Trial Outcomes & Findings for Efficacy and Safety of Nintedanib in Patients With Progressive Fibrosing Interstitial Lung Disease (PF-ILD) (NCT NCT02999178)

Last Updated: 2020-05-05

Results Overview

Forced Vital Capacity (FVC) is the volume of air (measured in milliliter) which can be forcibly exhaled from the lungs after taking the deepest breath possible. Overall population consists of all randomized participants with HRCT fibrotic pattern=UIP-like fibrotic pattern only or HRCT fibrotic pattern= Other fibrotic patterns. Annual rate of decline in Forced Vital Capacity in milliliter (mL) per year in the overall population is based on a random coefficient regression with fixed effects for treatment, HRCT fibrotic pattern, and baseline FVC \[mL\], and including treatment-by-time and baseline-by-time interactions. Within-participant errors are modelled by an unstructured variance-covariance matrix.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

663 participants

Primary outcome timeframe

Baseline, 2, 4, 6, 12, 24, 36, 52 weeks after first drug intake (planned post-baseline visits)

Results posted on

2020-05-05

Participant Flow

Randomized (1:1 ratio), placebo-controlled, double-blind, parallel-group trial comparing nintedanib to placebo over a 52-week treatment period (Part A). Participants continued on blinded, randomized treatment beyond 52 weeks (Part B). Data base lock (DBL) one was on 6-June-2019, DBL two was on 11-September-2019. Overall Study Period=Part A and B.

All subjects were screened for eligibility prior to participation in the trial. Subjects attended a specialist site which ensured that they (the subjects) strictly met all inclusion and none of the exclusion criteria. Subjects were not to be allocated to a treatment group if any of the entry criteria were violated.

Participant milestones

Participant milestones
Measure	150 mg Nintedanib 150 milligram (mg) Nintedanib as soft gelatine capsule, administered orally, twice daily (bid), with optional dose reduction to 100 mg bid to manage adverse events (AEs). Continuous daily dosing over a 52-week treatment period (Part A). After completion of the 52-week treatment period, participants continued on blinded treatment until the end of the trial or until a reason for treatment withdrawal was met (Part B).	Placebo 150 mg Nintedanib matching placebo, soft gelatine capsule, administered orally, bid, with optional dose reduction to 100 mg bid to manage AEs. Continuous daily dosing over a 52-week treatment period (Part A). After completion of the 52-week treatment period, participants continued on blinded treatment until the end of the trial or until a reason for treatment withdrawal was met (Part B).
Overall Study STARTED	332	331
Overall Study COMPLETED	218	231
Overall Study NOT COMPLETED	114	100

Reasons for withdrawal

Reasons for withdrawal
Measure	150 mg Nintedanib 150 milligram (mg) Nintedanib as soft gelatine capsule, administered orally, twice daily (bid), with optional dose reduction to 100 mg bid to manage adverse events (AEs). Continuous daily dosing over a 52-week treatment period (Part A). After completion of the 52-week treatment period, participants continued on blinded treatment until the end of the trial or until a reason for treatment withdrawal was met (Part B).	Placebo 150 mg Nintedanib matching placebo, soft gelatine capsule, administered orally, bid, with optional dose reduction to 100 mg bid to manage AEs. Continuous daily dosing over a 52-week treatment period (Part A). After completion of the 52-week treatment period, participants continued on blinded treatment until the end of the trial or until a reason for treatment withdrawal was met (Part B).
Overall Study Adverse Event	85	62
Overall Study Protocol Violation	1	2
Overall Study Lost to Follow-up	0	2
Overall Study Withdrawal by Subject	21	21
Overall Study Other reason not defined above	7	13

Baseline Characteristics

All randomized participants with HRCT fibrotic pattern=UIP-like fibrotic pattern only who received at least 1 dose of trial medication.

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	150 mg Nintedanib n=332 Participants 150 milligram (mg) Nintedanib as soft gelatine capsule, administered orally, twice daily (bid), with optional dose reduction to 100 mg bid to manage adverse events (AEs). Continuous daily dosing over a 52-week treatment period (Part A). After completion of the 52-week treatment period, participants continued on blinded treatment until the end of the trial or until a reason for treatment withdrawal was met (Part B).	Placebo n=331 Participants 150 mg Nintedanib matching placebo, soft gelatine capsule, administered orally, bid, with optional dose reduction to 100 mg bid to manage AEs. Continuous daily dosing over a 52-week treatment period (Part A). After completion of the 52-week treatment period, participants continued on blinded treatment until the end of the trial or until a reason for treatment withdrawal was met (Part B).	Total n=663 Participants Total of all reporting groups
Age, Continuous	65.2 Years STANDARD_DEVIATION 9.7 • n=332 Participants	66.3 Years STANDARD_DEVIATION 9.8 • n=331 Participants	65.8 Years STANDARD_DEVIATION 9.8 • n=663 Participants
Sex: Female, Male Female	153 Participants n=332 Participants	154 Participants n=331 Participants	307 Participants n=663 Participants
Sex: Female, Male Male	179 Participants n=332 Participants	177 Participants n=331 Participants	356 Participants n=663 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	47 Participants n=332 Participants	49 Participants n=331 Participants	96 Participants n=663 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	285 Participants n=332 Participants	282 Participants n=331 Participants	567 Participants n=663 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=332 Participants	0 Participants n=331 Participants	0 Participants n=663 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=332 Participants	0 Participants n=331 Participants	0 Participants n=663 Participants
Race (NIH/OMB) Asian	83 Participants n=332 Participants	80 Participants n=331 Participants	163 Participants n=663 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	1 Participants n=332 Participants	0 Participants n=331 Participants	1 Participants n=663 Participants
Race (NIH/OMB) Black or African American	5 Participants n=332 Participants	5 Participants n=331 Participants	10 Participants n=663 Participants
Race (NIH/OMB) White	242 Participants n=332 Participants	246 Participants n=331 Participants	488 Participants n=663 Participants
Race (NIH/OMB) More than one race	1 Participants n=332 Participants	0 Participants n=331 Participants	1 Participants n=663 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=332 Participants	0 Participants n=331 Participants	0 Participants n=663 Participants
Baseline High Resolution Computed Tomography (HRCT) fibrotic pattern UIP-like fibrotic pattern only	206 Participants n=332 Participants	206 Participants n=331 Participants	412 Participants n=663 Participants
Baseline High Resolution Computed Tomography (HRCT) fibrotic pattern Other fibrotic patterns	126 Participants n=332 Participants	125 Participants n=331 Participants	251 Participants n=663 Participants
Baseline Forced Vital Capacity (FVC) - Overall Population	2340.07 Milliliter (mL) STANDARD_DEVIATION 740.19 • n=332 Participants	2321.15 Milliliter (mL) STANDARD_DEVIATION 727.97 • n=331 Participants	2330.62 Milliliter (mL) STANDARD_DEVIATION 733.62 • n=663 Participants
Baseline FVC - Participants with HRCT fibrotic pattern=UIP-like fibrotic pattern only	2363.43 Milliliter (mL) STANDARD_DEVIATION 762.89 • n=206 Participants • All randomized participants with HRCT fibrotic pattern=UIP-like fibrotic pattern only who received at least 1 dose of trial medication.	2373.59 Milliliter (mL) STANDARD_DEVIATION 720.05 • n=206 Participants • All randomized participants with HRCT fibrotic pattern=UIP-like fibrotic pattern only who received at least 1 dose of trial medication.	2368.51 Milliliter (mL) STANDARD_DEVIATION 740.89 • n=412 Participants • All randomized participants with HRCT fibrotic pattern=UIP-like fibrotic pattern only who received at least 1 dose of trial medication.

