit, and treatment-by-visit interaction terms, including all data up to Week 130 * The relative change was calculated as 100% \* ( value at later time point minus value at baseline ) / value at baseline, with lower values indicating a decrease and higher values indicating an increase.

Outcome measures

Outcome measures
Measure	Simtuzumab n=272 Participants Simtuzumab 125 mg/mL administered subcutaneously once a week	Simtuzumab Placebo n=272 Participants Simtuzumab placebo administered subcutaneously once a week
Relative Change From Baseline in FVC % Predicted Week 54	-9.20 Percent change in FVC % predicted Standard Error 0.643	-8.88 Percent change in FVC % predicted Standard Error 0.658
Relative Change From Baseline in FVC % Predicted Week 106	-13.70 Percent change in FVC % predicted Standard Error 0.883	-12.16 Percent change in FVC % predicted Standard Error 0.908
Relative Change From Baseline in FVC % Predicted Week 130	-18.09 Percent change in FVC % predicted Standard Error 1.712	-11.83 Percent change in FVC % predicted Standard Error 1.600

SECONDARY outcome

Timeframe: Up to 148 weeks

Population: Participants in the ITT Analysis Set with adjudicated respiratory hospitalizations were analyzed.

Outcome measures

Outcome measures
Measure	Simtuzumab n=99 Participants Simtuzumab 125 mg/mL administered subcutaneously once a week	Simtuzumab Placebo n=84 Participants Simtuzumab placebo administered subcutaneously once a week
Definite Acute Exacerbations of IPF Among Adjudicated Respiratory Hospitalizations	5 Participants	5 Participants

SECONDARY outcome

Timeframe: Up to 148 weeks

Population: Participants in ITT Analysis Set with total hospitalizations were analyzed.

Outcome measures

Outcome measures
Measure	Simtuzumab n=181 Participants Simtuzumab 125 mg/mL administered subcutaneously once a week	Simtuzumab Placebo n=154 Participants Simtuzumab placebo administered subcutaneously once a week
Number of Adjudicated Respiratory Hospitalizations (ARP) Among Total Hospitalizations	99 Participants	84 Participants

SECONDARY outcome

Timeframe: Up to 148 weeks

Population: Participants in the ITT Analysis Set with adjudicated deaths were analyzed.

Outcome measures

Outcome measures
Measure	Simtuzumab n=19 Participants Simtuzumab 125 mg/mL administered subcutaneously once a week	Simtuzumab Placebo n=17 Participants Simtuzumab placebo administered subcutaneously once a week
Number of Participants Experiencing Adjudicated Respiratory Deaths Among Those With Adjudicated Death	17 Participants	13 Participants

SECONDARY outcome

Timeframe: Weeks 58, 106, and 130

* Adjusted means were from MMRM model with baseline 6MWD, FVC % predicted, sLOXL2 level, concomitant pirfenidone/nintedanib use (never vs. ever), treatment, visit, and treatment-by-visit interaction terms, including all data up to Week 130. * The absolute change was calculated as value at later time point minus value at baseline, with lower values indicating a decrease and higher values indicating an increase.

Outcome measures

Outcome measures
Measure	Simtuzumab n=272 Participants Simtuzumab 125 mg/mL administered subcutaneously once a week	Simtuzumab Placebo n=272 Participants Simtuzumab placebo administered subcutaneously once a week
Absolute Change From Baseline in 6 Minute Walk Distance (6MWD) Week 58	-33.76 Meters Standard Error 6.617	-14.70 Meters Standard Error 6.596
Absolute Change From Baseline in 6 Minute Walk Distance (6MWD) Week 106	-37.43 Meters Standard Error 9.710	-24.30 Meters Standard Error 10.318
Absolute Change From Baseline in 6 Minute Walk Distance (6MWD) Week 130	-71.20 Meters Standard Error 19.140	-31.65 Meters Standard Error 18.458

SECONDARY outcome

Timeframe: Week 58, 106, and 130

* The SGRQ is a disease-specific questionnaire designed to measure impact on overall health, daily life, and perceived well-being in patients with obstructive airways disease. Patients respond to questions about symptoms (frequency \& severity) and impact components (social functioning and psychological disturbances resulting from airways disease). Scores range from 0 to 100, with higher scores indicating more limitations. * The absolute change was calculated as value at later time point minus value at baseline, with lower values indicating a decrease and higher values indicating an increase.

