Trial Outcomes & Findings for Study of Pulmonary Rehabilitation in Patients With Idiopathic Pulmonary Fibrosis (IPF) (NCT NCT03717012)

NCT ID: NCT03717012

Last Updated: 2021-06-09

Results Overview

Absolute change from baseline in the 6 minute walk distance (6MWD) test at 12 weeks. The last assessment before treatment period start (included) will be used as baseline. If the baseline value is missing and the screening value is available, then the baseline value will be defined as the screening value taken closest to baseline date.

• Recruitment status: TERMINATED
• Study phase: PHASE4
• Target enrollment: 19 participants
• Primary outcome timeframe: Baseline (day 1) and week 12 (day 85).
• Results posted on: 2021-06-09

Participant Flow

This was a randomised, open-label, prospective, Phase IV clinical trial of pulmonary rehabilitation during the first 12 weeks of a 24-week treatment period, compared with no pulmonary rehabilitation, in patients already taking nintedanib for idiopathic pulmonary fibrosis.

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

Participant milestones

Measure	Nintedanib 150 mg Subjects were required to be treated on a stable (up to 30 months) dose of nintedanib 150 milligram (mg) twice a day (BID) administered per prescribing instructions and to continue on this dose throughout the trial. Patients who recently started nintedanib 150 mg BID and have started by the day of randomization must be on nintedanib 150 mg BID a minimum of 10 days by the first day of pulmonary rehabilitation. Patients that have had an interruption in nintedanib treatment or a temporary dose reduction can be entered into the trial when they have returned to a dose of 150 mg BID and their condition is determined to be stable by the investigator and temporary dose reductions to treat adverse events is permitted during the trial.	Nintedanib 150 mg + Pulmonary Rehabilitation Subjects were required to be treated on a stable (up to 30 months) dose of nintedanib 150 milligram (mg) twice a day (BID) administered per prescribing instructions and to continue on this dose throughout the trial. Patients who recently started nintedanib 150 mg BID and have started by the day of randomization must be on nintedanib 150 mg BID a minimum of 10 days by the first day of pulmonary rehabilitation. Patients that have had an interruption in nintedanib treatment or a temporary dose reduction can be entered into the trial when they have returned to a dose of 150 mg BID and their condition is determined to be stable by the investigator and temporary dose reductions to treat adverse events is permitted during the trial. In addition patients received a standard pulmonary rehabilitation regimen two or three times weekly for 12 weeks. The pulmonary rehabilitation should follow the facility's standard regimen as long as the regimen meets basic standards.
Overall Study STARTED	9	10
Overall Study COMPLETED	8	4
Overall Study NOT COMPLETED	1	6

Reasons for withdrawal

Measure	Nintedanib 150 mg Subjects were required to be treated on a stable (up to 30 months) dose of nintedanib 150 milligram (mg) twice a day (BID) administered per prescribing instructions and to continue on this dose throughout the trial. Patients who recently started nintedanib 150 mg BID and have started by the day of randomization must be on nintedanib 150 mg BID a minimum of 10 days by the first day of pulmonary rehabilitation. Patients that have had an interruption in nintedanib treatment or a temporary dose reduction can be entered into the trial when they have returned to a dose of 150 mg BID and their condition is determined to be stable by the investigator and temporary dose reductions to treat adverse events is permitted during the trial.	Nintedanib 150 mg + Pulmonary Rehabilitation Subjects were required to be treated on a stable (up to 30 months) dose of nintedanib 150 milligram (mg) twice a day (BID) administered per prescribing instructions and to continue on this dose throughout the trial. Patients who recently started nintedanib 150 mg BID and have started by the day of randomization must be on nintedanib 150 mg BID a minimum of 10 days by the first day of pulmonary rehabilitation. Patients that have had an interruption in nintedanib treatment or a temporary dose reduction can be entered into the trial when they have returned to a dose of 150 mg BID and their condition is determined to be stable by the investigator and temporary dose reductions to treat adverse events is permitted during the trial. In addition patients received a standard pulmonary rehabilitation regimen two or three times weekly for 12 weeks. The pulmonary rehabilitation should follow the facility's standard regimen as long as the regimen meets basic standards.
Overall Study Due to trial termination	1	2
Overall Study Protocol Violation	0	2
Overall Study Adverse Event	0	1
Overall Study Lung transplant	0	1