PRIMARY outcome

Timeframe: Baseline, 2, 4, 6, 12, 24, 36, 52 weeks after first drug intake (planned post-baseline visits)

Population: All randomized participants in the overall population who received at least 1 dose of trial medication.

Outcome measures

Outcome measures
Measure	150 mg Nintedanib n=332 Participants 150 milligram (mg) Nintedanib as soft gelatine capsule, administered orally, twice daily (bid), with optional dose reduction to 100 mg bid to manage adverse events (AEs). Continuous daily dosing over a 52-week treatment period (Part A). After completion of the 52-week treatment period, participants continued on blinded treatment until the end of the trial or until a reason for treatment withdrawal was met (Part B).	Placebo n=331 Participants 150 mg Nintedanib matching placebo, soft gelatine capsule, administered orally, bid, with optional dose reduction to 100 mg bid to manage AEs. Continuous daily dosing over a 52-week treatment period (Part A). After completion of the 52-week treatment period, participants continued on blinded treatment until the end of the trial or until a reason for treatment withdrawal was met (Part B).
Annual Rate of Decline in Forced Vital Capacity - Overall Population	-80.82 Milliliter per year Interval -110.42 to -51.22	-187.78 Milliliter per year Interval -216.92 to -158.64

PRIMARY outcome

Timeframe: Baseline, 2, 4, 6, 12, 24, 36, 52 weeks after first drug intake (planned post-baseline visits)

Population: All randomized participants with HRCT fibrotic pattern=UIP-like fibrotic pattern only who received at least 1 dose of trial medication.

Forced Vital Capacity (FVC) is the volume of air (measured in milliliter) which can be forcibly exhaled from the lungs after taking the deepest breath possible. Annual rate of decline in Forced Vital Capacity in milliliter (mL) per year in participants with HRCT fibrotic pattern=UIP-like fibrotic pattern only is based on a random coefficient regression with fixed effects for treatment, baseline FVC \[mL\], and including treatment-by-time and baseline-by-time interactions. Within-participant errors are modelled by an unstructured variance-covariance matrix.

Outcome measures

Outcome measures
Measure	150 mg Nintedanib n=206 Participants 150 milligram (mg) Nintedanib as soft gelatine capsule, administered orally, twice daily (bid), with optional dose reduction to 100 mg bid to manage adverse events (AEs). Continuous daily dosing over a 52-week treatment period (Part A). After completion of the 52-week treatment period, participants continued on blinded treatment until the end of the trial or until a reason for treatment withdrawal was met (Part B).	Placebo n=206 Participants 150 mg Nintedanib matching placebo, soft gelatine capsule, administered orally, bid, with optional dose reduction to 100 mg bid to manage AEs. Continuous daily dosing over a 52-week treatment period (Part A). After completion of the 52-week treatment period, participants continued on blinded treatment until the end of the trial or until a reason for treatment withdrawal was met (Part B).
Annual Rate of Decline in Forced Vital Capacity - Participants With HRCT Fibrotic Pattern=UIP-like Fibrotic Pattern Only	-82.87 Milliliter per year Interval -123.73 to -42.02	-211.07 Milliliter per year Interval -251.38 to -170.77

SECONDARY outcome

Timeframe: Baseline, 12, 24, 36, 52 weeks after first drug intake (planned post-baseline visits)

Population: All randomized participants in the overall population who received at least 1 dose of trial medication and contributed to the model evaluation.

King's Brief Interstitial Lung Disease questionnaire (K-BILD) consists of 15 items and 3 domains: breathlessness and activities, psychological, and chest symptoms. Possible score ranges from 0-100, score of 100 representing the best health status. If missing items were \>50% per domain, the domain score was set to missing. If any of the domain scores were missing, the total score was set to missing. Absolute change from baseline in K-BILD Total score at week 52 in the overall population was based on a Mixed Model Repeated Measures (MMRM), with fixed effects for baseline K-BILD Total score, HRCT fibrotic pattern, visit, treatment-by-visit interaction, baseline-by-visit interactions and random effect for participant. Visit was the repeated measure. Within-participant errors were modelled by unstructured variance-covariance matrix.

Outcome measures

Outcome measures
Measure	150 mg Nintedanib n=332 Participants 150 milligram (mg) Nintedanib as soft gelatine capsule, administered orally, twice daily (bid), with optional dose reduction to 100 mg bid to manage adverse events (AEs). Continuous daily dosing over a 52-week treatment period (Part A). After completion of the 52-week treatment period, participants continued on blinded treatment until the end of the trial or until a reason for treatment withdrawal was met (Part B).	Placebo n=330 Participants 150 mg Nintedanib matching placebo, soft gelatine capsule, administered orally, bid, with optional dose reduction to 100 mg bid to manage AEs. Continuous daily dosing over a 52-week treatment period (Part A). After completion of the 52-week treatment period, participants continued on blinded treatment until the end of the trial or until a reason for treatment withdrawal was met (Part B).
Absolute Change From Baseline in King's Brief Interstitial Lung Disease Questionnaire (K-BILD) Total Score at Week 52 - Overall Population	0.55 Unit on scale Interval -0.62 to 1.72	-0.79 Unit on scale Interval -1.94 to 0.37

SECONDARY outcome

Timeframe: Baseline, 12, 24, 36, 52 weeks after first drug intake (planned post-baseline visits)

Population: All randomized participants with HRCT fibrotic pattern=UIP-like fibrotic pattern only who received at least 1 dose of trial medication and who contributed to the model evaluation.

King's Brief Interstitial Lung Disease questionnaire (K-BILD) consists of 15 items and 3 domains: breathlessness and activities, psychological, and chest symptoms. Possible score ranges from 0-100, score of 100 representing the best health status. If missing items were \>50% per domain, the domain score was set to missing. If any of the domain scores were missing, the total score was set to missing. Absolute change from baseline in K-BILD Total score at week 52 in participants with HRCT fibrotic pattern=UIP-like fibrotic pattern only was based on a Mixed Model Repeated Measures (MMRM), with fixed effects for baseline K-BILD Total score, HRCT fibrotic pattern, visit, treatment-by-visit interaction, baseline-by-visit interactions and random effect for participant. Visit was the repeated measure. Within-participant errors were modelled by unstructured variance-covariance matrix.

