Trial Outcomes & Findings for Safety and Efficacy of BIBF 1120 at High Dose in Idiopathic Pulmonary Fibrosis Patients II (NCT NCT01335477)

Last Updated: 2016-07-25

Results Overview

Forced vital capacity (FVC) is the total amount of air exhaled during the lung function test. For this endpoint reported means represent the adjusted rate.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

551 participants

Primary outcome timeframe

52 weeks

Results posted on

2016-07-25

Participant Flow

Participant milestones

Participant milestones
Measure	Placebo Oral administration of Placebo matching nintedanib soft gelatine capsules	Nintedanib 150 mg Bid Oral administration of soft gelatine capsules of nintedanib 150mg twice daily (bid). Dose interruption and reduction to 100 mg bid dose were allowed to manage adverse events.
Overall Study STARTED	220	331
Overall Study COMPLETED	179	272
Overall Study NOT COMPLETED	41	59

Reasons for withdrawal

Reasons for withdrawal
Measure	Placebo Oral administration of Placebo matching nintedanib soft gelatine capsules	Nintedanib 150 mg Bid Oral administration of soft gelatine capsules of nintedanib 150mg twice daily (bid). Dose interruption and reduction to 100 mg bid dose were allowed to manage adverse events.
Overall Study Adverse Event	30	42
Overall Study Non compliant with protocol	0	2
Overall Study Lost to Follow-up	1	2
Overall Study Consent withdrawn, not due to AE	7	9
Overall Study Not treated	1	2
Overall Study Reason other than those stated above	2	2

Baseline Characteristics

Safety and Efficacy of BIBF 1120 at High Dose in Idiopathic Pulmonary Fibrosis Patients II

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Placebo n=219 Participants Oral administration of Placebo matching nintedanib soft gelatine capsules	Nintedanib 150 mg Bid n=329 Participants Oral administration of soft gelatine capsules of nintedanib 150mg twice daily (bid). Dose interruption and reduction to 100 mg bid dose were allowed to manage adverse events.	Total n=548 Participants Total of all reporting groups
Age, Continuous	67.1 years STANDARD_DEVIATION 7.5 • n=5 Participants	66.4 years STANDARD_DEVIATION 7.9 • n=7 Participants	66.6 years STANDARD_DEVIATION 7.8 • n=5 Participants
Sex: Female, Male Female	48 Participants n=5 Participants	73 Participants n=7 Participants	121 Participants n=5 Participants
Sex: Female, Male Male	171 Participants n=5 Participants	256 Participants n=7 Participants	427 Participants n=5 Participants

PRIMARY outcome

Timeframe: 52 weeks

Population: Treated Set

Forced vital capacity (FVC) is the total amount of air exhaled during the lung function test. For this endpoint reported means represent the adjusted rate.

Outcome measures

Outcome measures
Measure	Placebo n=219 Participants Oral administration of Placebo matching nintedanib soft gelatine capsules	Nintedanib 150 mg Bid n=329 Participants Oral administration of soft gelatine capsules of nintedanib 150mg twice daily (bid). Dose interruption and reduction to 100 mg bid dose were allowed to manage adverse events.
Annual Rate of Decline in Forced Vital Capacity (FVC) Over 52 Weeks.	-207.32 mL/year Standard Error 19.309	-113.59 mL/year Standard Error 15.726

SECONDARY outcome

Timeframe: Baseline and 52 weeks

Population: Treated Set (Only patients with observed cases (OC) values were analysed)

This is a key secondary endpoint. SGRQ is a health-related quality of life questionnaire divided into 3 components : symptoms, activity and impact. The total score (summed weights) can range from 0 to 100 with a lower score denoting a better health status. Means provided are the adjusted means based on all analyzed patients in the model (not only patients with a baseline and measurement at week 52).

Outcome measures

Outcome measures
Measure	Placebo n=213 Participants Oral administration of Placebo matching nintedanib soft gelatine capsules	Nintedanib 150 mg Bid n=320 Participants Oral administration of soft gelatine capsules of nintedanib 150mg twice daily (bid). Dose interruption and reduction to 100 mg bid dose were allowed to manage adverse events.
Change From Baseline in Saint George's Respiratory Questionnaire (SGRQ) Total Score at 52 Weeks	5.48 points on a scale Standard Error 0.891	2.80 points on a scale Standard Error 0.730

SECONDARY outcome

Timeframe: 52 weeks

Population: Treated Set

Due to rare events, the median of time to event is not calculable, thus the percentages of patients with (IPF) exacerbation are reported and represented as a key secondary endpoint. An acute exacerbation (reported as an AE by the investigator) was defined as follows: Otherwise unexplained clinical features including all of the following: Unexplained worsening or development of dyspnoea within 30 days New diffuse pulmonary infiltrates on chest X-ray, and/or new HRCT parenchymal abnormalities with no pneumothorax or pleural effusion (new ground-glass opacities) since the last visit Exclusion of infection as per routine clinical practice and microbiological studies Exclusion of alternative causes as per routine clinical practice including left heart failure, pulmonary embolism and identifiable cause of acute lung injury. Failure is the proportion of patients with at least one acute IPF exacerbation over 52 weeks, based on all investigator-reported AEs .

