Efficacy and Safety of Nintedanib in Patients With Progressive Fibrosing Interstitial Lung Disease (PF-ILD) (INBUILD®)

• ClinicalTrials.gov Identifier: NCT02999178
• Recruitment Status: Completed
• First Posted: December 21, 2016
• Results First Posted: May 5, 2020
• Last Update Posted: May 5, 2020
• Sponsor: Boehringer Ingelheim
• Information provided by (Responsible Party): Boehringer Ingelheim

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double; Primary Purpose: Treatment
• Condition: Lung Diseases, Interstitial
• Interventions: Drug: Nintedanib; Drug: Placebo
• Enrollment: 663

Participant Flow

Recruitment Details	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.
Pre-assignment Details	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.

Arm/Group Title	150 mg Nintedanib	Placebo
Arm/Group Description	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).	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).
Period Title: Overall Study
Started	332	331
Completed	218 [1]	231 [1]
Not Completed	114	100
Reason Not Completed
Adverse Event	85	62
Protocol Violation	1	2
Lost to Follow-up	0	2
Withdrawal by Subject	21	21
Other reason not defined above	7	13
[1] On treatment at analysis cut-off date, 12-August-2019

Baseline Characteristics

Arm/Group Title		150 mg Nintedanib	Placebo	Total
Arm/Group Description		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).	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 of all reporting groups
Overall Number of Baseline Participants		332	331	663
Baseline Analysis Population Description		Treated set: This set included all randomized participants who received at least 1 dose of trial medication.
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	332 participants	331 participants	663 participants
		65.2 (9.7)	66.3 (9.8)	65.8 (9.8)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	332 participants	331 participants	663 participants
	Female	153 46.1%	154 46.5%	307 46.3%
	Male	179 53.9%	177 53.5%	356 53.7%
Ethnicity (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	332 participants	331 participants	663 participants
	Hispanic or Latino	47 14.2%	49 14.8%	96 14.5%
	Not Hispanic or Latino	285 85.8%	282 85.2%	567 85.5%
	Unknown or Not Reported	0 0.0%	0 0.0%	0 0.0%
Race (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	332 participants	331 participants	663 participants
	American Indian or Alaska Native	0 0.0%	0 0.0%	0 0.0%
	Asian	83 25.0%	80 24.2%	163 24.6%
	Native Hawaiian or Other Pacific Islander	1 0.3%	0 0.0%	1 0.2%
	Black or African American	5 1.5%	5 1.5%	10 1.5%
	White	242 72.9%	246 74.3%	488 73.6%
	More than one race	1 0.3%	0 0.0%	1 0.2%
	Unknown or Not Reported	0 0.0%	0 0.0%	0 0.0%
Baseline High Resolution Computed Tomography (HRCT) fibrotic pattern [1]; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	332 participants	331 participants	663 participants
	UIP-like fibrotic pattern only	206 62.0%	206 62.2%	412 62.1%
	Other fibrotic patterns	126 38.0%	125 37.8%	251 37.9%
		[1] Measure Description: HRCT fibrotic pattern, i.e. imaging pattern of the lung disease on high-resolution computed tomography assessed by central review. HRCT fibrotic pattern had two categories: 'Usual Interstitial Pneumonia (UIP)-like fibrotic pattern only', 'Other fibrotic patterns'.
Baseline Forced Vital Capacity (FVC) - Overall Population [1]; Mean (Standard Deviation); Unit of measure: Milliliter (mL)
	Number Analyzed	332 participants	331 participants	663 participants
		2340.07 (740.19)	2321.15 (727.97)	2330.62 (733.62)
		[1] Measure Description: FVC is the volume of air (measured in milliliter) which can be forcibly exhaled from the lungs after taking the deepest breath possible.
Baseline FVC - Participants with HRCT fibrotic pattern=UIP-like fibrotic pattern only [1] [2]; Mean (Standard Deviation); Unit of measure: Milliliter (mL)
	Number Analyzed	206 participants	206 participants	412 participants
		2363.43 (762.89)	2373.59 (720.05)	2368.51 (740.89)
		[1] Measure Description: FVC is the volume of air (measured in milliliter) which can be forcibly exhaled from the lungs after taking the deepest breath possible.; [2] Measure Analysis Population Description: All randomized participants with HRCT fibrotic pattern=UIP-like fibrotic pattern only who received at least 1 dose of trial medication.

Outcome Measures

1. Primary Outcome

Title	Annual Rate of Decline in Forced Vital Capacity - Overall Population
Description	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.
Time Frame	Baseline, 2, 4, 6, 12, 24, 36, 52 weeks after first drug intake (planned post-baseline visits)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	150 mg Nintedanib	Placebo
Arm/Group Description:	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).	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 Number of Participants Analyzed	332	331
Least Squares Mean (95% Confidence Interval); Unit of Measure: Milliliter per year
	-80.82; (-110.42 to -51.22)	-187.78; (-216.92 to -158.64)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	150 mg Nintedanib, Placebo
	Comments	The decrease in FVC was assumed to be linear within each participant over 52 weeks. The intercepts and slopes were assumed to be normally distributed with unstructured covariance matrix. The within participant error was assumed to be independent and normally distributed with mean 0 and a common variance. The Kenward-Roger approximation was used to estimate denominator degrees of freedom and adjust standard errors (SEs).
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<.0001
	Comments	Treatment comparison of slopes was assessed through the treatment-by-time interaction coefficient. P-value was not adjusted for multiple comparisons.
	Method	Mixed Models Analysis
	Comments	Fixed effects: Treatment, HRCT fibrotic pattern, baseline FVC (mL), treatment-by-time, baseline-by-time interactions. Random effects: time, intercept.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	106.96
	Confidence Interval	(2-Sided) 95%; 65.42 to 148.50
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 21.15
	Estimation Comments	Difference of adjusted annual rates of decline was calculated as Nintedanib - Placebo.

2. Primary Outcome

Title	Annual Rate of Decline in Forced Vital Capacity - Participants With HRCT Fibrotic Pattern=UIP-like Fibrotic Pattern Only
Description	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.
Time Frame	Baseline, 2, 4, 6, 12, 24, 36, 52 weeks after first drug intake (planned post-baseline visits)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	150 mg Nintedanib	Placebo
Arm/Group Description:	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).	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 Number of Participants Analyzed	206	206
Least Squares Mean (95% Confidence Interval); Unit of Measure: Milliliter per year
	-82.87; (-123.73 to -42.02)	-211.07; (-251.38 to -170.77)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	150 mg Nintedanib, Placebo
	Comments	The decrease in FVC was assumed to be linear within each participant over 52 weeks. The intercepts and slopes were assumed to be normally distributed with unstructured covariance matrix. The within participant error was assumed to be independent and normally distributed with mean 0 and a common variance. The Kenward-Roger approximation was used to estimate denominator degrees of freedom and adjust standard errors (SEs).
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<.0001
	Comments	Treatment comparison of slopes was assessed through the treatment-by-time interaction coefficient. P-value was not adjusted for multiple comparisons.
	Method	Mixed Models Analysis
	Comments	Fixed effects: Treatment, baseline FVC (mL), treatment-by-time, baseline-by-time interactions. Random effects: time, intercept.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	128.20
	Confidence Interval	(2-Sided) 95%; 70.81 to 185.59
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 29.17
	Estimation Comments	Difference of adjusted annual rates of decline was calculated as Nintedanib - Placebo.