Outcome measures

Outcome measures
Measure	150 mg Nintedanib n=206 Participants 150 milligram (mg) Nintedanib as soft gelatine capsule, administered orally, twice daily (bid), with optional dose reduction to 100 mg bid to manage adverse events (AEs). Continuous daily dosing over a 52-week treatment period (Part A). After completion of the 52-week treatment period, participants continued on blinded treatment until the end of the trial or until a reason for treatment withdrawal was met (Part B).	Placebo n=205 Participants 150 mg Nintedanib matching placebo, soft gelatine capsule, administered orally, bid, with optional dose reduction to 100 mg bid to manage AEs. Continuous daily dosing over a 52-week treatment period (Part A). After completion of the 52-week treatment period, participants continued on blinded treatment until the end of the trial or until a reason for treatment withdrawal was met (Part B).
Absolute Change From Baseline in King's Brief Interstitial Lung Disease (K-BILD) Questionnaire Total Score at Week 52 - Participants With HRCT Fibrotic Pattern=UIP-like Fibrotic Pattern Only	0.75 Unit on scale Interval -0.82 to 2.31	-0.78 Unit on scale Interval -2.34 to 0.78

SECONDARY outcome

Timeframe: From first drug intake until date of first acute ILD exacerbation or date of death or last contact date, up to 372 days

Population: All randomized participants in the overall population who received at least 1 dose of trial medication.

Time to first acute ILD exacerbation or death over 52 weeks was defined as time to first acute ILD exacerbation or death due to any cause within the first 52 weeks and was computed as earliest of date of first documented acute ILD exacerbation or death - date of first drug intake + 1. Participants alive who did not experience any ILD exacerbation event or with unknown status within the first 52 weeks were censored.

Outcome measures

Outcome measures
Measure	150 mg Nintedanib n=332 Participants 150 milligram (mg) Nintedanib as soft gelatine capsule, administered orally, twice daily (bid), with optional dose reduction to 100 mg bid to manage adverse events (AEs). Continuous daily dosing over a 52-week treatment period (Part A). After completion of the 52-week treatment period, participants continued on blinded treatment until the end of the trial or until a reason for treatment withdrawal was met (Part B).	Placebo n=331 Participants 150 mg Nintedanib matching placebo, soft gelatine capsule, administered orally, bid, with optional dose reduction to 100 mg bid to manage AEs. Continuous daily dosing over a 52-week treatment period (Part A). After completion of the 52-week treatment period, participants continued on blinded treatment until the end of the trial or until a reason for treatment withdrawal was met (Part B).
Time to First Acute Interstitial Lung Disease (ILD) Exacerbation or Death Over 52 Weeks - Overall Population	NA Days Non-calculable because the 25 percentile was not reached.	NA Days Non-calculable because the 25 percentile was not reached.

SECONDARY outcome

Timeframe: From first drug intake until date of first acute ILD exacerbation or date of death or last contact date, up to 372 days

Population: All randomized participants with HRCT fibrotic pattern=UIP-like fibrotic pattern only who received at least 1 dose of trial medication.

Outcome measures

Outcome measures
Measure	150 mg Nintedanib n=206 Participants 150 milligram (mg) Nintedanib as soft gelatine capsule, administered orally, twice daily (bid), with optional dose reduction to 100 mg bid to manage adverse events (AEs). Continuous daily dosing over a 52-week treatment period (Part A). After completion of the 52-week treatment period, participants continued on blinded treatment until the end of the trial or until a reason for treatment withdrawal was met (Part B).	Placebo n=206 Participants 150 mg Nintedanib matching placebo, soft gelatine capsule, administered orally, bid, with optional dose reduction to 100 mg bid to manage AEs. Continuous daily dosing over a 52-week treatment period (Part A). After completion of the 52-week treatment period, participants continued on blinded treatment until the end of the trial or until a reason for treatment withdrawal was met (Part B).
Time to First Acute Interstitial Lung Disease (ILD) Exacerbation or Death Over 52 Weeks - Participants With HRCT Fibrotic Pattern=UIP-like Fibrotic Pattern Only	NA Days Non-calculable because the 25 percentile was not reached.	NA Days Non-calculable because the 25 percentile was not reached.

SECONDARY outcome

Timeframe: From first drug intake until date of death or last contact date, up to 372 days

Population: All randomized participants in the overall population who received at least 1 dose of trial medication.

Time to death over 52 weeks defined as the time from date of first drug intake until date of death from any cause for participants with known date of death (from any cause) within the first 52 weeks. Participants with no event (death from any cause) or unknown status within the first 52 weeks were censored.

Outcome measures

Outcome measures
Measure	150 mg Nintedanib n=332 Participants 150 milligram (mg) Nintedanib as soft gelatine capsule, administered orally, twice daily (bid), with optional dose reduction to 100 mg bid to manage adverse events (AEs). Continuous daily dosing over a 52-week treatment period (Part A). After completion of the 52-week treatment period, participants continued on blinded treatment until the end of the trial or until a reason for treatment withdrawal was met (Part B).	Placebo n=331 Participants 150 mg Nintedanib matching placebo, soft gelatine capsule, administered orally, bid, with optional dose reduction to 100 mg bid to manage AEs. Continuous daily dosing over a 52-week treatment period (Part A). After completion of the 52-week treatment period, participants continued on blinded treatment until the end of the trial or until a reason for treatment withdrawal was met (Part B).
Time to Death Over 52 Weeks - Overall Population	NA Days Non-calculable because the 25 percentile was not reached.	NA Days Non-calculable because the 25 percentile was not reached.

SECONDARY outcome

Timeframe: From first drug intake until date of death or last contact date, up to 372 days

Population: All randomized participants with HRCT fibrotic pattern=UIP-like fibrotic pattern only who received at least 1 dose of trial medication.

Outcome measures

Outcome measures
Measure	150 mg Nintedanib n=206 Participants 150 milligram (mg) Nintedanib as soft gelatine capsule, administered orally, twice daily (bid), with optional dose reduction to 100 mg bid to manage adverse events (AEs). Continuous daily dosing over a 52-week treatment period (Part A). After completion of the 52-week treatment period, participants continued on blinded treatment until the end of the trial or until a reason for treatment withdrawal was met (Part B).	Placebo n=206 Participants 150 mg Nintedanib matching placebo, soft gelatine capsule, administered orally, bid, with optional dose reduction to 100 mg bid to manage AEs. Continuous daily dosing over a 52-week treatment period (Part A). After completion of the 52-week treatment period, participants continued on blinded treatment until the end of the trial or until a reason for treatment withdrawal was met (Part B).
Time to Death Over 52 Weeks - Participants With HRCT Fibrotic Pattern=UIP-like Fibrotic Pattern Only	NA Days Non-calculable because the 25 percentile was not reached.	NA Days Non-calculable because the 25 percentile was not reached.

SECONDARY outcome

Timeframe: From date of first trial drug intake up to date of death from respiratory causes or last contact date, up to 372 days

Population: All randomized participants in the overall population who received at least 1 dose of trial medication.

Time to death due to respiratory cause over 52 weeks is defined as the time from date of first drug intake until date of death attributed to respiratory causes (determined by an independent Adjudication Committee) for participants with known date of death (from respiratory causes) within the first 52 weeks. Participants with no event (death from respiratory causes) or unknown status within the first 52 weeks were censored. As less than 4.95% of the total of participants in the analysis population experienced an event, only descriptive statistics were performed, as pre-specified.