Outcome measures

Outcome measures
Measure	Placebo n=219 Participants Oral administration of Placebo matching nintedanib soft gelatine capsules	Nintedanib 150 mg Bid n=329 Participants Oral administration of soft gelatine capsules of nintedanib 150mg twice daily (bid). Dose interruption and reduction to 100 mg bid dose were allowed to manage adverse events.
Time to First Acute Idiopathic Pulmonary Fibrosis (IPF) Exacerbation Censored	90.4 percentage of participants	96.4 percentage of participants
Time to First Acute Idiopathic Pulmonary Fibrosis (IPF) Exacerbation Failure	9.6 percentage of participants	3.6 percentage of participants

SECONDARY outcome

Timeframe: Baseline and 52 weeks

Population: Treated Set (Only patients with observed cases (OC) values were analysed)

Means provided are the adjusted means and are based on all analysed patients in the model (not only patients with a change from baseline to week 52).

Outcome measures

Outcome measures
Measure	Placebo n=217 Participants Oral administration of Placebo matching nintedanib soft gelatine capsules	Nintedanib 150 mg Bid n=327 Participants Oral administration of soft gelatine capsules of nintedanib 150mg twice daily (bid). Dose interruption and reduction to 100 mg bid dose were allowed to manage adverse events.
Absolute Change From Baseline in Forced Vital Capacity (FVC) Over 52 Weeks	-205.03 mL Standard Error 16.629	-95.26 mL Standard Error 14.200

SECONDARY outcome

Timeframe: Baseline and 52 weeks

Population: Treated Set (Only patients with observed cases (OC) values were analysed)

Percentage change from baseline in FVC over 52 weeks. Means provided are the adjusted means and are based on all analysed patients in the model (not only patients with a change from baseline to week 52).

Outcome measures

Outcome measures
Measure	Placebo n=217 Participants Oral administration of Placebo matching nintedanib soft gelatine capsules	Nintedanib 150 mg Bid n=327 Participants Oral administration of soft gelatine capsules of nintedanib 150mg twice daily (bid). Dose interruption and reduction to 100 mg bid dose were allowed to manage adverse events.
Relative Change From Baseline in Forced Vital Capacity (FVC) Over 52 Weeks	-8.14 percent change Standard Error 0.620	-3.90 percent change Standard Error 0.528

SECONDARY outcome

Timeframe: Baseline and 52 weeks

Population: Treated Set (Only patients with observed cases (OC) values were analysed)

Means provided are the adjusted means and are based on all analysed patients in the model (not only patients with a change from baseline to week 52).

Outcome measures

Outcome measures
Measure	Placebo n=217 Participants Oral administration of Placebo matching nintedanib soft gelatine capsules	Nintedanib 150 mg Bid n=327 Participants Oral administration of soft gelatine capsules of nintedanib 150mg twice daily (bid). Dose interruption and reduction to 100 mg bid dose were allowed to manage adverse events.
Absolute Change From Baseline in Forced Vital Capacity (FVC) (% Predicted) Over 52 Weeks	-6.15 %predicted Standard Error 0.505	-3.09 %predicted Standard Error 0.433

SECONDARY outcome

Timeframe: Baseline and 52 weeks

Population: Treated Set (Only patients with observed cases (OC) values were analysed)

Percentage change from baseline in FVC (% predicted) at 52 weeks. Means provided are the adjusted means and are based on all analysed patients in the model (not only patients with a change from baseline to week 52).

Outcome measures

Outcome measures
Measure	Placebo n=217 Participants Oral administration of Placebo matching nintedanib soft gelatine capsules	Nintedanib 150 mg Bid n=327 Participants Oral administration of soft gelatine capsules of nintedanib 150mg twice daily (bid). Dose interruption and reduction to 100 mg bid dose were allowed to manage adverse events.
Relative Change From Baseline in Forced Vital Capacity (FVC) (% Predicted) Over 52 Weeks	-8.13 percent change Standard Error 0.614	-3.92 percent change Standard Error 0.525

SECONDARY outcome

Timeframe: Baseline and 52 weeks

Population: Treated Set (for patients with change from baseline in FVC (% predicted) at Week 52)

Absolute categorical change of FVC (% predicted) by categories over 52 weeks - 5% threshold (decrease by \>5%, increase by \>5%, and change within ≤5%).