3. Secondary Outcome

Title	Absolute Change From Baseline in King's Brief Interstitial Lung Disease Questionnaire (K-BILD) Total Score at Week 52 - Overall Population
Description	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.
Time Frame	Baseline, 12, 24, 36, 52 weeks after first drug intake (planned post-baseline visits)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	150 mg Nintedanib	Placebo
Arm/Group Description:	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).	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 Number of Participants Analyzed	332	330
Least Squares Mean (95% Confidence Interval); Unit of Measure: Unit on scale
	0.55; (-0.62 to 1.72)	-0.79; (-1.94 to 0.37)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	150 mg Nintedanib, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Other
	Comments	No formal hypotheses were tested.
Statistical Test of Hypothesis	P-Value	0.1115
	Comments	[Not Specified]
	Method	Mixed Model Repeated Measures (MMRM)
	Comments	Fixed effects: baseline K-BILD Total score, visit, treatment-by-visit and baseline-by-visit interactions, random effect: participant.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	1.34
	Confidence Interval	(2-Sided) 95%; -0.31 to 2.98
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.84
	Estimation Comments	Adjusted mean difference was calculated as Nintedanib - Placebo.

4. Secondary Outcome

Title	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
Description	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.
Time Frame	Baseline, 12, 24, 36, 52 weeks after first drug intake (planned post-baseline visits)

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	150 mg Nintedanib	Placebo
Arm/Group Description:	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).	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 Number of Participants Analyzed	206	205
Least Squares Mean (95% Confidence Interval); Unit of Measure: Unit on scale
	0.75; (-0.82 to 2.31)	-0.78; (-2.34 to 0.78)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	150 mg Nintedanib, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Other
	Comments	No formal hypotheses were tested.
Statistical Test of Hypothesis	P-Value	0.1747
	Comments	[Not Specified]
	Method	Mixed Model Repeated Measures (MMRM)
	Comments	Fixed effects: baseline K-BILD Total score, visit, treatment-by-visit and baseline-by-visit interactions, random effect: participant.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	1.53
	Confidence Interval	(2-Sided) 95%; -0.68 to 3.74
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.12
	Estimation Comments	Adjusted mean difference was calculated as Nintedanib - Placebo.

5. Secondary Outcome

Title	Time to First Acute Interstitial Lung Disease (ILD) Exacerbation or Death Over 52 Weeks - Overall Population
Description	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.
Time Frame	From first drug intake until date of first acute ILD exacerbation or date of death or last contact date, up to 372 days

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	150 mg Nintedanib	Placebo
Arm/Group Description:	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).	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 Number of Participants Analyzed	332	331
Median (Inter-Quartile Range); Unit of Measure: Days
	NA [1]; (NA to NA)	NA [1]; (NA to NA)

[1]

Non-calculable because the 25 percentile was not reached.

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	150 mg Nintedanib, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Other
	Comments	No formal hypotheses were tested.
Statistical Test of Hypothesis	P-Value	0.3948
	Comments	[Not Specified]
	Method	Log Rank
	Comments	Stratified by HRCT fibrotic pattern.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.80
	Confidence Interval	(2-Sided) 95%; 0.48 to 1.34
	Estimation Comments	A Cox proportional hazards model, stratified by HRCT fibrotic pattern, was used to estimate the hazard ratio calculated as Nintedanib divided by Placebo.

6. Secondary Outcome

Title	Time to First Acute Interstitial Lung Disease (ILD) Exacerbation or Death Over 52 Weeks - Participants With HRCT Fibrotic Pattern=UIP-like Fibrotic Pattern Only
Description	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.
Time Frame	From first drug intake until date of first acute ILD exacerbation or date of death or last contact date, up to 372 days

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	150 mg Nintedanib	Placebo
Arm/Group Description:	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).	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 Number of Participants Analyzed	206	206
Median (Inter-Quartile Range); Unit of Measure: Days
	NA [1]; (NA to NA)	NA [1]; (NA to NA)

[1]

Non-calculable because the 25 percentile was not reached.

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	150 mg Nintedanib, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Other
	Comments	No formal hypotheses were tested.
Statistical Test of Hypothesis	P-Value	0.1985
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.67
	Confidence Interval	(2-Sided) 95%; 0.36 to 1.24
	Estimation Comments	A Cox proportional hazards model was used to estimate the hazard ratio calculated as Nintedanib divided by Placebo.

7. Secondary Outcome

Title	Time to Death Over 52 Weeks - Overall Population
Description	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.
Time Frame	From first drug intake until date of death or last contact date, up to 372 days

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	150 mg Nintedanib	Placebo
Arm/Group Description:	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).	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 Number of Participants Analyzed	332	331
Median (Inter-Quartile Range); Unit of Measure: Days
	NA [1]; (NA to NA)	NA [1]; (NA to NA)

[1]

Non-calculable because the 25 percentile was not reached.

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	150 mg Nintedanib, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Other
	Comments	No formal hypotheses were tested.
Statistical Test of Hypothesis	P-Value	0.8544
	Comments	[Not Specified]
	Method	Log Rank
	Comments	Stratified by HRCT fibrotic pattern.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.94
	Confidence Interval	(2-Sided) 95%; 0.47 to 1.86
	Estimation Comments	A Cox proportional hazards model, stratified by HRCT fibrotic pattern, was used to estimate the hazard ratio calculated as Nintedanib divided by Placebo.

8. Secondary Outcome

Title	Time to Death Over 52 Weeks - Participants With HRCT Fibrotic Pattern=UIP-like Fibrotic Pattern Only
Description	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.
Time Frame	From first drug intake until date of death or last contact date, up to 372 days

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	150 mg Nintedanib	Placebo
Arm/Group Description:	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).	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 Number of Participants Analyzed	206	206
Median (Inter-Quartile Range); Unit of Measure: Days
	NA [1]; (NA to NA)	NA [1]; (NA to NA)

[1]

Non-calculable because the 25 percentile was not reached.

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	150 mg Nintedanib, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Other
	Comments	No formal hypotheses were tested.
Statistical Test of Hypothesis	P-Value	0.3291
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.68
	Confidence Interval	(2-Sided) 95%; 0.32 to 1.47
	Estimation Comments	A Cox proportional hazards model was used to estimate the hazard ratio calculated as Nintedanib divided by Placebo.

9. Secondary Outcome

Title	Time to Death Due to Respiratory Cause Over 52 Weeks - Overall Population
Description	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.
Time Frame	From date of first trial drug intake up to date of death from respiratory causes or last contact date, up to 372 days

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	150 mg Nintedanib	Placebo
Arm/Group Description:	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).	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 Number of Participants Analyzed	332	331
Median (Inter-Quartile Range); Unit of Measure: Days
	NA [1]; (NA to NA)	NA [1]; (NA to NA)

[1]

Non-calculable because the 25 percentile was not reached.