Outcome measures

Outcome measures
Measure	150 mg Nintedanib n=332 Participants 150 milligram (mg) Nintedanib as soft gelatine capsule, administered orally, twice daily (bid), with optional dose reduction to 100 mg bid to manage adverse events (AEs). Continuous daily dosing over a 52-week treatment period (Part A). After completion of the 52-week treatment period, participants continued on blinded treatment until the end of the trial or until a reason for treatment withdrawal was met (Part B).	Placebo n=331 Participants 150 mg Nintedanib matching placebo, soft gelatine capsule, administered orally, bid, with optional dose reduction to 100 mg bid to manage AEs. Continuous daily dosing over a 52-week treatment period (Part A). After completion of the 52-week treatment period, participants continued on blinded treatment until the end of the trial or until a reason for treatment withdrawal was met (Part B).
Time to Death Due to Respiratory Cause Over 52 Weeks - Overall Population	NA Days Non-calculable because the 25 percentile was not reached.	NA Days Non-calculable because the 25 percentile was not reached.

SECONDARY outcome

Timeframe: From date of first trial drug intake up to date of death from respiratory causes or last contact date, up to 372 days

Population: All randomized participants with HRCT fibrotic pattern=UIP-like fibrotic pattern only who received at least 1 dose of trial medication.

Outcome measures

Outcome measures
Measure	150 mg Nintedanib n=206 Participants 150 milligram (mg) Nintedanib as soft gelatine capsule, administered orally, twice daily (bid), with optional dose reduction to 100 mg bid to manage adverse events (AEs). Continuous daily dosing over a 52-week treatment period (Part A). After completion of the 52-week treatment period, participants continued on blinded treatment until the end of the trial or until a reason for treatment withdrawal was met (Part B).	Placebo n=206 Participants 150 mg Nintedanib matching placebo, soft gelatine capsule, administered orally, bid, with optional dose reduction to 100 mg bid to manage AEs. Continuous daily dosing over a 52-week treatment period (Part A). After completion of the 52-week treatment period, participants continued on blinded treatment until the end of the trial or until a reason for treatment withdrawal was met (Part B).
Time to Death Due to Respiratory Cause Over 52 Weeks - Participants With HRCT Fibrotic Pattern=UIP-like Fibrotic Pattern Only	NA Days Non-calculable because the 25 percentile was not reached.	NA Days Non-calculable because the 25 percentile was not reached.

SECONDARY outcome

Timeframe: From first drug intake until date of progression or date of death or last contact date, up to 372 days

Population: All randomized participants in the overall population who received at least 1 dose of trial medication.

Time to progression or death over 52 weeks is defined as the time from date of first drug intake to date of progression, or date of death (from any cause) if a participant died earlier. Participants with no event (progression or death from any cause) or unknown status were censored. Date of progression is defined as the date when ≥ 10% of absolute decline in FVC percent predicted compared to baseline occured for the first time. Forced Vital Capacity (FVC) is the volume of air (measured in milliliter) which can be forcibly exhaled from the lungs after taking the deepest breath possible. Predicted normal values of FVC were calculated according to the Global Lung Initiative. FVC percent predicted (FVC % pred) is the FVC divided by its predicted value in percent.

Outcome measures

Outcome measures
Measure	150 mg Nintedanib n=332 Participants 150 milligram (mg) Nintedanib as soft gelatine capsule, administered orally, twice daily (bid), with optional dose reduction to 100 mg bid to manage adverse events (AEs). Continuous daily dosing over a 52-week treatment period (Part A). After completion of the 52-week treatment period, participants continued on blinded treatment until the end of the trial or until a reason for treatment withdrawal was met (Part B).	Placebo n=331 Participants 150 mg Nintedanib matching placebo, soft gelatine capsule, administered orally, bid, with optional dose reduction to 100 mg bid to manage AEs. Continuous daily dosing over a 52-week treatment period (Part A). After completion of the 52-week treatment period, participants continued on blinded treatment until the end of the trial or until a reason for treatment withdrawal was met (Part B).
Time to Progression or Death Over 52 Weeks - Overall Population	NA Days Interval 367.0 to Non-calculable because the 50 percentile was not reached.	NA Days Interval 269.0 to Non-calculable because the 50 percentile was not reached.

SECONDARY outcome

Timeframe: From first drug intake until date of progression or date of death or last contact date, up to 372 days

Population: All randomized participants with HRCT fibrotic pattern=UIP-like fibrotic pattern only who received at least 1 dose of trial medication.

Outcome measures

Outcome measures
Measure	150 mg Nintedanib n=206 Participants 150 milligram (mg) Nintedanib as soft gelatine capsule, administered orally, twice daily (bid), with optional dose reduction to 100 mg bid to manage adverse events (AEs). Continuous daily dosing over a 52-week treatment period (Part A). After completion of the 52-week treatment period, participants continued on blinded treatment until the end of the trial or until a reason for treatment withdrawal was met (Part B).	Placebo n=206 Participants 150 mg Nintedanib matching placebo, soft gelatine capsule, administered orally, bid, with optional dose reduction to 100 mg bid to manage AEs. Continuous daily dosing over a 52-week treatment period (Part A). After completion of the 52-week treatment period, participants continued on blinded treatment until the end of the trial or until a reason for treatment withdrawal was met (Part B).
Time to Progression or Death Over 52 Weeks - Participants With HRCT Fibrotic Pattern=UIP-like Fibrotic Pattern Only	NA Days Interval 365.0 to Non-calculable because the 50 percentile was not reached.	NA Days Interval 254.0 to Non-calculable because the 50 percentile was not reached.

SECONDARY outcome

Timeframe: Baseline and up to 52 weeks after first drug intake

Population: All randomized participants in the overall population who received at least 1 dose of trial medication.

Forced Vital Capacity (FVC) is the volume of air (measured in milliliter) which can be forcibly exhaled from the lungs after taking the deepest breath possible. Predicted normal values of FVC were calculated according to the Global Lung Initiative. FVC percent predicted (FVC % pred) is the FVC divided by its predicted value in percent. Participants with relative decline from baseline in FVC % pred greater than 10% at week 52 were those participants with a negative relative change from baseline in FVC % pred at week 52 the absolute value of which being greater than 10% and those participants with missing data (worst case analysis).

Outcome measures

Outcome measures
Measure	150 mg Nintedanib n=332 Participants 150 milligram (mg) Nintedanib as soft gelatine capsule, administered orally, twice daily (bid), with optional dose reduction to 100 mg bid to manage adverse events (AEs). Continuous daily dosing over a 52-week treatment period (Part A). After completion of the 52-week treatment period, participants continued on blinded treatment until the end of the trial or until a reason for treatment withdrawal was met (Part B).	Placebo n=331 Participants 150 mg Nintedanib matching placebo, soft gelatine capsule, administered orally, bid, with optional dose reduction to 100 mg bid to manage AEs. Continuous daily dosing over a 52-week treatment period (Part A). After completion of the 52-week treatment period, participants continued on blinded treatment until the end of the trial or until a reason for treatment withdrawal was met (Part B).
Percentage of Participants With a Relative Decline From Baseline in FVC Percent Predicted of More Than 10 Percent at Week 52 - Overall Population	40.7 Percentage of participants	48.9 Percentage of participants

SECONDARY outcome

Timeframe: Baseline and up to 52 weeks after first drug intake

Population: All randomized participants with HRCT fibrotic pattern=UIP-like fibrotic pattern only who received at least 1 dose of trial medication.