Outcome measures

Outcome measures
Measure	Placebo n=180 Participants Oral administration of Placebo matching nintedanib soft gelatine capsules	Nintedanib 150 mg Bid n=269 Participants Oral administration of soft gelatine capsules of nintedanib 150mg twice daily (bid). Dose interruption and reduction to 100 mg bid dose were allowed to manage adverse events.
Absolute Categorical Change From Baseline of FVC (% Predicted) by Categories Over 52 Weeks - 5% Threshold Decrease > 5%	52.2 percentage of participants	34.9 percentage of participants
Absolute Categorical Change From Baseline of FVC (% Predicted) by Categories Over 52 Weeks - 5% Threshold Change within ≤ 5%	45.0 percentage of participants	50.2 percentage of participants
Absolute Categorical Change From Baseline of FVC (% Predicted) by Categories Over 52 Weeks - 5% Threshold Increase > 5%	2.8 percentage of participants	14.9 percentage of participants

SECONDARY outcome

Timeframe: Baseline and 52 weeks

Population: Treated Set (for patients with change from baseline in FVC (% predicted) at Week 52)

Absolute categorical change of FVC (% predicted) by categories over 52 weeks - 10% threshold (decrease by 10%, increase by \>10%, and change within ≤10%)

Outcome measures

Outcome measures
Measure	Placebo n=180 Participants Oral administration of Placebo matching nintedanib soft gelatine capsules	Nintedanib 150 mg Bid n=269 Participants Oral administration of soft gelatine capsules of nintedanib 150mg twice daily (bid). Dose interruption and reduction to 100 mg bid dose were allowed to manage adverse events.
Absolute Categorical Change From Baseline of FVC (% Predicted) by Categories Over 52 Weeks - 10% Threshold Decrease > 10%	22.2 percentage of participants	14.9 percentage of participants
Absolute Categorical Change From Baseline of FVC (% Predicted) by Categories Over 52 Weeks - 10% Threshold Change within ≤ 10%	77.2 percentage of participants	80.7 percentage of participants
Absolute Categorical Change From Baseline of FVC (% Predicted) by Categories Over 52 Weeks - 10% Threshold Increase > 10%	0.6 percentage of participants	4.5 percentage of participants

SECONDARY outcome

Timeframe: 52 weeks

Population: Treated Set

FVC responders using 10% threshold at 52 weeks, defined as patients with absolute decline in FVC% predicted no greater than 10% and with an FVC evaluation at 52 weeks.

Outcome measures

Outcome measures
Measure	Placebo n=219 Participants Oral administration of Placebo matching nintedanib soft gelatine capsules	Nintedanib 150 mg Bid n=329 Participants Oral administration of soft gelatine capsules of nintedanib 150mg twice daily (bid). Dose interruption and reduction to 100 mg bid dose were allowed to manage adverse events.
FVC Responders Using 10% Threshold at 52 Weeks	63.93 percentage of participants Interval 57.38 to 70.0	69.60 percentage of participants Interval 64.43 to 74.33

SECONDARY outcome

Timeframe: 52 weeks

Population: Treated Set

Proportion of FVC responders using 5% threshold at 52 weeks, defined as patients with absolute decline in FVC% predicted no greater than 5% and with an FVC evaluation at 52 weeks.

Outcome measures

Outcome measures
Measure	Placebo n=219 Participants Oral administration of Placebo matching nintedanib soft gelatine capsules	Nintedanib 150 mg Bid n=329 Participants Oral administration of soft gelatine capsules of nintedanib 150mg twice daily (bid). Dose interruption and reduction to 100 mg bid dose were allowed to manage adverse events.
Proportion of FVC Responders Using 5% Threshold at 52 Weeks	39.27 percentage of participants Interval 33.04 to 45.87	53.19 percentage of participants Interval 47.79 to 58.52

SECONDARY outcome

Timeframe: baseline and 52 weeks

Population: Treated Set

Proportion of SGRQ responders at 52 weeks. Responders defined as \<= -4 points change in change from baseline in SGRQ total score at 52 weeks.

Outcome measures

Outcome measures
Measure	Placebo n=219 Participants Oral administration of Placebo matching nintedanib soft gelatine capsules	Nintedanib 150 mg Bid n=329 Participants Oral administration of soft gelatine capsules of nintedanib 150mg twice daily (bid). Dose interruption and reduction to 100 mg bid dose were allowed to manage adverse events.
Proportion of SGRQ Responders at 52 Weeks: Patient Reported Outcomes (PROs)	16.89 percentage of participants Interval 12.51 to 22.42	25.23 percentage of participants Interval 20.84 to 30.19

SECONDARY outcome

Timeframe: baseline and 52 weeks

Population: Treated Set (Only patients with observed cases (OC) values were analysed)

SGRQ Symptom score is a sub-component of SGRQ total score and is concerned with the effect of respiratory symptoms, their frequency and severity. This score calculated as summed weights ranges from 0 to 100 with lower score denoting a better symptom-related quality of life. Means presented are the adjusted means and are based on all analyzed patients in the model (not only patients with a baseline and measurement at week 52).