10. Secondary Outcome

Title	Time to Death Due to Respiratory Cause Over 52 Weeks - Participants With HRCT Fibrotic Pattern=UIP-like Fibrotic Pattern Only
Description	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.
Time Frame	From date of first trial drug intake up to date of death from respiratory causes or last contact date, up to 372 days

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	150 mg Nintedanib	Placebo
Arm/Group Description:	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).	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 Number of Participants Analyzed	206	206
Median (Inter-Quartile Range); Unit of Measure: Days
	NA [1]; (NA to NA)	NA [1]; (NA to NA)

[1]

Non-calculable because the 25 percentile was not reached.

11. Secondary Outcome

Title	Time to Progression or Death Over 52 Weeks - Overall Population
Description	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.
Time Frame	From first drug intake until date of progression or date of death or last contact date, up to 372 days

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	150 mg Nintedanib	Placebo
Arm/Group Description:	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).	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 Number of Participants Analyzed	332	331
Median (Inter-Quartile Range); Unit of Measure: Days
	NA [1]; (367 to NA)	NA [1]; (269 to NA)

[1]

Non-calculable because the 50 percentile was not reached.

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	150 mg Nintedanib, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Other
	Comments	No formal hypotheses were tested.
Statistical Test of Hypothesis	P-Value	0.0017
	Comments	[Not Specified]
	Method	Log Rank
	Comments	Stratified by HRCT fibrotic pattern.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.65
	Confidence Interval	(2-Sided) 95%; 0.49 to 0.85
	Estimation Comments	A Cox proportional hazards model, stratified by HRCT fibrotic pattern, was used to estimate the hazard ratio calculated as Nintedanib divided by Placebo.

12. Secondary Outcome

Title	Time to Progression or Death Over 52 Weeks - Participants With HRCT Fibrotic Pattern=UIP-like Fibrotic Pattern Only
Description	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.
Time Frame	From first drug intake until date of progression or date of death or last contact date, up to 372 days

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	150 mg Nintedanib	Placebo
Arm/Group Description:	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).	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 Number of Participants Analyzed	206	206
Median (Inter-Quartile Range); Unit of Measure: Days
	NA [1]; (365 to NA)	NA [1]; (254 to NA)

[1]

Non-calculable because the 50 percentile was not reached.

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	150 mg Nintedanib, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Other
	Comments	No formal hypotheses were tested.
Statistical Test of Hypothesis	P-Value	0.0081
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.64
	Confidence Interval	(2-Sided) 95%; 0.45 to 0.89
	Estimation Comments	A Cox proportional hazards model was used to estimate the hazard ratio calculated as Nintedanib divided by Placebo.

13. Secondary Outcome

Title	Percentage of Participants With a Relative Decline From Baseline in FVC Percent Predicted of More Than 10 Percent at Week 52 - Overall Population
Description	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).
Time Frame	Baseline and up to 52 weeks after first drug intake

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	150 mg Nintedanib	Placebo
Arm/Group Description:	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).	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 Number of Participants Analyzed	332	331
Measure Type: Number; Unit of Measure: Percentage of participants
	40.7	48.9

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	150 mg Nintedanib, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Other
	Comments	No formal hypotheses were tested.
Statistical Test of Hypothesis	P-Value	[Not Specified]
	Comments	[Not Specified]
	Method	Regression, Logistic
	Comments	Logistic regression model with continuous covariate baseline FVC % pred and binary covariate HRCT fibrotic pattern.
Method of Estimation	Estimation Parameter	Adjusted Odds Ratio
	Estimated Value	0.70
	Confidence Interval	(2-Sided) 95%; 0.52 to 0.96
	Estimation Comments	Ratio calculated as Nintedanib divided by Placebo.

14. Secondary Outcome

Title	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
Description	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).
Time Frame	Baseline and up to 52 weeks after first drug intake

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	150 mg Nintedanib	Placebo
Arm/Group Description:	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).	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 Number of Participants Analyzed	206	206
Measure Type: Number; Unit of Measure: Percentage of participants
	41.3	52.4

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	150 mg Nintedanib, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Other
	Comments	No formal hypotheses were tested.
Statistical Test of Hypothesis	P-Value	[Not Specified]
	Comments	[Not Specified]
	Method	Regression, Logistic
	Comments	Logistic regression model with continuous covariate baseline FVC % pred.
Method of Estimation	Estimation Parameter	Adjusted Odds Ratio
	Estimated Value	0.63
	Confidence Interval	(2-Sided) 95%; 0.43 to 0.94
	Estimation Comments	Ratio calculated as Nintedanib divided by Placebo.

15. Secondary Outcome

Title	Percentage of Participants With a Relative Decline From Baseline in FVC Percent Predicted of More Than 5 Percent at Week 52 - Overall Population
Description	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).
Time Frame	Baseline and up to 52 weeks after first drug intake

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	150 mg Nintedanib	Placebo
Arm/Group Description:	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).	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 Number of Participants Analyzed	332	331
Measure Type: Number; Unit of Measure: Percentage of participants
	52.4	68.6

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	150 mg Nintedanib, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Other
	Comments	No formal hypotheses were tested.
Statistical Test of Hypothesis	P-Value	[Not Specified]
	Comments	[Not Specified]
	Method	Regression, Logistic
	Comments	Logistic regression model with continuous covariate baseline FVC % pred and binary covariate HRCT fibrotic pattern.
Method of Estimation	Estimation Parameter	Adjusted Odds Ratio
	Estimated Value	0.50
	Confidence Interval	(2-Sided) 95%; 0.36 to 0.68
	Estimation Comments	Ratio calculated as Nintedanib divided by Placebo.

16. Secondary Outcome

Title	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
Description	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).
Time Frame	Baseline and up to 52 weeks after first drug intake

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	150 mg Nintedanib	Placebo
Arm/Group Description:	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).	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 Number of Participants Analyzed	206	206
Measure Type: Number; Unit of Measure: Percentage of participants
	52.4	70.4

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	150 mg Nintedanib, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Other
	Comments	No formal hypotheses were tested.
Statistical Test of Hypothesis	P-Value	[Not Specified]
	Comments	[Not Specified]
	Method	Regression, Logistic
	Comments	Logistic regression model with continuous covariate baseline FVC % pred.
Method of Estimation	Estimation Parameter	Adjusted Odds Ratio
	Estimated Value	0.46
	Confidence Interval	(2-Sided) 95%; 0.31 to 0.69
	Estimation Comments	Ratio calculated as Nintedanib divided by Placebo.