Outcome measures

Outcome measures
Measure	150 mg Nintedanib n=206 Participants 150 milligram (mg) Nintedanib as soft gelatine capsule, administered orally, twice daily (bid), with optional dose reduction to 100 mg bid to manage adverse events (AEs). Continuous daily dosing over a 52-week treatment period (Part A). After completion of the 52-week treatment period, participants continued on blinded treatment until the end of the trial or until a reason for treatment withdrawal was met (Part B).	Placebo n=206 Participants 150 mg Nintedanib matching placebo, soft gelatine capsule, administered orally, bid, with optional dose reduction to 100 mg bid to manage AEs. Continuous daily dosing over a 52-week treatment period (Part A). After completion of the 52-week treatment period, participants continued on blinded treatment until the end of the trial or until a reason for treatment withdrawal was met (Part B).
Percentage of Participants With a Relative Decline From Baseline in FVC Percent Predicted of More Than 10 Percent at Week 52 - Participants With HRCT Fibrotic Pattern=UIP-like Fibrotic Pattern Only	41.3 Percentage of participants	52.4 Percentage of participants

SECONDARY outcome

Timeframe: Baseline and up to 52 weeks after first drug intake

Population: All randomized participants in the overall population who received at least 1 dose of trial medication.

Forced Vital Capacity (FVC) is the volume of air (measured in milliliter) which can be forcibly exhaled from the lungs after taking the deepest breath possible. Predicted normal values of FVC were calculated according to the Global Lung Initiative. FVC percent predicted (FVC % pred) is the FVC divided by its predicted value in percent. Participants with relative decline from baseline in FVC % pred greater than 5% at week 52 were those participants with a negative relative change from baseline in FVC % pred at week 52 the absolute value of which being greater than 5% and those participants with missing data (worst case analysis).

Outcome measures

Outcome measures
Measure	150 mg Nintedanib n=332 Participants 150 milligram (mg) Nintedanib as soft gelatine capsule, administered orally, twice daily (bid), with optional dose reduction to 100 mg bid to manage adverse events (AEs). Continuous daily dosing over a 52-week treatment period (Part A). After completion of the 52-week treatment period, participants continued on blinded treatment until the end of the trial or until a reason for treatment withdrawal was met (Part B).	Placebo n=331 Participants 150 mg Nintedanib matching placebo, soft gelatine capsule, administered orally, bid, with optional dose reduction to 100 mg bid to manage AEs. Continuous daily dosing over a 52-week treatment period (Part A). After completion of the 52-week treatment period, participants continued on blinded treatment until the end of the trial or until a reason for treatment withdrawal was met (Part B).
Percentage of Participants With a Relative Decline From Baseline in FVC Percent Predicted of More Than 5 Percent at Week 52 - Overall Population	52.4 Percentage of participants	68.6 Percentage of participants

SECONDARY outcome

Timeframe: Baseline and up to 52 weeks after first drug intake

Population: All randomized participants with HRCT fibrotic pattern=UIP-like fibrotic pattern only who received at least 1 dose of trial medication.

Forced Vital Capacity (FVC) is the volume of air (measured in milliliter) which can be forcibly exhaled from the lungs after taking the deepest breath possible. Predicted normal values of FVC were calculated according to the Global Lung Initiative. FVC percent predicted (FVC % pred) is the FVC divided by its predicted value in percent. Participants with relative decline from baseline in FVC % pred greater than 5% at week 52 were those participants with a negative relative change from baseline in FVC % pred at week 52 the absolute value of which being greater than 5% and those participants with missing data (worst case analysis).

Outcome measures

Outcome measures
Measure	150 mg Nintedanib n=206 Participants 150 milligram (mg) Nintedanib as soft gelatine capsule, administered orally, twice daily (bid), with optional dose reduction to 100 mg bid to manage adverse events (AEs). Continuous daily dosing over a 52-week treatment period (Part A). After completion of the 52-week treatment period, participants continued on blinded treatment until the end of the trial or until a reason for treatment withdrawal was met (Part B).	Placebo n=206 Participants 150 mg Nintedanib matching placebo, soft gelatine capsule, administered orally, bid, with optional dose reduction to 100 mg bid to manage AEs. Continuous daily dosing over a 52-week treatment period (Part A). After completion of the 52-week treatment period, participants continued on blinded treatment until the end of the trial or until a reason for treatment withdrawal was met (Part B).
Percentage of Participants With a Relative Decline From Baseline in FVC Percent Predicted of More Than 5 Percent at Week 52 - Participants With HRCT Fibrotic Pattern=UIP-like Fibrotic Pattern Only	52.4 Percentage of participants	70.4 Percentage of participants

SECONDARY outcome

Timeframe: Baseline, 12, 24, 36, 52 weeks after first drug intake (planned post-baseline visits)

Population: All randomized participants in the overall population who received at least 1 dose of trial medication and contributed to the model evaluation.

Living with Pulmonary Fibrosis (L-PF) questionnaire is a 44 item questionnaire with two modules Symptoms (23 items) and Impacts (21 items) where the symptoms module yields three domain scores dyspnea, cough and fatigue as well as a total symptoms score (impacts module yields a single impacts score). L-PF Symptoms dyspnea domain score (dyspnea score) ranges from 0-100, the higher the score the greater the impairment. If missing items were ≥50 % within a score, then the corresponding score was set to missing. Absolute change from baseline in dyspnea score at week 52 is based on a Mixed Model Repeated Measures, with fixed effects for baseline dyspnea score, HRCT fibrotic pattern, visit, treatment-by-visit interaction, baseline dyspnea score-by-visit interaction and random effect for participant, visit as repeated measure. The Adjusted mean is based on all analysed participants in the model (not only participants with a baseline and measurement at week 52).

Outcome measures

Outcome measures
Measure	150 mg Nintedanib n=329 Participants 150 milligram (mg) Nintedanib as soft gelatine capsule, administered orally, twice daily (bid), with optional dose reduction to 100 mg bid to manage adverse events (AEs). Continuous daily dosing over a 52-week treatment period (Part A). After completion of the 52-week treatment period, participants continued on blinded treatment until the end of the trial or until a reason for treatment withdrawal was met (Part B).	Placebo n=323 Participants 150 mg Nintedanib matching placebo, soft gelatine capsule, administered orally, bid, with optional dose reduction to 100 mg bid to manage AEs. Continuous daily dosing over a 52-week treatment period (Part A). After completion of the 52-week treatment period, participants continued on blinded treatment until the end of the trial or until a reason for treatment withdrawal was met (Part B).
Absolute Change From Baseline in Living With Pulmonary Fibrosis (L-PF) Symptoms Dyspnea Domain Score at Week 52 - Overall Population	4.28 Unit on scale Interval 2.43 to 6.14	7.81 Unit on scale Interval 5.97 to 9.66

SECONDARY outcome

Timeframe: Baseline, 12, 24, 36, 52 weeks after first drug intake (planned post-baseline visits)

Population: All randomized participants with HRCT fibrotic pattern=UIP-like fibrotic pattern only who received at least 1 dose of trial medication and contributed to the model evaluation.