Outcome measures

Outcome measures
Measure	Placebo n=214 Participants Oral administration of Placebo matching nintedanib soft gelatine capsules	Nintedanib 150 mg Bid n=323 Participants Oral administration of soft gelatine capsules of nintedanib 150mg twice daily (bid). Dose interruption and reduction to 100 mg bid dose were allowed to manage adverse events.
Change From Baseline in SGRQ Symptom Score at 52 Weeks (Points): Patient Reported Outcomes (PROs)	3.43 points on a scale Standard Error 1.297	2.03 points on a scale Standard Error 1.061

SECONDARY outcome

Timeframe: baseline and 52 weeks

Population: Treated Set (Only patients with observed cases (OC) values were analysed)

SGRQ Impact score is a sub-component of SGRQ total score and covers a range of aspects concerned with social functioning and psychological disturbances resulting from airway disease. This score calculated as summed weights ranges from 0 to 100 with lower score denoting a better impact-related quality of life. Means presented are the adjusted means and are based on all analyzed patients in the model (not only patients with a baseline and measurement at week 52).

Outcome measures

Outcome measures
Measure	Placebo n=215 Participants Oral administration of Placebo matching nintedanib soft gelatine capsules	Nintedanib 150 mg Bid n=320 Participants Oral administration of soft gelatine capsules of nintedanib 150mg twice daily (bid). Dose interruption and reduction to 100 mg bid dose were allowed to manage adverse events.
Change From Baseline in SGRQ Impact Score at 52 Weeks (Points): Patient Reported Outcomes (PROs)	5.93 points on a scale Standard Error 1.036	2.85 points on a scale Standard Error 0.852

SECONDARY outcome

Timeframe: baseline and 52 weeks

Population: Treated Set (Only patients with observed cases (OC) values were analysed)

SGRQ Activity score is a sub-component of SGRQ total score and concerned with activities that cause or are limited by breathlessness. This score calculated as summed weights ranges from 0 to 100 with lower score denoting a better activity-related quality of life. Means presented are the adjusted means and are based on all analyzed patients in the model (not only patients with a baseline and measurement at week 52).

Outcome measures

Outcome measures
Measure	Placebo n=214 Participants Oral administration of Placebo matching nintedanib soft gelatine capsules	Nintedanib 150 mg Bid n=322 Participants Oral administration of soft gelatine capsules of nintedanib 150mg twice daily (bid). Dose interruption and reduction to 100 mg bid dose were allowed to manage adverse events.
Change From Baseline in SGRQ Activity Score at 52 Weeks (Points): Patient Reported Outcomes (PROs)	7.20 points on a scale Standard Error 1.052	3.89 points on a scale Standard Error 0.863

SECONDARY outcome

Timeframe: baseline and 52 weeks

Population: Treated Set (Only patients with observed cases (OC) values were analysed)

SGRQ-I is the IPF specific version of SGRQ comprises of selected items from the SGRQ divided into three components, Symptoms, Activity and Impact. Each component is scored separately. The weights for all items with a positive responses are summed and the weights from missed items are deducted from the maximum possible weight for the total score. The total score is calculated by dividing the summed weights from positive items in the questionnaire by maximum possible weight for all items in the questionnaire. The total score can range from 0 to 100 with a lower score denoting a better health-related quality of life. Change from baseline is calculated as the difference between total score at week 52 and total score at baseline as measured by the scale.

Outcome measures

Outcome measures
Measure	Placebo n=213 Participants Oral administration of Placebo matching nintedanib soft gelatine capsules	Nintedanib 150 mg Bid n=320 Participants Oral administration of soft gelatine capsules of nintedanib 150mg twice daily (bid). Dose interruption and reduction to 100 mg bid dose were allowed to manage adverse events.
Change From Baseline in Idiopathic Pulmonary Fibrosis (IPF) Specific Version of SGRQ (SGRQ-I) Total Score at 52 Weeks (Points): Patient Reported Outcomes (PROs)	5.84 points on a scale Standard Error 0.921	2.72 points on a scale Standard Error 0.757

SECONDARY outcome

Timeframe: baseline and 52 weeks

Population: Treated Set (Only patients with observed cases (OC) values were analysed)

Shortness of Breath Questionnaire measures the shortness of breath. It comprises of 24 items. Each item is scored on a scale between 0-5 where 5 represents maximal breathlessness. The responses to all items are summed up to provide the overall score that can range from 0 (best outcome) to 120 (worst outcome). Means presented are the adjusted means and are based on all analyzed patients in the model (not only patients with a baseline and measurement at week 52).