17. Secondary Outcome

Title	Absolute Change From Baseline in Living With Pulmonary Fibrosis (L-PF) Symptoms Dyspnea Domain Score at Week 52 - Overall Population
Description	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).
Time Frame	Baseline, 12, 24, 36, 52 weeks after first drug intake (planned post-baseline visits)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	150 mg Nintedanib	Placebo
Arm/Group Description:	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).	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 Number of Participants Analyzed	329	323
Least Squares Mean (95% Confidence Interval); Unit of Measure: Unit on scale
	4.28; (2.43 to 6.14)	7.81; (5.97 to 9.66)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	150 mg Nintedanib, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Other
	Comments	No formal hypotheses were tested.
Statistical Test of Hypothesis	P-Value	[Not Specified]
	Comments	[Not Specified]
	Method	Mixed Model Repeated Measures
	Comments	Fixed effects: baseline, HRCT fibrotic pattern, visit, treatment-by-visit interaction, baseline-by-visit interaction, random effect: participant.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	-3.53
	Confidence Interval	(2-Sided) 95%; -6.14 to -0.92
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.33
	Estimation Comments	Adjusted mean difference was calculated as Nintedanib - Placebo.

18. Secondary Outcome

Title	Absolute Change From Baseline in L-PF Symptoms Dyspnea Domain Score at Week 52 - Participants With HRCT Fibrotic Pattern=UIP-like Fibrotic Pattern Only
Description	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).
Time Frame	Baseline, 12, 24, 36, 52 weeks after first drug intake (planned post-baseline visits)

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	150 mg Nintedanib	Placebo
Arm/Group Description:	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).	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 Number of Participants Analyzed	204	201
Least Squares Mean (95% Confidence Interval); Unit of Measure: Unit on scale
	4.14; (1.81 to 6.47)	8.32; (5.99 to 10.66)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	150 mg Nintedanib, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Other
	Comments	No formal hypotheses were tested.
Statistical Test of Hypothesis	P-Value	[Not Specified]
	Comments	[Not Specified]
	Method	Mixed Model Repeated Measures
	Comments	Fixed effects: baseline, visit, treatment-by-visit interaction, baseline-by-visit interaction, random effect: participant.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	-4.18
	Confidence Interval	(2-Sided) 95%; -7.48 to -0.88
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.68
	Estimation Comments	Adjusted mean difference was calculated as Nintedanib - Placebo.

19. Secondary Outcome

Title	Absolute Change From Baseline in L-PF Symptoms Cough Domain Score at Week 52 - Overall Population
Description	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).
Time Frame	Baseline, 12, 24, 36, 52 weeks after first drug intake (planned post-baseline visits)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	150 mg Nintedanib	Placebo
Arm/Group Description:	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).	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 Number of Participants Analyzed	327	320
Least Squares Mean (95% Confidence Interval); Unit of Measure: Unit on scale
	-1.84; (-4.36 to 0.69)	4.25; (1.74 to 6.76)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	150 mg Nintedanib, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Other
	Comments	No formal hypotheses were tested.
Statistical Test of Hypothesis	P-Value	[Not Specified]
	Comments	[Not Specified]
	Method	Mixed Model Repeated Measures
	Comments	Fixed effects: baseline, HRCT fibrotic pattern, visit, treatment-by-visit interaction, baseline-by-visit interaction, random effect: participant.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	-6.09
	Confidence Interval	(2-Sided) 95%; -9.65 to -2.53
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.81
	Estimation Comments	Adjusted mean difference was calculated as Nintedanib - Placebo.

20. Secondary Outcome

Title	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
Description	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).
Time Frame	Baseline, 12, 24, 36, 52 weeks after first drug intake (planned post-baseline visits)

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	150 mg Nintedanib	Placebo
Arm/Group Description:	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).	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 Number of Participants Analyzed	203	199
Least Squares Mean (95% Confidence Interval); Unit of Measure: Unit on scale
	-3.20; (-6.43 to 0.04)	4.09; (0.85 to 7.32)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	150 mg Nintedanib, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Other
	Comments	No formal hypotheses were tested.
Statistical Test of Hypothesis	P-Value	[Not Specified]
	Comments	[Not Specified]
	Method	Mixed Model Repeated Measures
	Comments	Fixed effects: baseline, visit, treatment-by-visit interaction, baseline-by-visit interaction, random effect: participant.
Method of Estimation	Estimation Parameter	Adjusted mean difference
	Estimated Value	-7.28
	Confidence Interval	(2-Sided) 95%; -11.86 to -2.71
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.33
	Estimation Comments	Adjusted mean difference was calculated as Nintedanib - Placebo.