Outcome measures

Outcome measures
Measure	Simtuzumab n=272 Participants Simtuzumab 125 mg/mL administered subcutaneously once a week	Simtuzumab Placebo n=272 Participants Simtuzumab placebo administered subcutaneously once a week
Absolute Change From Baseline in St. George's Respiratory Questionnaire (SGRQ) Score Week 58	6.07 units on a scale Standard Error 1.015	3.62 units on a scale Standard Error 1.010
Absolute Change From Baseline in St. George's Respiratory Questionnaire (SGRQ) Score Week 106	10.34 units on a scale Standard Error 1.425	6.54 units on a scale Standard Error 1.559
Absolute Change From Baseline in St. George's Respiratory Questionnaire (SGRQ) Score Week 130	18.10 units on a scale Standard Error 2.424	1.08 units on a scale Standard Error 2.473

Adverse Events

Simtuzumab

Serious events: 101 serious events

Other events: 237 other events

Deaths: 31 deaths

Simtuzumab Placebo

Serious events: 97 serious events

Other events: 246 other events

Deaths: 32 deaths

Serious adverse events

Other adverse events

Additional Information

Clinical Trial Disclosures

Gilead Sciences

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee After conclusion of the study and without prior written approval from Gilead, investigators in this study may communicate, orally present, or publish in scientific journals or other media only after the following conditions have been met: * The results of the study in their entirety have been publicly disclosed by or with the consent of Gilead in an abstract, manuscript, or presentation form; or * The study has been completed at all study sites for at least 2 years
Publication restrictions are in place