Outcome measures

Outcome measures
Measure	Placebo n=204 Participants Oral administration of Placebo matching nintedanib soft gelatine capsules	Nintedanib 150 mg Bid n=302 Participants Oral administration of soft gelatine capsules of nintedanib 150mg twice daily (bid). Dose interruption and reduction to 100 mg bid dose were allowed to manage adverse events.
Change From Baseline in Shortness of Breath Questionnaire (SOBQ) at 52 Weeks: Patient Reported Outcomes (PROs)	9.07 points on a scale Standard Error 1.300	6.69 points on a scale Standard Error 1.073

SECONDARY outcome

Timeframe: baseline and 52 weeks

Population: Treated Set (Only patients with observed cases (OC) values were analysed)

The cough domains of the Cough and Sputum Assessment Questionnaire (CASAQ(CD)) assess the frequency and severity of cough and sputum and their impact on everyday life. It contains 4 domains cough/sputum symptom and impact with each scale ranging from 0 to 100 with lower scores indicating higher symptoms/impact levels (worst outcome). Means presented are the adjusted means and are based on all analyzed patients in the model (not only patients with a baseline and measurement at week 52).

Outcome measures

Outcome measures
Measure	Placebo n=215 Participants Oral administration of Placebo matching nintedanib soft gelatine capsules	Nintedanib 150 mg Bid n=323 Participants Oral administration of soft gelatine capsules of nintedanib 150mg twice daily (bid). Dose interruption and reduction to 100 mg bid dose were allowed to manage adverse events.
Change From Baseline in Cough Symptom Score of the Cough and Sputum Assessment Questionnaire (CASA-Q) Score at 52 Weeks: Patient Reported Outcomes (PROs)	-2.38 points on a scale Standard Error 1.325	-0.33 points on a scale Standard Error 1.087

SECONDARY outcome

Timeframe: baseline and 52 weeks

Population: Treated Set (Only patients with observed cases (OC) values were analysed)

The cough domains of the Cough and Sputum Assessment Questionnaire (CASA- Q) assess the frequency and severity of cough and sputum and their impact on everyday life. It contains 4 domains cough/sputum symptom and impact with each scale ranging from 0 to 100 with lower scores indicating higher symptoms/impact levels (worst outcome). Means presented are the adjusted means and are based on all analyzed patients in the model (not only patients with a baseline and measurement at week 52).

Outcome measures

Outcome measures
Measure	Placebo n=215 Participants Oral administration of Placebo matching nintedanib soft gelatine capsules	Nintedanib 150 mg Bid n=322 Participants Oral administration of soft gelatine capsules of nintedanib 150mg twice daily (bid). Dose interruption and reduction to 100 mg bid dose were allowed to manage adverse events.
Change From Baseline in Cough Impact Score of the Cough and Sputum Assessment Questionnaire (CASA-Q) Score at 52 Weeks: Patient Reported Outcomes (PROs)	-4.39 points on a scale Standard Error 1.209	-2.58 points on a scale Standard Error 0.991

SECONDARY outcome

Timeframe: 52 weeks

Population: Treated Set

Patient's Global Impression of Change (PGI-C) responders are defined as 'Very much better'/ 'Much better'/ 'A little better'/ 'No change'.

Outcome measures

Outcome measures
Measure	Placebo n=219 Participants Oral administration of Placebo matching nintedanib soft gelatine capsules	Nintedanib 150 mg Bid n=329 Participants Oral administration of soft gelatine capsules of nintedanib 150mg twice daily (bid). Dose interruption and reduction to 100 mg bid dose were allowed to manage adverse events.
Proportion of Patient's Global Impression of Change (PGI-C) Responders at 52 Weeks: Patient Reported Outcomes (PROs)	53.88 percentage of participants Interval 47.27 to 60.36	61.70 percentage of participants Interval 56.34 to 66.79

SECONDARY outcome

Timeframe: baseline, 12 weeks, 24 weeks and 52 weeks

Population: Treated Set

The EuroQol 5-dimensional Health State is based on a visual analog scale (EQ-VAS) representing the general patient's health state labelled from 100 (best imaginable health state) to 0 (worst imaginable health state). A higher score indicating a better health state. Change from baseline is calculated as the difference between health state at week 12, 24 and 52 respectively and health state at baseline as measured by the scale.