Adverse Events

Time Frame	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.
Adverse Event Reporting Description	All participants who signed the informed consent.
Arm/Group Title	Nintedanib	Placebo
Arm/Group Description	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).	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).
All-Cause Mortality
	Nintedanib	Placebo
	Affected / at Risk (%)	Affected / at Risk (%)
Total	36/332 (10.84%)	45/331 (13.60%)
Serious Adverse Events
	Nintedanib	Placebo
	Affected / at Risk (%)	Affected / at Risk (%)
Total	147/332 (44.28%)	164/331 (49.55%)
Blood and lymphatic system disorders
Blood loss anaemia † 1	1/332 (0.30%)	0/331 (0.00%)
Disseminated intravascular coagulation † 1	0/332 (0.00%)	1/331 (0.30%)
Leukocytosis † 1	0/332 (0.00%)	1/331 (0.30%)
Pancytopenia † 1	0/332 (0.00%)	1/331 (0.30%)
Cardiac disorders
Acute coronary syndrome † 1	0/332 (0.00%)	1/331 (0.30%)
Acute myocardial infarction † 1	3/332 (0.90%)	1/331 (0.30%)
Angina pectoris † 1	2/332 (0.60%)	3/331 (0.91%)
Angina unstable † 1	0/332 (0.00%)	1/331 (0.30%)
Arteriosclerosis coronary artery † 1	1/332 (0.30%)	0/331 (0.00%)
Atrial fibrillation † 1	5/332 (1.51%)	1/331 (0.30%)
Atrial flutter † 1	1/332 (0.30%)	2/331 (0.60%)
Atrial thrombosis † 1	0/332 (0.00%)	1/331 (0.30%)
Bradycardia † 1	1/332 (0.30%)	0/331 (0.00%)
Bundle branch block left † 1	0/332 (0.00%)	1/331 (0.30%)
Cardiac arrest † 1	1/332 (0.30%)	0/331 (0.00%)
Cardiac failure † 1	3/332 (0.90%)	2/331 (0.60%)
Cardiac failure chronic † 1	1/332 (0.30%)	0/331 (0.00%)
Cardiac failure congestive † 1	1/332 (0.30%)	2/331 (0.60%)
Chronic right ventricular failure † 1	0/332 (0.00%)	1/331 (0.30%)
Cor pulmonale acute † 1	0/332 (0.00%)	1/331 (0.30%)
Coronary artery disease † 1	1/332 (0.30%)	3/331 (0.91%)
Coronary artery occlusion † 1	1/332 (0.30%)	0/331 (0.00%)
Ischaemic cardiomyopathy † 1	0/332 (0.00%)	1/331 (0.30%)
Long QT syndrome † 1	0/332 (0.00%)	1/331 (0.30%)
Myocardial infarction † 1	2/332 (0.60%)	2/331 (0.60%)
Myocardial ischaemia † 1	1/332 (0.30%)	1/331 (0.30%)
Prinzmetal angina † 1	0/332 (0.00%)	1/331 (0.30%)
Right ventricular failure † 1	1/332 (0.30%)	1/331 (0.30%)
Supraventricular tachycardia † 1	1/332 (0.30%)	0/331 (0.00%)
Systolic anterior motion of mitral valve † 1	0/332 (0.00%)	1/331 (0.30%)
Ear and labyrinth disorders
Deafness unilateral † 1	0/332 (0.00%)	1/331 (0.30%)
Mixed deafness † 1	1/332 (0.30%)	0/331 (0.00%)
Vertigo † 1	0/332 (0.00%)	1/331 (0.30%)
Endocrine disorders
Inappropriate antidiuretic hormone secretion † 1	0/332 (0.00%)	1/331 (0.30%)
Eye disorders
Amaurosis fugax † 1	0/332 (0.00%)	1/331 (0.30%)
Cataract † 1	1/332 (0.30%)	2/331 (0.60%)
Glaucoma † 1	1/332 (0.30%)	1/331 (0.30%)
Retinal artery occlusion † 1	0/332 (0.00%)	1/331 (0.30%)
Retinal vascular thrombosis † 1	1/332 (0.30%)	0/331 (0.00%)
Gastrointestinal disorders
Abdominal pain † 1	1/332 (0.30%)	1/331 (0.30%)
Abdominal pain upper † 1	0/332 (0.00%)	1/331 (0.30%)
Colitis ischaemic † 1	1/332 (0.30%)	0/331 (0.00%)
Constipation † 1	1/332 (0.30%)	0/331 (0.00%)
Diarrhoea † 1	3/332 (0.90%)	0/331 (0.00%)
Dyspepsia † 1	1/332 (0.30%)	0/331 (0.00%)
Enterocolitis haemorrhagic † 1	0/332 (0.00%)	1/331 (0.30%)
Gastrointestinal haemorrhage † 1	3/332 (0.90%)	0/331 (0.00%)
Gastrooesophageal reflux disease † 1	1/332 (0.30%)	0/331 (0.00%)
Haematemesis † 1	1/332 (0.30%)	0/331 (0.00%)
Haemorrhoids † 1	1/332 (0.30%)	0/331 (0.00%)
Ileus † 1	0/332 (0.00%)	3/331 (0.91%)
Pancreatitis † 1	1/332 (0.30%)	0/331 (0.00%)
Pancreatitis acute † 1	1/332 (0.30%)	0/331 (0.00%)
Rectal prolapse † 1	1/332 (0.30%)	0/331 (0.00%)
General disorders
Asthenia † 1	1/332 (0.30%)	0/331 (0.00%)
Cardiac death † 1	0/332 (0.00%)	1/331 (0.30%)
Chest pain † 1	0/332 (0.00%)	1/331 (0.30%)
Condition aggravated † 1	2/332 (0.60%)	1/331 (0.30%)
Death † 1	1/332 (0.30%)	0/331 (0.00%)
Discomfort † 1	0/332 (0.00%)	1/331 (0.30%)
Disease progression † 1	0/332 (0.00%)	2/331 (0.60%)
General physical health deterioration † 1	0/332 (0.00%)	1/331 (0.30%)
Pyrexia † 1	0/332 (0.00%)	1/331 (0.30%)
Sudden cardiac death † 1	0/332 (0.00%)	1/331 (0.30%)
Sudden death † 1	0/332 (0.00%)	1/331 (0.30%)
Hepatobiliary disorders
Cholecystitis acute † 1	1/332 (0.30%)	0/331 (0.00%)
Cholelithiasis † 1	1/332 (0.30%)	1/331 (0.30%)
Drug-induced liver injury † 1	6/332 (1.81%)	0/331 (0.00%)
Hepatic cirrhosis † 1	1/332 (0.30%)	1/331 (0.30%)
Liver injury † 1	3/332 (0.90%)	2/331 (0.60%)
Infections and infestations
Adenovirus infection † 1	0/332 (0.00%)	1/331 (0.30%)
Appendicitis † 1	2/332 (0.60%)	0/331 (0.00%)
Atypical pneumonia † 1	1/332 (0.30%)	0/331 (0.00%)
Bacterial sepsis † 1	1/332 (0.30%)	0/331 (0.00%)
Bronchitis † 1	4/332 (1.20%)	5/331 (1.51%)
Bronchopulmonary aspergillosis † 1	2/332 (0.60%)	2/331 (0.60%)
Cellulitis † 1	1/332 (0.30%)	1/331 (0.30%)
Clostridium difficile colitis † 1	1/332 (0.30%)	0/331 (0.00%)
Diverticulitis † 1	2/332 (0.60%)	0/331 (0.00%)
Encephalitis † 1	0/332 (0.00%)	1/331 (0.30%)
Febrile infection † 1	0/332 (0.00%)	1/331 (0.30%)
Gastroenteritis norovirus † 1	1/332 (0.30%)	0/331 (0.00%)
Herpes zoster † 1	1/332 (0.30%)	2/331 (0.60%)
Herpes zoster oticus † 1	1/332 (0.30%)	0/331 (0.00%)
Infectious pleural effusion † 1	0/332 (0.00%)	1/331 (0.30%)
Influenza † 1	4/332 (1.20%)	4/331 (1.21%)