Living with Pulmonary Fibrosis (L-PF) questionnaire is a 44 item questionnaire with two modules Symptoms (23 items) and Impacts (21 items) where the symptoms module yields three domain scores dyspnea, cough and fatigue as well as a total symptoms score (impacts module yields a single impacts score). L-PF Symptoms dyspnea domain score (dyspnea score) ranges from 0-100, the higher the score the greater the impairment. If missing items were ≥50 % within a score, then the corresponding score was set to missing. Absolute change from baseline in dyspnea score at week 52 is based on a Mixed Model Repeated Measures, with fixed effects for baseline dyspnea score, visit, treatment-by-visit interaction, baseline dyspnea score-by-visit interaction and random effect for participant, visit as repeated measure. The Adjusted mean is based on all analysed participants in the model (not only participants with a baseline and measurement at week 52).

Outcome measures

Outcome measures
Measure	150 mg Nintedanib n=204 Participants 150 milligram (mg) Nintedanib as soft gelatine capsule, administered orally, twice daily (bid), with optional dose reduction to 100 mg bid to manage adverse events (AEs). Continuous daily dosing over a 52-week treatment period (Part A). After completion of the 52-week treatment period, participants continued on blinded treatment until the end of the trial or until a reason for treatment withdrawal was met (Part B).	Placebo n=201 Participants 150 mg Nintedanib matching placebo, soft gelatine capsule, administered orally, bid, with optional dose reduction to 100 mg bid to manage AEs. Continuous daily dosing over a 52-week treatment period (Part A). After completion of the 52-week treatment period, participants continued on blinded treatment until the end of the trial or until a reason for treatment withdrawal was met (Part B).
Absolute Change From Baseline in L-PF Symptoms Dyspnea Domain Score at Week 52 - Participants With HRCT Fibrotic Pattern=UIP-like Fibrotic Pattern Only	4.14 Unit on scale Interval 1.81 to 6.47	8.32 Unit on scale Interval 5.99 to 10.66

SECONDARY outcome

Timeframe: Baseline, 12, 24, 36, 52 weeks after first drug intake (planned post-baseline visits)

Population: All randomized participants in the overall population who received at least 1 dose of trial medication and contributed to the model evaluation.

Living with Pulmonary Fibrosis (L-PF) questionnaire is a 44 item questionnaire with two modules Symptoms (23 items) and Impacts (21 items) where the symptoms module yields three domain scores dyspnea, cough and fatigue as well as a total symptoms score (impacts module yields a single impacts score). L-PF Symptoms cough domain score (cough score) ranges from 0-100, the higher the score the greater the impairment. If missing items were ≥50 % within a score, then the corresponding score was set to missing. Absolute change from baseline in cough score at week 52 is based on a Mixed Model Repeated Measures, with fixed effects for baseline cough score, HRCT fibrotic pattern, visit, treatment-by-visit interaction, baseline cough score-by-visit interaction and random effect for participant, visit as repeated measure. The Adjusted mean is based on all analysed participants in the model (not only participants with a baseline and measurement at week 52).

Outcome measures

Outcome measures
Measure	150 mg Nintedanib n=327 Participants 150 milligram (mg) Nintedanib as soft gelatine capsule, administered orally, twice daily (bid), with optional dose reduction to 100 mg bid to manage adverse events (AEs). Continuous daily dosing over a 52-week treatment period (Part A). After completion of the 52-week treatment period, participants continued on blinded treatment until the end of the trial or until a reason for treatment withdrawal was met (Part B).	Placebo n=320 Participants 150 mg Nintedanib matching placebo, soft gelatine capsule, administered orally, bid, with optional dose reduction to 100 mg bid to manage AEs. Continuous daily dosing over a 52-week treatment period (Part A). After completion of the 52-week treatment period, participants continued on blinded treatment until the end of the trial or until a reason for treatment withdrawal was met (Part B).
Absolute Change From Baseline in L-PF Symptoms Cough Domain Score at Week 52 - Overall Population	-1.84 Unit on scale Interval -4.36 to 0.69	4.25 Unit on scale Interval 1.74 to 6.76

SECONDARY outcome

Timeframe: Baseline, 12, 24, 36, 52 weeks after first drug intake (planned post-baseline visits)

Population: All randomized participants with HRCT fibrotic pattern=UIP-like fibrotic pattern only who received at least 1 dose of trial medication and contributed to the model evaluation.

Living with Pulmonary Fibrosis (L-PF) questionnaire is a 44 item questionnaire with two modules Symptoms (23 items) and Impacts (21 items) where the symptoms module yields three domain scores dyspnea, cough and fatigue as well as a total symptoms score (impacts module yields a single impacts score). L-PF Symptoms cough domain score (cough score) ranges from 0-100, the higher the score the greater the impairment. If missing items were ≥50 % within a score, then the corresponding score was set to missing. Absolute change from baseline in cough score at week 52 is based on a Mixed Model Repeated Measures, with fixed effects for baseline cough score, visit, treatment-by-visit interaction, baseline cough score-by-visit interaction and random effect for participant, visit as repeated measure. The Adjusted mean is based on all analysed participants in the model (not only participants with a baseline and measurement at week 52).

Outcome measures

Outcome measures
Measure	150 mg Nintedanib n=203 Participants 150 milligram (mg) Nintedanib as soft gelatine capsule, administered orally, twice daily (bid), with optional dose reduction to 100 mg bid to manage adverse events (AEs). Continuous daily dosing over a 52-week treatment period (Part A). After completion of the 52-week treatment period, participants continued on blinded treatment until the end of the trial or until a reason for treatment withdrawal was met (Part B).	Placebo n=199 Participants 150 mg Nintedanib matching placebo, soft gelatine capsule, administered orally, bid, with optional dose reduction to 100 mg bid to manage AEs. Continuous daily dosing over a 52-week treatment period (Part A). After completion of the 52-week treatment period, participants continued on blinded treatment until the end of the trial or until a reason for treatment withdrawal was met (Part B).
Absolute Change From Baseline in Living With Pulmonary Fibrosis (L-PF) Symptoms Cough Domain Score at Week 52 - Participants With HRCT Fibrotic Pattern=UIP-like Fibrotic Pattern Only	-3.20 Unit on scale Interval -6.43 to 0.04	4.09 Unit on scale Interval 0.85 to 7.32

Adverse Events

Nintedanib

Serious events: 147 serious events

Other events: 308 other events

Deaths: 36 deaths

Placebo

Serious events: 164 serious events

Other events: 266 other events

Deaths: 45 deaths

Serious adverse events

Other adverse events

Additional Information

Boehringer Ingelheim Call Center

Boehringer Ingelheim

Phone: 1-800-243-0127

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Publication restrictions are in place