Baseline Characteristics

Study of Pulmonary Rehabilitation in Patients With Idiopathic Pulmonary Fibrosis (IPF)

Baseline characteristics by cohort

Measure	Nintedanib 150 mg n=9 Participants Subjects were required to be treated on a stable (up to 30 months) dose of nintedanib 150 milligram (mg) twice a day (BID) administered per prescribing instructions and to continue on this dose throughout the trial. Patients who recently started nintedanib 150 mg BID and have started by the day of randomization must be on nintedanib 150 mg BID a minimum of 10 days by the first day of pulmonary rehabilitation. Patients that have had an interruption in nintedanib treatment or a temporary dose reduction can be entered into the trial when they have returned to a dose of 150 mg BID and their condition is determined to be stable by the investigator and temporary dose reductions to treat adverse events is permitted during the trial.	Nintedanib 150 mg + Pulmonary Rehabilitation n=10 Participants Subjects were required to be treated on a stable (up to 30 months) dose of nintedanib 150 milligram (mg) twice a day (BID) administered per prescribing instructions and to continue on this dose throughout the trial. Patients who recently started nintedanib 150 mg BID and have started by the day of randomization must be on nintedanib 150 mg BID a minimum of 10 days by the first day of pulmonary rehabilitation. Patients that have had an interruption in nintedanib treatment or a temporary dose reduction can be entered into the trial when they have returned to a dose of 150 mg BID and their condition is determined to be stable by the investigator and temporary dose reductions to treat adverse events is permitted during the trial. In addition patients received a standard pulmonary rehabilitation regimen two or three times weekly for 12 weeks. The pulmonary rehabilitation should follow the facility's standard regimen as long as the regimen meets basic standards.	Total n=19 Participants Total of all reporting groups
Age, Continuous	67.0 years STANDARD_DEVIATION 6.5 • n=5 Participants	70.9 years STANDARD_DEVIATION 11.9 • n=7 Participants	69.1 years STANDARD_DEVIATION 9.7 • n=5 Participants
Sex: Female, Male Female	2 Participants n=5 Participants	2 Participants n=7 Participants	4 Participants n=5 Participants
Sex: Female, Male Male	7 Participants n=5 Participants	8 Participants n=7 Participants	15 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	3 Participants n=5 Participants	1 Participants n=7 Participants	4 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	6 Participants n=5 Participants	9 Participants n=7 Participants	15 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) White	9 Participants n=5 Participants	10 Participants n=7 Participants	19 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
6 minute walk distance (6MWD) test	360 meter STANDARD_DEVIATION 159.03 • n=5 Participants	322.33 meter STANDARD_DEVIATION 114.30 • n=7 Participants	340.17 meter STANDARD_DEVIATION 134.71 • n=5 Participants

PRIMARY outcome

Timeframe: Baseline (day 1) and week 12 (day 85).

Population: Randomized set (RS): This patient set includes all randomized patients, whether treated with pulmonary rehabilitation or not. Patients with no data available at week 12 were excluded.

Absolute change from baseline in the 6 minute walk distance (6MWD) test at 12 weeks. The last assessment before treatment period start (included) will be used as baseline. If the baseline value is missing and the screening value is available, then the baseline value will be defined as the screening value taken closest to baseline date.

Outcome measures

Measure	Nintedanib 150 mg n=7 Participants Subjects were required to be treated on a stable (up to 30 months) dose of nintedanib 150 milligram (mg) twice a day (BID) administered per prescribing instructions and to continue on this dose throughout the trial. Patients who recently started nintedanib 150 mg BID and have started by the day of randomization must be on nintedanib 150 mg BID a minimum of 10 days by the first day of pulmonary rehabilitation. Patients that have had an interruption in nintedanib treatment or a temporary dose reduction can be entered into the trial when they have returned to a dose of 150 mg BID and their condition is determined to be stable by the investigator and temporary dose reductions to treat adverse events is permitted during the trial.	Nintedanib 150 mg + Pulmonary Rehabilitation n=8 Participants Subjects were required to be treated on a stable (up to 30 months) dose of nintedanib 150 milligram (mg) twice a day (BID) administered per prescribing instructions and to continue on this dose throughout the trial. Patients who recently started nintedanib 150 mg BID and have started by the day of randomization must be on nintedanib 150 mg BID a minimum of 10 days by the first day of pulmonary rehabilitation. Patients that have had an interruption in nintedanib treatment or a temporary dose reduction can be entered into the trial when they have returned to a dose of 150 mg BID and their condition is determined to be stable by the investigator and temporary dose reductions to treat adverse events is permitted during the trial. In addition patients received a standard pulmonary rehabilitation regimen two or three times weekly for 12 weeks. The pulmonary rehabilitation should follow the facility's standard regimen as long as the regimen meets basic standards.
Change From Baseline in the 6 Minute Walk Test (6MWD) at 12 Weeks	-20.60 meter Standard Deviation 31.24	-14.10 meter Standard Deviation 53.99