Restriction type: OTHER

Measure	Simtuzumab n=271 participants at risk Simtuzumab 125 mg/mL administered subcutaneously once a week	Simtuzumab Placebo n=272 participants at risk Simtuzumab placebo administered subcutaneously once a week
Gastrointestinal disorders Constipation	5.9% 16/271 • 30 days post last study treatment (up to 148 weeks) Safety Analysis Set included all randomized participants who received at least 1 dose of study drug and was analyzed according to treatment received.	4.8% 13/272 • 30 days post last study treatment (up to 148 weeks) Safety Analysis Set included all randomized participants who received at least 1 dose of study drug and was analyzed according to treatment received.
Gastrointestinal disorders Diarrhoea	16.2% 44/271 • 30 days post last study treatment (up to 148 weeks) Safety Analysis Set included all randomized participants who received at least 1 dose of study drug and was analyzed according to treatment received.	17.3% 47/272 • 30 days post last study treatment (up to 148 weeks) Safety Analysis Set included all randomized participants who received at least 1 dose of study drug and was analyzed according to treatment received.
Gastrointestinal disorders Gastrooesophageal reflux disease	7.7% 21/271 • 30 days post last study treatment (up to 148 weeks) Safety Analysis Set included all randomized participants who received at least 1 dose of study drug and was analyzed according to treatment received.	8.1% 22/272 • 30 days post last study treatment (up to 148 weeks) Safety Analysis Set included all randomized participants who received at least 1 dose of study drug and was analyzed according to treatment received.
Gastrointestinal disorders Nausea	12.2% 33/271 • 30 days post last study treatment (up to 148 weeks) Safety Analysis Set included all randomized participants who received at least 1 dose of study drug and was analyzed according to treatment received.	12.9% 35/272 • 30 days post last study treatment (up to 148 weeks) Safety Analysis Set included all randomized participants who received at least 1 dose of study drug and was analyzed according to treatment received.
General disorders Asthenia	5.5% 15/271 • 30 days post last study treatment (up to 148 weeks) Safety Analysis Set included all randomized participants who received at least 1 dose of study drug and was analyzed according to treatment received.	6.2% 17/272 • 30 days post last study treatment (up to 148 weeks) Safety Analysis Set included all randomized participants who received at least 1 dose of study drug and was analyzed according to treatment received.
General disorders Chest pain	6.6% 18/271 • 30 days post last study treatment (up to 148 weeks) Safety Analysis Set included all randomized participants who received at least 1 dose of study drug and was analyzed according to treatment received.	5.9% 16/272 • 30 days post last study treatment (up to 148 weeks) Safety Analysis Set included all randomized participants who received at least 1 dose of study drug and was analyzed according to treatment received.
General disorders Fatigue	18.1% 49/271 • 30 days post last study treatment (up to 148 weeks) Safety Analysis Set included all randomized participants who received at least 1 dose of study drug and was analyzed according to treatment received.	17.6% 48/272 • 30 days post last study treatment (up to 148 weeks) Safety Analysis Set included all randomized participants who received at least 1 dose of study drug and was analyzed according to treatment received.
General disorders Injection site bruising	6.3% 17/271 • 30 days post last study treatment (up to 148 weeks) Safety Analysis Set included all randomized participants who received at least 1 dose of study drug and was analyzed according to treatment received.	3.7% 10/272 • 30 days post last study treatment (up to 148 weeks) Safety Analysis Set included all randomized participants who received at least 1 dose of study drug and was analyzed according to treatment received.
General disorders Oedema peripheral	7.7% 21/271 • 30 days post last study treatment (up to 148 weeks) Safety Analysis Set included all randomized participants who received at least 1 dose of study drug and was analyzed according to treatment received.	4.4% 12/272 • 30 days post last study treatment (up to 148 weeks) Safety Analysis Set included all randomized participants who received at least 1 dose of study drug and was analyzed according to treatment received.
General disorders Pyrexia	7.7% 21/271 • 30 days post last study treatment (up to 148 weeks) Safety Analysis Set included all randomized participants who received at least 1 dose of study drug and was analyzed according to treatment received.	4.4% 12/272 • 30 days post last study treatment (up to 148 weeks) Safety Analysis Set included all randomized participants who received at least 1 dose of study drug and was analyzed according to treatment received.
Infections and infestations Bronchitis	11.8% 32/271 • 30 days post last study treatment (up to 148 weeks) Safety Analysis Set included all randomized participants who received at least 1 dose of study drug and was analyzed according to treatment received.	14.3% 39/272 • 30 days post last study treatment (up to 148 weeks) Safety Analysis Set included all randomized participants who received at least 1 dose of study drug and was analyzed according to treatment received.
Infections and infestations Lower respiratory tract infection	3.0% 8/271 • 30 days post last study treatment (up to 148 weeks) Safety Analysis Set included all randomized participants who received at least 1 dose of study drug and was analyzed according to treatment received.	5.5% 15/272 • 30 days post last study treatment (up to 148 weeks) Safety Analysis Set included all randomized participants who received at least 1 dose of study drug and was analyzed according to treatment received.