Leishmaniasis † 1	0/332 (0.00%)	1/331 (0.30%)
Localised infection † 1	1/332 (0.30%)	0/331 (0.00%)
Lower respiratory tract infection † 1	1/332 (0.30%)	3/331 (0.91%)
Lung infection † 1	3/332 (0.90%)	3/331 (0.91%)
Meningitis aseptic † 1	1/332 (0.30%)	0/331 (0.00%)
Metapneumovirus infection † 1	0/332 (0.00%)	1/331 (0.30%)
Orchitis † 1	1/332 (0.30%)	0/331 (0.00%)
Pneumococcal infection † 1	0/332 (0.00%)	1/331 (0.30%)
Pneumonia † 1	24/332 (7.23%)	16/331 (4.83%)
Pneumonia bacterial † 1	1/332 (0.30%)	3/331 (0.91%)
Pneumonia legionella † 1	1/332 (0.30%)	0/331 (0.00%)
Pneumonia pneumococcal † 1	0/332 (0.00%)	3/331 (0.91%)
Pneumonia viral † 1	0/332 (0.00%)	2/331 (0.60%)
Pseudomembranous colitis † 1	1/332 (0.30%)	0/331 (0.00%)
Pulmonary sepsis † 1	1/332 (0.30%)	0/331 (0.00%)
Pyelonephritis acute † 1	1/332 (0.30%)	0/331 (0.00%)
Respiratory syncytial virus infection † 1	0/332 (0.00%)	1/331 (0.30%)
Respiratory tract infection † 1	3/332 (0.90%)	3/331 (0.91%)
Sepsis † 1	1/332 (0.30%)	2/331 (0.60%)
Septic shock † 1	2/332 (0.60%)	0/331 (0.00%)
Sinusitis † 1	0/332 (0.00%)	1/331 (0.30%)
Skin infection † 1	1/332 (0.30%)	0/331 (0.00%)
Staphylococcal sepsis † 1	1/332 (0.30%)	0/331 (0.00%)
Urinary tract infection † 1	2/332 (0.60%)	1/331 (0.30%)
Urosepsis † 1	0/332 (0.00%)	1/331 (0.30%)
Viral infection † 1	1/332 (0.30%)	0/331 (0.00%)
Viral upper respiratory tract infection † 1	1/332 (0.30%)	0/331 (0.00%)
Injury, poisoning and procedural complications
Anastomotic stenosis † 1	0/332 (0.00%)	1/331 (0.30%)
Coronary artery restenosis † 1	1/332 (0.30%)	0/331 (0.00%)
Fall † 1	3/332 (0.90%)	4/331 (1.21%)
Humerus fracture † 1	1/332 (0.30%)	1/331 (0.30%)
Lower limb fracture † 1	0/332 (0.00%)	1/331 (0.30%)
Rib fracture † 1	0/332 (0.00%)	1/331 (0.30%)
Spinal compression fracture † 1	1/332 (0.30%)	2/331 (0.60%)
Spinal fracture † 1	2/332 (0.60%)	1/331 (0.30%)
Subdural haematoma † 1	0/332 (0.00%)	1/331 (0.30%)
Thoracic vertebral fracture † 1	1/332 (0.30%)	0/331 (0.00%)
Wrist fracture † 1	1/332 (0.30%)	1/331 (0.30%)
Investigations
Alanine aminotransferase increased † 1	2/332 (0.60%)	1/331 (0.30%)
Aspartate aminotransferase increased † 1	2/332 (0.60%)	1/331 (0.30%)
Blood lactate dehydrogenase increased † 1	0/332 (0.00%)	1/331 (0.30%)
Electrocardiogram Q wave abnormal † 1	0/332 (0.00%)	1/331 (0.30%)
Gamma-glutamyltransferase increased † 1	0/332 (0.00%)	1/331 (0.30%)
Hepatic enzyme increased † 1	1/332 (0.30%)	1/331 (0.30%)
Rotavirus test positive † 1	1/332 (0.30%)	0/331 (0.00%)
Transaminases increased † 1	1/332 (0.30%)	0/331 (0.00%)
Metabolism and nutrition disorders
Decreased appetite † 1	0/332 (0.00%)	1/331 (0.30%)
Diabetes mellitus † 1	0/332 (0.00%)	1/331 (0.30%)
Fluid overload † 1	0/332 (0.00%)	1/331 (0.30%)
Hyperglycaemia † 1	0/332 (0.00%)	1/331 (0.30%)
Hypervolaemia † 1	0/332 (0.00%)	1/331 (0.30%)
Hypokalaemia † 1	1/332 (0.30%)	0/331 (0.00%)
Malnutrition † 1	0/332 (0.00%)	1/331 (0.30%)
Musculoskeletal and connective tissue disorders
Arthralgia † 1	1/332 (0.30%)	1/331 (0.30%)
Back pain † 1	0/332 (0.00%)	2/331 (0.60%)
Connective tissue disorder † 1	0/332 (0.00%)	1/331 (0.30%)
Groin pain † 1	0/332 (0.00%)	1/331 (0.30%)
Intervertebral disc protrusion † 1	1/332 (0.30%)	1/331 (0.30%)
Lumbar spinal stenosis † 1	0/332 (0.00%)	1/331 (0.30%)
Myositis † 1	0/332 (0.00%)	1/331 (0.30%)
Osteoarthritis † 1	2/332 (0.60%)	0/331 (0.00%)
Osteonecrosis † 1	0/332 (0.00%)	1/331 (0.30%)
Osteoporosis † 1	0/332 (0.00%)	1/331 (0.30%)
Polymyositis † 1	1/332 (0.30%)	0/331 (0.00%)
Rotator cuff syndrome † 1	0/332 (0.00%)	1/331 (0.30%)
Scleroderma † 1	1/332 (0.30%)	1/331 (0.30%)
Sjogren's syndrome † 1	1/332 (0.30%)	1/331 (0.30%)
Spinal pain † 1	1/332 (0.30%)	0/331 (0.00%)
Spinal stenosis † 1	0/332 (0.00%)	1/331 (0.30%)
Systemic lupus erythematosus † 1	0/332 (0.00%)	2/331 (0.60%)
Systemic scleroderma † 1	1/332 (0.30%)	0/331 (0.00%)
Winged scapula † 1	0/332 (0.00%)	1/331 (0.30%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Basal cell carcinoma † 1	2/332 (0.60%)	4/331 (1.21%)
Bladder cancer † 1	1/332 (0.30%)	0/331 (0.00%)
Bowen's disease † 1	0/332 (0.00%)	1/331 (0.30%)
Bronchial carcinoma † 1	1/332 (0.30%)	0/331 (0.00%)
Cancer pain † 1	0/332 (0.00%)	1/331 (0.30%)
Colon cancer † 1	1/332 (0.30%)	0/331 (0.00%)
Gallbladder adenocarcinoma † 1	0/332 (0.00%)	1/331 (0.30%)
Hepatic cancer † 1	1/332 (0.30%)	0/331 (0.00%)
Hepatocellular carcinoma † 1	1/332 (0.30%)	0/331 (0.00%)
Lung neoplasm malignant † 1	1/332 (0.30%)	1/331 (0.30%)
Lung squamous cell carcinoma metastatic † 1	0/332 (0.00%)	1/331 (0.30%)
Lymphangiosis carcinomatosa † 1	0/332 (0.00%)	1/331 (0.30%)
Neoplasm malignant † 1	0/332 (0.00%)	2/331 (0.60%)
Salivary gland adenoma † 1	0/332 (0.00%)	1/331 (0.30%)
Skin cancer † 1	0/332 (0.00%)	1/331 (0.30%)
Small cell lung cancer † 1	2/332 (0.60%)	0/331 (0.00%)
Squamous cell carcinoma † 1	0/332 (0.00%)	1/331 (0.30%)
Squamous cell carcinoma of lung † 1	0/332 (0.00%)	1/331 (0.30%)
Transitional cell carcinoma † 1	1/332 (0.30%)	0/331 (0.00%)
Nervous system disorders
Cerebellar infarction † 1	1/332 (0.30%)	0/331 (0.00%)
Cerebral haemorrhage † 1	0/332 (0.00%)	1/331 (0.30%)
Cerebral infarction † 1	1/332 (0.30%)	0/331 (0.00%)
Cerebrovascular accident † 1	1/332 (0.30%)	0/331 (0.00%)
Dementia † 1	1/332 (0.30%)	0/331 (0.00%)
Hypokinesia † 1	0/332 (0.00%)	1/331 (0.30%)