SECONDARY outcome

Timeframe: Baseline (day 1) and week 24 (day 169).

Population: Randomized set (RS): This patient set includes all randomized patients, whether treated with pulmonary rehabilitation or not. Patients with no data available at week 24 were excluded.

Absolute change from baseline in the 6 minute walk distance (6MWD) test at 24 weeks. The last assessment before treatment period start (included) will be used as baseline. If the baseline value is missing and the screening value is available, then the baseline value will be defined as the screening value taken closest to baseline date.

Outcome measures

Measure	Nintedanib 150 mg n=5 Participants Subjects were required to be treated on a stable (up to 30 months) dose of nintedanib 150 milligram (mg) twice a day (BID) administered per prescribing instructions and to continue on this dose throughout the trial. Patients who recently started nintedanib 150 mg BID and have started by the day of randomization must be on nintedanib 150 mg BID a minimum of 10 days by the first day of pulmonary rehabilitation. Patients that have had an interruption in nintedanib treatment or a temporary dose reduction can be entered into the trial when they have returned to a dose of 150 mg BID and their condition is determined to be stable by the investigator and temporary dose reductions to treat adverse events is permitted during the trial.	Nintedanib 150 mg + Pulmonary Rehabilitation n=3 Participants Subjects were required to be treated on a stable (up to 30 months) dose of nintedanib 150 milligram (mg) twice a day (BID) administered per prescribing instructions and to continue on this dose throughout the trial. Patients who recently started nintedanib 150 mg BID and have started by the day of randomization must be on nintedanib 150 mg BID a minimum of 10 days by the first day of pulmonary rehabilitation. Patients that have had an interruption in nintedanib treatment or a temporary dose reduction can be entered into the trial when they have returned to a dose of 150 mg BID and their condition is determined to be stable by the investigator and temporary dose reductions to treat adverse events is permitted during the trial. In addition patients received a standard pulmonary rehabilitation regimen two or three times weekly for 12 weeks. The pulmonary rehabilitation should follow the facility's standard regimen as long as the regimen meets basic standards.
Change From Baseline in the 6 Minute Walk Test (6MWD) at 24 Weeks	-38.34 meter Standard Deviation 63.24	9.04 meter Standard Deviation 10.82

SECONDARY outcome

Timeframe: Baseline (day 1), week 12 (day 85) and week 24 (day 169).

Population: Randomized set (RS): This patient set includes all randomized patients, whether treated with pulmonary rehabilitation or not. Patients with no data available at week 12 or week 24 were excluded from their respective analyses.

Absolute change from baseline in the St George's Respiratory Questionnaire (SGRQ) total score at 12 and 24 weeks. The SGRQ is a widely used disease specific questionnaire evaluating health related quality of life. The SGRQ Total Score is measured using patient self-reported question on disease impact on symptoms, patient activity, and daily life. SGRQ scores are calculated using weights attached to each item of the questionnaire which provides an estimate of the distress associated with the symptoms or state described in each item. The total score for SGRQ ranges from 0 to 100, with higher scores indicating more limitations.