Restriction type: OTHER

Measure	Nintedanib n=332 participants at risk 150 milligram (mg) Nintedanib as soft gelatine capsule, administered orally, twice daily (bid), with optional dose reduction to 100 mg bid to manage adverse events (AEs). Continuous daily dosing over a 52-week treatment period (Part A). After completion of the 52-week treatment period, participants continued on blinded treatment until the end of the trial or until a reason for treatment withdrawal was met (Part B).	Placebo n=331 participants at risk 150 mg Nintedanib matching placebo, soft gelatine capsule, administered orally, bid, with optional dose reduction to 100 mg bid to manage AEs. Continuous daily dosing over a 52-week treatment period (Part A). After completion of the 52-week treatment period, participants continued on blinded treatment until the end of the trial or until a reason for treatment withdrawal was met (Part B).
Gastrointestinal disorders Abdominal pain	10.2% 34/332 • Treatment period plus 28 days (residual effect period), up to 836 days. Time frame for All-Cause-Mortality: Treatment period plus Follow-up, up to 900 days. All participants who signed the informed consent.	2.7% 9/331 • Treatment period plus 28 days (residual effect period), up to 836 days. Time frame for All-Cause-Mortality: Treatment period plus Follow-up, up to 900 days. All participants who signed the informed consent.
Gastrointestinal disorders Abdominal pain upper	9.9% 33/332 • Treatment period plus 28 days (residual effect period), up to 836 days. Time frame for All-Cause-Mortality: Treatment period plus Follow-up, up to 900 days. All participants who signed the informed consent.	1.8% 6/331 • Treatment period plus 28 days (residual effect period), up to 836 days. Time frame for All-Cause-Mortality: Treatment period plus Follow-up, up to 900 days. All participants who signed the informed consent.
Gastrointestinal disorders Constipation	7.5% 25/332 • Treatment period plus 28 days (residual effect period), up to 836 days. Time frame for All-Cause-Mortality: Treatment period plus Follow-up, up to 900 days. All participants who signed the informed consent.	9.7% 32/331 • Treatment period plus 28 days (residual effect period), up to 836 days. Time frame for All-Cause-Mortality: Treatment period plus Follow-up, up to 900 days. All participants who signed the informed consent.
Gastrointestinal disorders Diarrhoea	72.0% 239/332 • Treatment period plus 28 days (residual effect period), up to 836 days. Time frame for All-Cause-Mortality: Treatment period plus Follow-up, up to 900 days. All participants who signed the informed consent.	25.7% 85/331 • Treatment period plus 28 days (residual effect period), up to 836 days. Time frame for All-Cause-Mortality: Treatment period plus Follow-up, up to 900 days. All participants who signed the informed consent.
Gastrointestinal disorders Nausea	30.1% 100/332 • Treatment period plus 28 days (residual effect period), up to 836 days. Time frame for All-Cause-Mortality: Treatment period plus Follow-up, up to 900 days. All participants who signed the informed consent.	10.0% 33/331 • Treatment period plus 28 days (residual effect period), up to 836 days. Time frame for All-Cause-Mortality: Treatment period plus Follow-up, up to 900 days. All participants who signed the informed consent.
Gastrointestinal disorders Vomiting	19.3% 64/332 • Treatment period plus 28 days (residual effect period), up to 836 days. Time frame for All-Cause-Mortality: Treatment period plus Follow-up, up to 900 days. All participants who signed the informed consent.	4.8% 16/331 • Treatment period plus 28 days (residual effect period), up to 836 days. Time frame for All-Cause-Mortality: Treatment period plus Follow-up, up to 900 days. All participants who signed the informed consent.
General disorders Asthenia	5.4% 18/332 • Treatment period plus 28 days (residual effect period), up to 836 days. Time frame for All-Cause-Mortality: Treatment period plus Follow-up, up to 900 days. All participants who signed the informed consent.	4.2% 14/331 • Treatment period plus 28 days (residual effect period), up to 836 days. Time frame for All-Cause-Mortality: Treatment period plus Follow-up, up to 900 days. All participants who signed the informed consent.
General disorders Chest pain	5.1% 17/332 • Treatment period plus 28 days (residual effect period), up to 836 days. Time frame for All-Cause-Mortality: Treatment period plus Follow-up, up to 900 days. All participants who signed the informed consent.	4.2% 14/331 • Treatment period plus 28 days (residual effect period), up to 836 days. Time frame for All-Cause-Mortality: Treatment period plus Follow-up, up to 900 days. All participants who signed the informed consent.
General disorders Fatigue	10.2% 34/332 • Treatment period plus 28 days (residual effect period), up to 836 days. Time frame for All-Cause-Mortality: Treatment period plus Follow-up, up to 900 days. All participants who signed the informed consent.	6.3% 21/331 • Treatment period plus 28 days (residual effect period), up to 836 days. Time frame for All-Cause-Mortality: Treatment period plus Follow-up, up to 900 days. All participants who signed the informed consent.
General disorders Oedema peripheral	5.4% 18/332 • Treatment period plus 28 days (residual effect period), up to 836 days. Time frame for All-Cause-Mortality: Treatment period plus Follow-up, up to 900 days. All participants who signed the informed consent.	6.6% 22/331 • Treatment period plus 28 days (residual effect period), up to 836 days. Time frame for All-Cause-Mortality: Treatment period plus Follow-up, up to 900 days. All participants who signed the informed consent.
General disorders Pyrexia	5.1% 17/332 • Treatment period plus 28 days (residual effect period), up to 836 days. Time frame for All-Cause-Mortality: Treatment period plus Follow-up, up to 900 days. All participants who signed the informed consent.	5.4% 18/331 • Treatment period plus 28 days (residual effect period), up to 836 days. Time frame for All-Cause-Mortality: Treatment period plus Follow-up, up to 900 days. All participants who signed the informed consent.
Hepatobiliary disorders Hepatic function abnormal	5.7% 19/332 • Treatment period plus 28 days (residual effect period), up to 836 days. Time frame for All-Cause-Mortality: Treatment period plus Follow-up, up to 900 days. All participants who signed the informed consent.	0.91% 3/331 • Treatment period plus 28 days (residual effect period), up to 836 days. Time frame for All-Cause-Mortality: Treatment period plus Follow-up, up to 900 days. All participants who signed the informed consent.
Infections and infestations Bronchitis	13.3% 44/332 • Treatment period plus 28 days (residual effect period), up to 836 days. Time frame for All-Cause-Mortality: Treatment period plus Follow-up, up to 900 days. All participants who signed the informed consent.	18.7% 62/331 • Treatment period plus 28 days (residual effect period), up to 836 days. Time frame for All-Cause-Mortality: Treatment period plus Follow-up, up to 900 days. All participants who signed the informed consent.
Infections and infestations Nasopharyngitis	16.3% 54/332 • Treatment period plus 28 days (residual effect period), up to 836 days. Time frame for All-Cause-Mortality: Treatment period plus Follow-up, up to 900 days. All participants who signed the informed consent.	14.5% 48/331 • Treatment period plus 28 days (residual effect period), up to 836 days. Time frame for All-Cause-Mortality: Treatment period plus Follow-up, up to 900 days. All participants who signed the informed consent.