Loss of consciousness † 1	1/332 (0.30%)	1/331 (0.30%)
Neuropathy peripheral † 1	1/332 (0.30%)	0/331 (0.00%)
Sciatica † 1	1/332 (0.30%)	0/331 (0.00%)
Syncope † 1	1/332 (0.30%)	0/331 (0.00%)
Transient ischaemic attack † 1	0/332 (0.00%)	3/331 (0.91%)
Psychiatric disorders
Anxiety disorder † 1	1/332 (0.30%)	0/331 (0.00%)
Drug abuse † 1	0/332 (0.00%)	1/331 (0.30%)
Suicide attempt † 1	0/332 (0.00%)	1/331 (0.30%)
Renal and urinary disorders
Acute kidney injury † 1	3/332 (0.90%)	0/331 (0.00%)
Calculus bladder † 1	0/332 (0.00%)	1/331 (0.30%)
Glomerulonephritis † 1	1/332 (0.30%)	0/331 (0.00%)
Haematuria † 1	1/332 (0.30%)	0/331 (0.00%)
Nephrolithiasis † 1	0/332 (0.00%)	1/331 (0.30%)
Renal failure † 1	1/332 (0.30%)	0/331 (0.00%)
Ureterolithiasis † 1	0/332 (0.00%)	1/331 (0.30%)
Urinary tract obstruction † 1	0/332 (0.00%)	1/331 (0.30%)
Reproductive system and breast disorders
Prostatitis † 1	1/332 (0.30%)	0/331 (0.00%)
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure † 1	16/332 (4.82%)	7/331 (2.11%)
Asthma † 1	0/332 (0.00%)	1/331 (0.30%)
Chronic respiratory failure † 1	1/332 (0.30%)	6/331 (1.81%)
Cough † 1	0/332 (0.00%)	1/331 (0.30%)
Dyspnoea † 1	6/332 (1.81%)	13/331 (3.93%)
Eosinophilic pneumonia chronic † 1	1/332 (0.30%)	0/331 (0.00%)
Haemoptysis † 1	0/332 (0.00%)	1/331 (0.30%)
Hypersensitivity pneumonitis † 1	2/332 (0.60%)	4/331 (1.21%)
Hypoxia † 1	3/332 (0.90%)	0/331 (0.00%)
Idiopathic interstitial pneumonia † 1	2/332 (0.60%)	1/331 (0.30%)
Interstitial lung disease † 1	19/332 (5.72%)	45/331 (13.60%)
Lung disorder † 1	0/332 (0.00%)	1/331 (0.30%)
Organising pneumonia † 1	2/332 (0.60%)	0/331 (0.00%)
Pleuritic pain † 1	1/332 (0.30%)	0/331 (0.00%)
Pneumomediastinum † 1	2/332 (0.60%)	1/331 (0.30%)
Pneumonia aspiration † 1	0/332 (0.00%)	2/331 (0.60%)
Pneumonitis † 1	1/332 (0.30%)	0/331 (0.00%)
Pneumothorax † 1	6/332 (1.81%)	6/331 (1.81%)
Pneumothorax spontaneous † 1	0/332 (0.00%)	1/331 (0.30%)
Pulmonary arterial hypertension † 1	0/332 (0.00%)	2/331 (0.60%)
Pulmonary embolism † 1	1/332 (0.30%)	5/331 (1.51%)
Pulmonary fibrosis † 1	7/332 (2.11%)	5/331 (1.51%)
Pulmonary hypertension † 1	5/332 (1.51%)	9/331 (2.72%)
Pulmonary oedema † 1	0/332 (0.00%)	1/331 (0.30%)
Respiratory arrest † 1	1/332 (0.30%)	0/331 (0.00%)
Respiratory disorder † 1	0/332 (0.00%)	1/331 (0.30%)
Respiratory distress † 1	0/332 (0.00%)	3/331 (0.91%)
Respiratory failure † 1	11/332 (3.31%)	10/331 (3.02%)
Skin and subcutaneous tissue disorders
Henoch-Schonlein purpura † 1	0/332 (0.00%)	1/331 (0.30%)
Pyoderma gangrenosum † 1	0/332 (0.00%)	1/331 (0.30%)
Vascular disorders
Aortic aneurysm † 1	1/332 (0.30%)	1/331 (0.30%)
Aortic aneurysm rupture † 1	0/332 (0.00%)	1/331 (0.30%)
Arteritis † 1	0/332 (0.00%)	1/331 (0.30%)
Circulatory collapse † 1	0/332 (0.00%)	1/331 (0.30%)
Deep vein thrombosis † 1	2/332 (0.60%)	2/331 (0.60%)
Diabetic vascular disorder † 1	0/332 (0.00%)	1/331 (0.30%)
Hypertensive crisis † 1	2/332 (0.60%)	1/331 (0.30%)
Peripheral artery stenosis † 1	0/332 (0.00%)	1/331 (0.30%)
Shock haemorrhagic † 1	0/332 (0.00%)	1/331 (0.30%)
Vasculitis † 1	2/332 (0.60%)	0/331 (0.00%)
1 Term from vocabulary, MedDRA 22.0; † Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Nintedanib	Placebo
	Affected / at Risk (%)	Affected / at Risk (%)
Total	308/332 (92.77%)	266/331 (80.36%)
Gastrointestinal disorders
Abdominal pain † 1	34/332 (10.24%)	9/331 (2.72%)
Abdominal pain upper † 1	33/332 (9.94%)	6/331 (1.81%)
Constipation † 1	25/332 (7.53%)	32/331 (9.67%)
Diarrhoea † 1	239/332 (71.99%)	85/331 (25.68%)
Nausea † 1	100/332 (30.12%)	33/331 (9.97%)
Vomiting † 1	64/332 (19.28%)	16/331 (4.83%)
General disorders
Asthenia † 1	18/332 (5.42%)	14/331 (4.23%)
Chest pain † 1	17/332 (5.12%)	14/331 (4.23%)
Fatigue † 1	34/332 (10.24%)	21/331 (6.34%)
Oedema peripheral † 1	18/332 (5.42%)	22/331 (6.65%)
Pyrexia † 1	17/332 (5.12%)	18/331 (5.44%)
Hepatobiliary disorders
Hepatic function abnormal † 1	19/332 (5.72%)	3/331 (0.91%)
Infections and infestations
Bronchitis † 1	44/332 (13.25%)	62/331 (18.73%)
Nasopharyngitis † 1	54/332 (16.27%)	48/331 (14.50%)
Respiratory tract infection † 1	18/332 (5.42%)	12/331 (3.63%)
Upper respiratory tract infection † 1	26/332 (7.83%)	25/331 (7.55%)
Urinary tract infection † 1	22/332 (6.63%)	20/331 (6.04%)
Investigations
Alanine aminotransferase increased † 1	47/332 (14.16%)	12/331 (3.63%)
Aspartate aminotransferase increased † 1	41/332 (12.35%)	12/331 (3.63%)
Gamma-glutamyltransferase increased † 1	22/332 (6.63%)	6/331 (1.81%)
Weight decreased † 1	49/332 (14.76%)	18/331 (5.44%)
Metabolism and nutrition disorders
Decreased appetite † 1	54/332 (16.27%)	22/331 (6.65%)
Musculoskeletal and connective tissue disorders
Arthralgia † 1	12/332 (3.61%)	23/331 (6.95%)
Back pain † 1	28/332 (8.43%)	26/331 (7.85%)
Nervous system disorders
Dizziness † 1	19/332 (5.72%)	15/331 (4.53%)
Headache † 1	37/332 (11.14%)	27/331 (8.16%)
Psychiatric disorders
Insomnia † 1	18/332 (5.42%)	18/331 (5.44%)
Respiratory, thoracic and mediastinal disorders
Cough † 1	40/332 (12.05%)	50/331 (15.11%)
Dyspnoea † 1	49/332 (14.76%)	46/331 (13.90%)
Skin and subcutaneous tissue disorders
Pruritus † 1	12/332 (3.61%)	18/331 (5.44%)
1 Term from vocabulary, MedDRA 22.0; † Indicates events were collected by systematic assessment