Outcome measures

Outcome measures
Measure	Placebo n=219 Participants Oral administration of Placebo matching nintedanib soft gelatine capsules	Nintedanib 150 mg Bid n=329 Participants Oral administration of soft gelatine capsules of nintedanib 150mg twice daily (bid). Dose interruption and reduction to 100 mg bid dose were allowed to manage adverse events.
Change From Baseline in EuroQol 5-Dimensional Quality of Life Questionnaire (EQ-5D) Health State up to 52 Weeks : Patient Reported Outcomes (PROs) 12 weeks (N=207, 306)	-1.48 points on a scale Standard Deviation 15.60	-0.57 points on a scale Standard Deviation 16.97
Change From Baseline in EuroQol 5-Dimensional Quality of Life Questionnaire (EQ-5D) Health State up to 52 Weeks : Patient Reported Outcomes (PROs) 24 weeks (N=204, 297)	-4.86 points on a scale Standard Deviation 16.94	-1.10 points on a scale Standard Deviation 16.81
Change From Baseline in EuroQol 5-Dimensional Quality of Life Questionnaire (EQ-5D) Health State up to 52 Weeks : Patient Reported Outcomes (PROs) 52 weeks (N=178, 265)	-5.60 points on a scale Standard Deviation 17.67	-2.52 points on a scale Standard Deviation 16.95

SECONDARY outcome

Timeframe: 52 weeks

Population: Treated Set

The incidence rate of exacerbations (calculated as the number of patients with at least 1 acute IPF exacerbation divided by the total number of years at risk in years\*100)

Outcome measures

Outcome measures
Measure	Placebo n=219 Participants Oral administration of Placebo matching nintedanib soft gelatine capsules	Nintedanib 150 mg Bid n=329 Participants Oral administration of soft gelatine capsules of nintedanib 150mg twice daily (bid). Dose interruption and reduction to 100 mg bid dose were allowed to manage adverse events.
Risk of an Acute IPF Exacerbation Over 52 Weeks	10.2 Participants/Year *100	3.9 Participants/Year *100

SECONDARY outcome

Timeframe: 52 weeks

Population: Treated Set

Due to rare events, the median of time to event is not calculable, thus the percentages of patients who did or did not experienced death before or at 372 days after randomisation or last contact date (whichever occurs first) are reported. Failure is the proportion of patients who died over 52 weeks (373 days time-period).

Outcome measures

Outcome measures
Measure	Placebo n=219 Participants Oral administration of Placebo matching nintedanib soft gelatine capsules	Nintedanib 150 mg Bid n=329 Participants Oral administration of soft gelatine capsules of nintedanib 150mg twice daily (bid). Dose interruption and reduction to 100 mg bid dose were allowed to manage adverse events.
Time to Death Over 52 Weeks Failure	9.1 percentage of participants	6.7 percentage of participants
Time to Death Over 52 Weeks Censored	90.9 percentage of participants	93.3 percentage of participants

SECONDARY outcome

Timeframe: 52 weeks

Population: Treated Set

Due to rare events, the median of time to event is not calculable, thus the percentages of participants who did or did not experienced death due to respiratory causes before or at 372 days after randomisation or last contact date (whichever occurs first) are reported. Failure is the the proportion of patients who died due to respiratory causes over 52 weeks (373 days time-period).

Outcome measures

Outcome measures
Measure	Placebo n=219 Participants Oral administration of Placebo matching nintedanib soft gelatine capsules	Nintedanib 150 mg Bid n=329 Participants Oral administration of soft gelatine capsules of nintedanib 150mg twice daily (bid). Dose interruption and reduction to 100 mg bid dose were allowed to manage adverse events.
Time to Death Due to Respiratory Cause Over 52 Weeks (Adjudicated) Failure	5.0 percentage of participants	4.3 percentage of participants
Time to Death Due to Respiratory Cause Over 52 Weeks (Adjudicated) Censored	95.0 percentage of participants	95.7 percentage of participants

SECONDARY outcome

Timeframe: 52 weeks

Population: Treated Set

Due to rare events, the median of time to event is not calculable, thus the percentages of participants who did or did not die before or at last trial medication intake + 28 days were censored at last trial medication intake + 28 days and reported. Failure is the the proportion of patients who died on-treatment.

Outcome measures

Outcome measures
Measure	Placebo n=219 Participants Oral administration of Placebo matching nintedanib soft gelatine capsules	Nintedanib 150 mg Bid n=329 Participants Oral administration of soft gelatine capsules of nintedanib 150mg twice daily (bid). Dose interruption and reduction to 100 mg bid dose were allowed to manage adverse events.
Time to On-treatment Death Failure	7.8 percentage of participants	4.9 percentage of participants
Time to On-treatment Death Censored	92.2 percentage of participants	95.1 percentage of participants

SECONDARY outcome

Timeframe: 52 weeks

Population: Treated Set

Due to rare events, the median of time to event is not calculable, thus the percentages of participants who did or did not experience event (death or lung transplant) before or at 372 days after randomisation or last contact date (whichever occurs first) are reported. Failure is the proportion of patients who died or had lung transplant over 52 weeks (373 days time-period).