Infections and infestations Respiratory tract infection	5.4% 18/332 • Treatment period plus 28 days (residual effect period), up to 836 days. Time frame for All-Cause-Mortality: Treatment period plus Follow-up, up to 900 days. All participants who signed the informed consent.	3.6% 12/331 • Treatment period plus 28 days (residual effect period), up to 836 days. Time frame for All-Cause-Mortality: Treatment period plus Follow-up, up to 900 days. All participants who signed the informed consent.
Infections and infestations Upper respiratory tract infection	7.8% 26/332 • Treatment period plus 28 days (residual effect period), up to 836 days. Time frame for All-Cause-Mortality: Treatment period plus Follow-up, up to 900 days. All participants who signed the informed consent.	7.6% 25/331 • Treatment period plus 28 days (residual effect period), up to 836 days. Time frame for All-Cause-Mortality: Treatment period plus Follow-up, up to 900 days. All participants who signed the informed consent.
Infections and infestations Urinary tract infection	6.6% 22/332 • Treatment period plus 28 days (residual effect period), up to 836 days. Time frame for All-Cause-Mortality: Treatment period plus Follow-up, up to 900 days. All participants who signed the informed consent.	6.0% 20/331 • Treatment period plus 28 days (residual effect period), up to 836 days. Time frame for All-Cause-Mortality: Treatment period plus Follow-up, up to 900 days. All participants who signed the informed consent.
Investigations Alanine aminotransferase increased	14.2% 47/332 • Treatment period plus 28 days (residual effect period), up to 836 days. Time frame for All-Cause-Mortality: Treatment period plus Follow-up, up to 900 days. All participants who signed the informed consent.	3.6% 12/331 • Treatment period plus 28 days (residual effect period), up to 836 days. Time frame for All-Cause-Mortality: Treatment period plus Follow-up, up to 900 days. All participants who signed the informed consent.
Investigations Aspartate aminotransferase increased	12.3% 41/332 • Treatment period plus 28 days (residual effect period), up to 836 days. Time frame for All-Cause-Mortality: Treatment period plus Follow-up, up to 900 days. All participants who signed the informed consent.	3.6% 12/331 • Treatment period plus 28 days (residual effect period), up to 836 days. Time frame for All-Cause-Mortality: Treatment period plus Follow-up, up to 900 days. All participants who signed the informed consent.
Investigations Gamma-glutamyltransferase increased	6.6% 22/332 • Treatment period plus 28 days (residual effect period), up to 836 days. Time frame for All-Cause-Mortality: Treatment period plus Follow-up, up to 900 days. All participants who signed the informed consent.	1.8% 6/331 • Treatment period plus 28 days (residual effect period), up to 836 days. Time frame for All-Cause-Mortality: Treatment period plus Follow-up, up to 900 days. All participants who signed the informed consent.
Investigations Weight decreased	14.8% 49/332 • Treatment period plus 28 days (residual effect period), up to 836 days. Time frame for All-Cause-Mortality: Treatment period plus Follow-up, up to 900 days. All participants who signed the informed consent.	5.4% 18/331 • Treatment period plus 28 days (residual effect period), up to 836 days. Time frame for All-Cause-Mortality: Treatment period plus Follow-up, up to 900 days. All participants who signed the informed consent.
Metabolism and nutrition disorders Decreased appetite	16.3% 54/332 • Treatment period plus 28 days (residual effect period), up to 836 days. Time frame for All-Cause-Mortality: Treatment period plus Follow-up, up to 900 days. All participants who signed the informed consent.	6.6% 22/331 • Treatment period plus 28 days (residual effect period), up to 836 days. Time frame for All-Cause-Mortality: Treatment period plus Follow-up, up to 900 days. All participants who signed the informed consent.
Musculoskeletal and connective tissue disorders Arthralgia	3.6% 12/332 • Treatment period plus 28 days (residual effect period), up to 836 days. Time frame for All-Cause-Mortality: Treatment period plus Follow-up, up to 900 days. All participants who signed the informed consent.	6.9% 23/331 • Treatment period plus 28 days (residual effect period), up to 836 days. Time frame for All-Cause-Mortality: Treatment period plus Follow-up, up to 900 days. All participants who signed the informed consent.
Musculoskeletal and connective tissue disorders Back pain	8.4% 28/332 • Treatment period plus 28 days (residual effect period), up to 836 days. Time frame for All-Cause-Mortality: Treatment period plus Follow-up, up to 900 days. All participants who signed the informed consent.	7.9% 26/331 • Treatment period plus 28 days (residual effect period), up to 836 days. Time frame for All-Cause-Mortality: Treatment period plus Follow-up, up to 900 days. All participants who signed the informed consent.
Nervous system disorders Dizziness	5.7% 19/332 • Treatment period plus 28 days (residual effect period), up to 836 days. Time frame for All-Cause-Mortality: Treatment period plus Follow-up, up to 900 days. All participants who signed the informed consent.	4.5% 15/331 • Treatment period plus 28 days (residual effect period), up to 836 days. Time frame for All-Cause-Mortality: Treatment period plus Follow-up, up to 900 days. All participants who signed the informed consent.
Nervous system disorders Headache	11.1% 37/332 • Treatment period plus 28 days (residual effect period), up to 836 days. Time frame for All-Cause-Mortality: Treatment period plus Follow-up, up to 900 days. All participants who signed the informed consent.	8.2% 27/331 • Treatment period plus 28 days (residual effect period), up to 836 days. Time frame for All-Cause-Mortality: Treatment period plus Follow-up, up to 900 days. All participants who signed the informed consent.
Psychiatric disorders Insomnia	5.4% 18/332 • Treatment period plus 28 days (residual effect period), up to 836 days. Time frame for All-Cause-Mortality: Treatment period plus Follow-up, up to 900 days. All participants who signed the informed consent.	5.4% 18/331 • Treatment period plus 28 days (residual effect period), up to 836 days. Time frame for All-Cause-Mortality: Treatment period plus Follow-up, up to 900 days. All participants who signed the informed consent.
Respiratory, thoracic and mediastinal disorders Cough	12.0% 40/332 • Treatment period plus 28 days (residual effect period), up to 836 days. Time frame for All-Cause-Mortality: Treatment period plus Follow-up, up to 900 days. All participants who signed the informed consent.	15.1% 50/331 • Treatment period plus 28 days (residual effect period), up to 836 days. Time frame for All-Cause-Mortality: Treatment period plus Follow-up, up to 900 days. All participants who signed the informed consent.
Respiratory, thoracic and mediastinal disorders Dyspnoea	14.8% 49/332 • Treatment period plus 28 days (residual effect period), up to 836 days. Time frame for All-Cause-Mortality: Treatment period plus Follow-up, up to 900 days. All participants who signed the informed consent.	13.9% 46/331 • Treatment period plus 28 days (residual effect period), up to 836 days. Time frame for All-Cause-Mortality: Treatment period plus Follow-up, up to 900 days. All participants who signed the informed consent.
Skin and subcutaneous tissue disorders Pruritus	3.6% 12/332 • Treatment period plus 28 days (residual effect period), up to 836 days. Time frame for All-Cause-Mortality: Treatment period plus Follow-up, up to 900 days. All participants who signed the informed consent.	5.4% 18/331 • Treatment period plus 28 days (residual effect period), up to 836 days. Time frame for All-Cause-Mortality: Treatment period plus Follow-up, up to 900 days. All participants who signed the informed consent.