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

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.

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.

Results Point of Contact

• Name/Title: Boehringer Ingelheim Call Center
• Organization: Boehringer Ingelheim
• Phone: 1-800-243-0127
• EMail: clintriage.rdg@boehringer-ingelheim.com

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Ogura T, Suda T, Inase N, Nishioka Y, Azuma A, Okamoto M, Takizawa A, Ito T, Rohr KB, Inoue Y. Effects of nintedanib on disease progression and safety in Japanese patients with progressive fibrosing interstitial lung diseases: Further subset analysis from the whole INBUILD trial. Respir Investig. 2022 Nov;60(6):787-797. doi: 10.1016/j.resinv.2022.06.009. Epub 2022 Aug 1.

Cottin V, Martinez FJ, Jenkins RG, Belperio JA, Kitamura H, Molina-Molina M, Tschoepe I, Coeck C, Lievens D, Costabel U. Safety and tolerability of nintedanib in patients with progressive fibrosing interstitial lung diseases: data from the randomized controlled INBUILD trial. Respir Res. 2022 Apr 7;23(1):85. doi: 10.1186/s12931-022-01974-2.

Swigris JJ, Bushnell DM, Rohr K, Mueller H, Baldwin M, Inoue Y. Responsiveness and meaningful change thresholds of the Living with Pulmonary Fibrosis (L-PF) questionnaire Dyspnoea and Cough scores in patients with progressive fibrosing interstitial lung diseases. BMJ Open Respir Res. 2022 Mar;9(1):e001167. doi: 10.1136/bmjresp-2021-001167.

Inoue Y, Suda T, Kitamura H, Okamoto M, Azuma A, Inase N, Kuwana M, Makino S, Nishioka Y, Ogura T, Takizawa A, Ugai H, Stowasser S, Schlenker-Herceg R, Takeuchi T. Efficacy and safety of nintedanib in Japanese patients with progressive fibrosing interstitial lung diseases: Subgroup analysis of the randomised, double-blind, placebo-controlled, phase 3 INBUILD trial. Respir Med. 2021 Oct;187:106574. doi: 10.1016/j.rmed.2021.106574. Epub 2021 Aug 12.

Flaherty KR, Wells AU, Cottin V, Devaraj A, Inoue Y, Richeldi L, Walsh SLF, Kolb M, Koschel D, Moua T, Stowasser S, Goeldner RG, Schlenker-Herceg R, Brown KK; INBUILD Trial Investigators. Nintedanib in progressive interstitial lung diseases: data from the whole INBUILD trial. Eur Respir J. 2022 Mar 17;59(3):2004538. doi: 10.1183/13993003.04538-2020. Print 2022 Mar.

Maher TM, Brown KK, Kreuter M, Devaraj A, Walsh SLF, Lancaster LH, Belloli EA, Padilla M, Behr J, Goeldner RG, Tetzlaff K, Schlenker-Herceg R, Flaherty KR; INBUILD trial investigators. Effects of nintedanib by inclusion criteria for progression of interstitial lung disease. Eur Respir J. 2022 Feb 3;59(2):2004587. doi: 10.1183/13993003.04587-2020. Print 2022 Feb.

Cottin V, Richeldi L, Rosas I, Otaola M, Song JW, Tomassetti S, Wijsenbeek M, Schmitz M, Coeck C, Stowasser S, Schlenker-Herceg R, Kolb M; INBUILD Trial Investigators. Nintedanib and immunomodulatory therapies in progressive fibrosing interstitial lung diseases. Respir Res. 2021 Mar 16;22(1):84. doi: 10.1186/s12931-021-01668-1.

Brown KK, Martinez FJ, Walsh SLF, Thannickal VJ, Prasse A, Schlenker-Herceg R, Goeldner RG, Clerisme-Beaty E, Tetzlaff K, Cottin V, Wells AU. The natural history of progressive fibrosing interstitial lung diseases. Eur Respir J. 2020 Jun 25;55(6):2000085. doi: 10.1183/13993003.00085-2020. Print 2020 Jun.

Wells AU, Flaherty KR, Brown KK, Inoue Y, Devaraj A, Richeldi L, Moua T, Crestani B, Wuyts WA, Stowasser S, Quaresma M, Goeldner RG, Schlenker-Herceg R, Kolb M; INBUILD trial investigators. Nintedanib in patients with progressive fibrosing interstitial lung diseases-subgroup analyses by interstitial lung disease diagnosis in the INBUILD trial: a randomised, double-blind, placebo-controlled, parallel-group trial. Lancet Respir Med. 2020 May;8(5):453-460. doi: 10.1016/S2213-2600(20)30036-9. Epub 2020 Mar 5.

Flaherty KR, Wells AU, Cottin V, Devaraj A, Walsh SLF, Inoue Y, Richeldi L, Kolb M, Tetzlaff K, Stowasser S, Coeck C, Clerisme-Beaty E, Rosenstock B, Quaresma M, Haeufel T, Goeldner RG, Schlenker-Herceg R, Brown KK; INBUILD Trial Investigators. Nintedanib in Progressive Fibrosing Interstitial Lung Diseases. N Engl J Med. 2019 Oct 31;381(18):1718-1727. doi: 10.1056/NEJMoa1908681. Epub 2019 Sep 29.

Flaherty KR, Brown KK, Wells AU, Clerisme-Beaty E, Collard HR, Cottin V, Devaraj A, Inoue Y, Le Maulf F, Richeldi L, Schmidt H, Walsh S, Mezzanotte W, Schlenker-Herceg R. Design of the PF-ILD trial: a double-blind, randomised, placebo-controlled phase III trial of nintedanib in patients with progressive fibrosing interstitial lung disease. BMJ Open Respir Res. 2017 Sep 17;4(1):e000212. doi: 10.1136/bmjresp-2017-000212. eCollection 2017.

• Responsible Party: Boehringer Ingelheim
• ClinicalTrials.gov Identifier: NCT02999178
• Other Study ID Numbers: 1199.247; 2015-003360-37 ( EudraCT Number )
• First Submitted: December 19, 2016
• First Posted: December 21, 2016
• Results First Submitted: April 22, 2020
• Results First Posted: May 5, 2020
• Last Update Posted: May 5, 2020