Outcome measures

Measure	Nintedanib 150 mg n=7 Participants Subjects were required to be treated on a stable (up to 30 months) dose of nintedanib 150 milligram (mg) twice a day (BID) administered per prescribing instructions and to continue on this dose throughout the trial. Patients who recently started nintedanib 150 mg BID and have started by the day of randomization must be on nintedanib 150 mg BID a minimum of 10 days by the first day of pulmonary rehabilitation. Patients that have had an interruption in nintedanib treatment or a temporary dose reduction can be entered into the trial when they have returned to a dose of 150 mg BID and their condition is determined to be stable by the investigator and temporary dose reductions to treat adverse events is permitted during the trial.	Nintedanib 150 mg + Pulmonary Rehabilitation n=8 Participants Subjects were required to be treated on a stable (up to 30 months) dose of nintedanib 150 milligram (mg) twice a day (BID) administered per prescribing instructions and to continue on this dose throughout the trial. Patients who recently started nintedanib 150 mg BID and have started by the day of randomization must be on nintedanib 150 mg BID a minimum of 10 days by the first day of pulmonary rehabilitation. Patients that have had an interruption in nintedanib treatment or a temporary dose reduction can be entered into the trial when they have returned to a dose of 150 mg BID and their condition is determined to be stable by the investigator and temporary dose reductions to treat adverse events is permitted during the trial. In addition patients received a standard pulmonary rehabilitation regimen two or three times weekly for 12 weeks. The pulmonary rehabilitation should follow the facility's standard regimen as long as the regimen meets basic standards.
Change From Baseline in the St George's Respiratory Questionnaire (SGRQ) Total Score at 12 and 24 Weeks Change from baseline at week 12	5.60 Score on a scale. Standard Deviation 11.43	-1.48 Score on a scale. Standard Deviation 9.03
Change From Baseline in the St George's Respiratory Questionnaire (SGRQ) Total Score at 12 and 24 Weeks Change from baseline at week 24	6.06 Score on a scale. Standard Deviation 13.38	-6.54 Score on a scale. Standard Deviation 4.97

SECONDARY outcome

Timeframe: Baseline (day 1), week 12 (day 85) and week 24 (day 169).

Population: Randomized set (RS): This patient set includes all randomized patients, whether treated with pulmonary rehabilitation or not. Patients with no data available at week 12 or week 24 were excluded from their respective analyses.

Absolute change from baseline in The King's Brief Interstitial Lung Disease (KBILD) questionnaire total score at 12 and 24 weeks. The KBILD questionnaire is a disease specific questionnaire evaluating health related quality of life. The questionnaire consists of 15 items. Raw total scores were weighted with a Likert response scale to create the total score, total scores were transformed to a range of 0-100 ((actual score-lowest possible score/range)*100), with a score of 100 representing the best health status.

Outcome measures

Measure	Nintedanib 150 mg n=7 Participants Subjects were required to be treated on a stable (up to 30 months) dose of nintedanib 150 milligram (mg) twice a day (BID) administered per prescribing instructions and to continue on this dose throughout the trial. Patients who recently started nintedanib 150 mg BID and have started by the day of randomization must be on nintedanib 150 mg BID a minimum of 10 days by the first day of pulmonary rehabilitation. Patients that have had an interruption in nintedanib treatment or a temporary dose reduction can be entered into the trial when they have returned to a dose of 150 mg BID and their condition is determined to be stable by the investigator and temporary dose reductions to treat adverse events is permitted during the trial.	Nintedanib 150 mg + Pulmonary Rehabilitation n=8 Participants Subjects were required to be treated on a stable (up to 30 months) dose of nintedanib 150 milligram (mg) twice a day (BID) administered per prescribing instructions and to continue on this dose throughout the trial. Patients who recently started nintedanib 150 mg BID and have started by the day of randomization must be on nintedanib 150 mg BID a minimum of 10 days by the first day of pulmonary rehabilitation. Patients that have had an interruption in nintedanib treatment or a temporary dose reduction can be entered into the trial when they have returned to a dose of 150 mg BID and their condition is determined to be stable by the investigator and temporary dose reductions to treat adverse events is permitted during the trial. In addition patients received a standard pulmonary rehabilitation regimen two or three times weekly for 12 weeks. The pulmonary rehabilitation should follow the facility's standard regimen as long as the regimen meets basic standards.
Absolute Change From Baseline in The King's Brief Interstitial Lung Disease (KBILD) Questionnaire Total Score at 12 and 24 Weeks Change from baseline at week 12	-3.20 Score on a scale. Standard Deviation 3.21	1.28 Score on a scale. Standard Deviation 5.36
Absolute Change From Baseline in The King's Brief Interstitial Lung Disease (KBILD) Questionnaire Total Score at 12 and 24 Weeks Change from baseline at week 24	-4.42 Score on a scale. Standard Deviation 8.80	-0.63 Score on a scale. Standard Deviation 4.87

SECONDARY outcome

Timeframe: Baseline (day 1), week 12 (day 85) and week 24 (day 169).