Outcome measures

Outcome measures
Measure	Placebo n=219 Participants Oral administration of Placebo matching nintedanib soft gelatine capsules	Nintedanib 150 mg Bid n=329 Participants Oral administration of soft gelatine capsules of nintedanib 150mg twice daily (bid). Dose interruption and reduction to 100 mg bid dose were allowed to manage adverse events.
Time to Death or Lung Transplant Over 52 Weeks Censored	90.0 percentage of participants	93.3 percentage of participants
Time to Death or Lung Transplant Over 52 Weeks Failure	10.0 percentage of participants	6.7 percentage of participants

SECONDARY outcome

Timeframe: 52 weeks

Population: Treated Set

Due to rare events, the median of time to event is not calculable, thus the percentages of participants who did or did not experienced death or lung transplant or qualifying for lung transplant over 52 weeks are reported. A patient was considered qualifying for lung transplant by the investigator if he or she fulfilled the following criteria: FVC \<45% predicted or Carbon monoxide diffusion capacity (DL(CO)) \<30% pred or Oxygen saturation on pulse oximetry (SpO2) \<88% at rest, at sea level (to be adapted for other heights). These criteria were evaluated by investigators judgement. Failure is the proportion of patients who died or had lung transplant or qualified for lung transplant over 52 weeks (373 days time-period).

Outcome measures

Outcome measures
Measure	Placebo n=219 Participants Oral administration of Placebo matching nintedanib soft gelatine capsules	Nintedanib 150 mg Bid n=329 Participants Oral administration of soft gelatine capsules of nintedanib 150mg twice daily (bid). Dose interruption and reduction to 100 mg bid dose were allowed to manage adverse events.
Time to Death or Lung Transplant or Qualifying for Lung Transplant Over 52 Weeks. Failure	23.7 percentage of participants	19.5 percentage of participants
Time to Death or Lung Transplant or Qualifying for Lung Transplant Over 52 Weeks. Censored	76.3 percentage of participants	80.5 percentage of participants

SECONDARY outcome

Timeframe: baseline and 52 weeks

Population: Treated Set (Only patients with observed cases (OC) values were analysed)

Means presented are the adjusted means. Adjusted mean is based on all analyzed patients in the model (not only patients with a change from baseline to week 52)

Outcome measures

Outcome measures
Measure	Placebo n=212 Participants Oral administration of Placebo matching nintedanib soft gelatine capsules	Nintedanib 150 mg Bid n=320 Participants Oral administration of soft gelatine capsules of nintedanib 150mg twice daily (bid). Dose interruption and reduction to 100 mg bid dose were allowed to manage adverse events.
Change From Baseline in SpO2 (Oxygen Saturation, Expressed in Percent) at Rest up Over 52 Weeks	-0.66 percent of oxygen saturation Standard Error 0.174	-0.39 percent of oxygen saturation Standard Error 0.149

SECONDARY outcome

Timeframe: baseline and 52 weeks

Population: Treated Set (Only patients with observed cases (OC) values were analysed)

Means provided are the adjusted means and are based on all analysed patients in the model (not only patients with a change from baseline to week 52).

Outcome measures

Outcome measures
Measure	Placebo n=202 Participants Oral administration of Placebo matching nintedanib soft gelatine capsules	Nintedanib 150 mg Bid n=302 Participants Oral administration of soft gelatine capsules of nintedanib 150mg twice daily (bid). Dose interruption and reduction to 100 mg bid dose were allowed to manage adverse events.
Change From Baseline in Carbon Monoxide Diffusion Capacity (DLCO) at Rest Over 52 Weeks	-0.400 mmol/min/kPa Standard Error 0.0843	-0.286 mmol/min/kPa Standard Error 0.0729

Adverse Events

Placebo

Serious events: 72 serious events

Other events: 193 other events

Deaths: 0 deaths

Nintedanib 150mg Bid

Serious events: 98 serious events

Other events: 308 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Boehringer Ingelheim Call Center

Boehringer Ingelheim

Phone: 1-800-243-0127

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Results disclosure agreements

Principal investigator is a sponsor employee Boehringer Ingelheim (BI) acknowledges that investigators have the right to publish the study results. Investigators shall provide BI with a copy of any publication or presentation for review prior to any submission. Such review will be done with regard to proprietary information, information related to patentable inventions, medical, scientific, and statistical accuracy within 60 days. BI may request a delay of the publication in order to protect BI's intellectual property rights.
Publication restrictions are in place