Infections and infestations Nasopharyngitis	13.3% 36/271 • 30 days post last study treatment (up to 148 weeks) Safety Analysis Set included all randomized participants who received at least 1 dose of study drug and was analyzed according to treatment received.	15.8% 43/272 • 30 days post last study treatment (up to 148 weeks) Safety Analysis Set included all randomized participants who received at least 1 dose of study drug and was analyzed according to treatment received.
Infections and infestations Respiratory tract infection	5.2% 14/271 • 30 days post last study treatment (up to 148 weeks) Safety Analysis Set included all randomized participants who received at least 1 dose of study drug and was analyzed according to treatment received.	6.2% 17/272 • 30 days post last study treatment (up to 148 weeks) Safety Analysis Set included all randomized participants who received at least 1 dose of study drug and was analyzed according to treatment received.
Infections and infestations Sinusitis	5.9% 16/271 • 30 days post last study treatment (up to 148 weeks) Safety Analysis Set included all randomized participants who received at least 1 dose of study drug and was analyzed according to treatment received.	5.1% 14/272 • 30 days post last study treatment (up to 148 weeks) Safety Analysis Set included all randomized participants who received at least 1 dose of study drug and was analyzed according to treatment received.
Infections and infestations Upper respiratory tract infection	21.0% 57/271 • 30 days post last study treatment (up to 148 weeks) Safety Analysis Set included all randomized participants who received at least 1 dose of study drug and was analyzed according to treatment received.	21.0% 57/272 • 30 days post last study treatment (up to 148 weeks) Safety Analysis Set included all randomized participants who received at least 1 dose of study drug and was analyzed according to treatment received.
Investigations Weight decreased	9.2% 25/271 • 30 days post last study treatment (up to 148 weeks) Safety Analysis Set included all randomized participants who received at least 1 dose of study drug and was analyzed according to treatment received.	8.8% 24/272 • 30 days post last study treatment (up to 148 weeks) Safety Analysis Set included all randomized participants who received at least 1 dose of study drug and was analyzed according to treatment received.
Metabolism and nutrition disorders Decreased appetite	10.7% 29/271 • 30 days post last study treatment (up to 148 weeks) Safety Analysis Set included all randomized participants who received at least 1 dose of study drug and was analyzed according to treatment received.	12.5% 34/272 • 30 days post last study treatment (up to 148 weeks) Safety Analysis Set included all randomized participants who received at least 1 dose of study drug and was analyzed according to treatment received.
Musculoskeletal and connective tissue disorders Arthralgia	12.9% 35/271 • 30 days post last study treatment (up to 148 weeks) Safety Analysis Set included all randomized participants who received at least 1 dose of study drug and was analyzed according to treatment received.	8.1% 22/272 • 30 days post last study treatment (up to 148 weeks) Safety Analysis Set included all randomized participants who received at least 1 dose of study drug and was analyzed according to treatment received.
Musculoskeletal and connective tissue disorders Back pain	10.0% 27/271 • 30 days post last study treatment (up to 148 weeks) Safety Analysis Set included all randomized participants who received at least 1 dose of study drug and was analyzed according to treatment received.	10.3% 28/272 • 30 days post last study treatment (up to 148 weeks) Safety Analysis Set included all randomized participants who received at least 1 dose of study drug and was analyzed according to treatment received.
Musculoskeletal and connective tissue disorders Pain in extremity	3.3% 9/271 • 30 days post last study treatment (up to 148 weeks) Safety Analysis Set included all randomized participants who received at least 1 dose of study drug and was analyzed according to treatment received.	5.1% 14/272 • 30 days post last study treatment (up to 148 weeks) Safety Analysis Set included all randomized participants who received at least 1 dose of study drug and was analyzed according to treatment received.
Nervous system disorders Dizziness	11.4% 31/271 • 30 days post last study treatment (up to 148 weeks) Safety Analysis Set included all randomized participants who received at least 1 dose of study drug and was analyzed according to treatment received.	9.6% 26/272 • 30 days post last study treatment (up to 148 weeks) Safety Analysis Set included all randomized participants who received at least 1 dose of study drug and was analyzed according to treatment received.
Nervous system disorders Headache	11.8% 32/271 • 30 days post last study treatment (up to 148 weeks) Safety Analysis Set included all randomized participants who received at least 1 dose of study drug and was analyzed according to treatment received.	12.9% 35/272 • 30 days post last study treatment (up to 148 weeks) Safety Analysis Set included all randomized participants who received at least 1 dose of study drug and was analyzed according to treatment received.
Psychiatric disorders Depression	5.2% 14/271 • 30 days post last study treatment (up to 148 weeks) Safety Analysis Set included all randomized participants who received at least 1 dose of study drug and was analyzed according to treatment received.	4.4% 12/272 • 30 days post last study treatment (up to 148 weeks) Safety Analysis Set included all randomized participants who received at least 1 dose of study drug and was analyzed according to treatment received.
Psychiatric disorders Insomnia	5.5% 15/271 • 30 days post last study treatment (up to 148 weeks) Safety Analysis Set included all randomized participants who received at least 1 dose of study drug and was analyzed according to treatment received.	6.2% 17/272 • 30 days post last study treatment (up to 148 weeks) Safety Analysis Set included all randomized participants who received at least 1 dose of study drug and was analyzed according to treatment received.
Respiratory, thoracic and mediastinal disorders Cough	37.6% 102/271 • 30 days post last study treatment (up to 148 weeks) Safety Analysis Set included all randomized participants who received at least 1 dose of study drug and was analyzed according to treatment received.	34.2% 93/272 • 30 days post last study treatment (up to 148 weeks) Safety Analysis Set included all randomized participants who received at least 1 dose of study drug and was analyzed according to treatment received.
Respiratory, thoracic and mediastinal disorders Dyspnoea	36.2% 98/271 • 30 days post last study treatment (up to 148 weeks) Safety Analysis Set included all randomized participants who received at least 1 dose of study drug and was analyzed according to treatment received.	26.8% 73/272 • 30 days post last study treatment (up to 148 weeks) Safety Analysis Set included all randomized participants who received at least 1 dose of study drug and was analyzed according to treatment received.
Respiratory, thoracic and mediastinal disorders Dyspnoea exertional	11.1% 30/271 • 30 days post last study treatment (up to 148 weeks) Safety Analysis Set included all randomized participants who received at least 1 dose of study drug and was analyzed according to treatment received.	10.7% 29/272 • 30 days post last study treatment (up to 148 weeks) Safety Analysis Set included all randomized participants who received at least 1 dose of study drug and was analyzed according to treatment received.
Respiratory, thoracic and mediastinal disorders Epistaxis	5.9% 16/271 • 30 days post last study treatment (up to 148 weeks) Safety Analysis Set included all randomized participants who received at least 1 dose of study drug and was analyzed according to treatment received.	3.3% 9/272 • 30 days post last study treatment (up to 148 weeks) Safety Analysis Set included all randomized participants who received at least 1 dose of study drug and was analyzed according to treatment received.
Respiratory, thoracic and mediastinal disorders Idiopathic pulmonary fibrosis	12.2% 33/271 • 30 days post last study treatment (up to 148 weeks) Safety Analysis Set included all randomized participants who received at least 1 dose of study drug and was analyzed according to treatment received.	9.9% 27/272 • 30 days post last study treatment (up to 148 weeks) Safety Analysis Set included all randomized participants who received at least 1 dose of study drug and was analyzed according to treatment received.
Respiratory, thoracic and mediastinal disorders Oropharyngeal pain	5.9% 16/271 • 30 days post last study treatment (up to 148 weeks) Safety Analysis Set included all randomized participants who received at least 1 dose of study drug and was analyzed according to treatment received.	5.5% 15/272 • 30 days post last study treatment (up to 148 weeks) Safety Analysis Set included all randomized participants who received at least 1 dose of study drug and was analyzed according to treatment received.
Respiratory, thoracic and mediastinal disorders Productive cough	8.1% 22/271 • 30 days post last study treatment (up to 148 weeks) Safety Analysis Set included all randomized participants who received at least 1 dose of study drug and was analyzed according to treatment received.	6.6% 18/272 • 30 days post last study treatment (up to 148 weeks) Safety Analysis Set included all randomized participants who received at least 1 dose of study drug and was analyzed according to treatment received.
Respiratory, thoracic and mediastinal disorders Rhinorrhoea	7.0% 19/271 • 30 days post last study treatment (up to 148 weeks) Safety Analysis Set included all randomized participants who received at least 1 dose of study drug and was analyzed according to treatment received.	5.5% 15/272 • 30 days post last study treatment (up to 148 weeks) Safety Analysis Set included all randomized participants who received at least 1 dose of study drug and was analyzed according to treatment received.
Respiratory, thoracic and mediastinal disorders Sputum increased	5.2% 14/271 • 30 days post last study treatment (up to 148 weeks) Safety Analysis Set included all randomized participants who received at least 1 dose of study drug and was analyzed according to treatment received.	1.5% 4/272 • 30 days post last study treatment (up to 148 weeks) Safety Analysis Set included all randomized participants who received at least 1 dose of study drug and was analyzed according to treatment received.
Skin and subcutaneous tissue disorders Pruritus	6.3% 17/271 • 30 days post last study treatment (up to 148 weeks) Safety Analysis Set included all randomized participants who received at least 1 dose of study drug and was analyzed according to treatment received.	2.9% 8/272 • 30 days post last study treatment (up to 148 weeks) Safety Analysis Set included all randomized participants who received at least 1 dose of study drug and was analyzed according to treatment received.
Skin and subcutaneous tissue disorders Rash	8.1% 22/271 • 30 days post last study treatment (up to 148 weeks) Safety Analysis Set included all randomized participants who received at least 1 dose of study drug and was analyzed according to treatment received.	7.7% 21/272 • 30 days post last study treatment (up to 148 weeks) Safety Analysis Set included all randomized participants who received at least 1 dose of study drug and was analyzed according to treatment received.
Vascular disorders Hypertension	5.5% 15/271 • 30 days post last study treatment (up to 148 weeks) Safety Analysis Set included all randomized participants who received at least 1 dose of study drug and was analyzed according to treatment received.	4.4% 12/272 • 30 days post last study treatment (up to 148 weeks) Safety Analysis Set included all randomized participants who received at least 1 dose of study drug and was analyzed according to treatment received.