Restriction type: OTHER

Measure	Placebo n=219 participants at risk Oral administration of Placebo matching nintedanib soft gelatine capsules.	Nintedanib 150mg Bid n=329 participants at risk Oral administration of soft gelatine capsules of Nintedanib 150 mg twice daily (bid). Dose interruption and reduction to 100 mg bid dose were allowed to manage adverse events.
Gastrointestinal disorders Abdominal pain	3.2% 7/219 • From the first drug administration until 28 days after the last drug administration, up to 425 days	9.1% 30/329 • From the first drug administration until 28 days after the last drug administration, up to 425 days
Gastrointestinal disorders Abdominal pain upper	2.7% 6/219 • From the first drug administration until 28 days after the last drug administration, up to 425 days	5.5% 18/329 • From the first drug administration until 28 days after the last drug administration, up to 425 days
Gastrointestinal disorders Constipation	4.6% 10/219 • From the first drug administration until 28 days after the last drug administration, up to 425 days	5.8% 19/329 • From the first drug administration until 28 days after the last drug administration, up to 425 days
Gastrointestinal disorders Diarrhoea	17.8% 39/219 • From the first drug administration until 28 days after the last drug administration, up to 425 days	62.9% 207/329 • From the first drug administration until 28 days after the last drug administration, up to 425 days
Gastrointestinal disorders Nausea	7.3% 16/219 • From the first drug administration until 28 days after the last drug administration, up to 425 days	26.1% 86/329 • From the first drug administration until 28 days after the last drug administration, up to 425 days
Gastrointestinal disorders Vomiting	3.2% 7/219 • From the first drug administration until 28 days after the last drug administration, up to 425 days	10.3% 34/329 • From the first drug administration until 28 days after the last drug administration, up to 425 days
General disorders Fatigue	9.1% 20/219 • From the first drug administration until 28 days after the last drug administration, up to 425 days	7.9% 26/329 • From the first drug administration until 28 days after the last drug administration, up to 425 days
Infections and infestations Bronchitis	7.8% 17/219 • From the first drug administration until 28 days after the last drug administration, up to 425 days	7.9% 26/329 • From the first drug administration until 28 days after the last drug administration, up to 425 days
Infections and infestations Nasopharyngitis	15.5% 34/219 • From the first drug administration until 28 days after the last drug administration, up to 425 days	14.6% 48/329 • From the first drug administration until 28 days after the last drug administration, up to 425 days
Infections and infestations Respiratory tract infection	5.9% 13/219 • From the first drug administration until 28 days after the last drug administration, up to 425 days	5.5% 18/329 • From the first drug administration until 28 days after the last drug administration, up to 425 days
Infections and infestations Upper respiratory tract infection	11.0% 24/219 • From the first drug administration until 28 days after the last drug administration, up to 425 days	9.1% 30/329 • From the first drug administration until 28 days after the last drug administration, up to 425 days
Investigations Weight decreased	0.91% 2/219 • From the first drug administration until 28 days after the last drug administration, up to 425 days	11.2% 37/329 • From the first drug administration until 28 days after the last drug administration, up to 425 days
Metabolism and nutrition disorders Decreased appetite	4.6% 10/219 • From the first drug administration until 28 days after the last drug administration, up to 425 days	12.8% 42/329 • From the first drug administration until 28 days after the last drug administration, up to 425 days
Musculoskeletal and connective tissue disorders Arthralgia	5.0% 11/219 • From the first drug administration until 28 days after the last drug administration, up to 425 days	2.4% 8/329 • From the first drug administration until 28 days after the last drug administration, up to 425 days
Musculoskeletal and connective tissue disorders Back pain	5.9% 13/219 • From the first drug administration until 28 days after the last drug administration, up to 425 days	6.1% 20/329 • From the first drug administration until 28 days after the last drug administration, up to 425 days
Nervous system disorders Headache	3.2% 7/219 • From the first drug administration until 28 days after the last drug administration, up to 425 days	6.7% 22/329 • From the first drug administration until 28 days after the last drug administration, up to 425 days
Respiratory, thoracic and mediastinal disorders Cough	14.2% 31/219 • From the first drug administration until 28 days after the last drug administration, up to 425 days	11.6% 38/329 • From the first drug administration until 28 days after the last drug administration, up to 425 days
Respiratory, thoracic and mediastinal disorders Dyspnoea	10.0% 22/219 • From the first drug administration until 28 days after the last drug administration, up to 425 days	7.6% 25/329 • From the first drug administration until 28 days after the last drug administration, up to 425 days
Respiratory, thoracic and mediastinal disorders Idiopathic pulmonary fibrosis	6.8% 15/219 • From the first drug administration until 28 days after the last drug administration, up to 425 days	4.0% 13/329 • From the first drug administration until 28 days after the last drug administration, up to 425 days
Vascular disorders Hypertension	5.0% 11/219 • From the first drug administration until 28 days after the last drug administration, up to 425 days	3.3% 11/329 • From the first drug administration until 28 days after the last drug administration, up to 425 days