Population: Randomized set (RS): This patient set includes all randomized patients, whether treated with pulmonary rehabilitation or not. Patients with no data available at week 12 or week 24 were excluded from their respective analyses.

Change from baseline in the University of California, San Diego Shortness of Breath Questionnaire (UCSD-SOBQ) total score at 12 and 24 weeks. The UCSD-SOBQ is a 24-item questionnaire that assesses self-reported shortness of breath while performing a variety of activities of daily living, scores for each item range from 0 to 5, with higher scores indicating more limitations. Total score is calculated as the sum of all individual scores. Scores range from 0 to 120, with higher scores indicating more limitations.

Outcome measures

Measure	Nintedanib 150 mg n=7 Participants Subjects were required to be treated on a stable (up to 30 months) dose of nintedanib 150 milligram (mg) twice a day (BID) administered per prescribing instructions and to continue on this dose throughout the trial. Patients who recently started nintedanib 150 mg BID and have started by the day of randomization must be on nintedanib 150 mg BID a minimum of 10 days by the first day of pulmonary rehabilitation. Patients that have had an interruption in nintedanib treatment or a temporary dose reduction can be entered into the trial when they have returned to a dose of 150 mg BID and their condition is determined to be stable by the investigator and temporary dose reductions to treat adverse events is permitted during the trial.	Nintedanib 150 mg + Pulmonary Rehabilitation n=8 Participants Subjects were required to be treated on a stable (up to 30 months) dose of nintedanib 150 milligram (mg) twice a day (BID) administered per prescribing instructions and to continue on this dose throughout the trial. Patients who recently started nintedanib 150 mg BID and have started by the day of randomization must be on nintedanib 150 mg BID a minimum of 10 days by the first day of pulmonary rehabilitation. Patients that have had an interruption in nintedanib treatment or a temporary dose reduction can be entered into the trial when they have returned to a dose of 150 mg BID and their condition is determined to be stable by the investigator and temporary dose reductions to treat adverse events is permitted during the trial. In addition patients received a standard pulmonary rehabilitation regimen two or three times weekly for 12 weeks. The pulmonary rehabilitation should follow the facility's standard regimen as long as the regimen meets basic standards.
Change From Baseline in the University of California, San Diego Shortness of Breath Questionnaire (UCSD-SOBQ) Total Score at 12 and 24 Weeks Change from baseline at week 24	17.50 Score on a scale. Standard Deviation 14.54	0.00 Score on a scale. Standard Deviation 19.97
Change From Baseline in the University of California, San Diego Shortness of Breath Questionnaire (UCSD-SOBQ) Total Score at 12 and 24 Weeks Change from baseline at week 12	13.29 Score on a scale. Standard Deviation 12.63	6.13 Score on a scale. Standard Deviation 18.71

SECONDARY outcome

Timeframe: Baseline (day 1), week 12 (day 85) and week 24 (day 169).

Population: Randomized set (RS): This patient set includes all randomized patients, whether treated with pulmonary rehabilitation or not. Patients with no data available at week 12 or week 24 were excluded from their respective analyses.

Absolute change from baseline of forced vital capacity (FVC) at 12 and 24 weeks. 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.

Outcome measures

Measure	Nintedanib 150 mg n=7 Participants Subjects were required to be treated on a stable (up to 30 months) dose of nintedanib 150 milligram (mg) twice a day (BID) administered per prescribing instructions and to continue on this dose throughout the trial. Patients who recently started nintedanib 150 mg BID and have started by the day of randomization must be on nintedanib 150 mg BID a minimum of 10 days by the first day of pulmonary rehabilitation. Patients that have had an interruption in nintedanib treatment or a temporary dose reduction can be entered into the trial when they have returned to a dose of 150 mg BID and their condition is determined to be stable by the investigator and temporary dose reductions to treat adverse events is permitted during the trial.	Nintedanib 150 mg + Pulmonary Rehabilitation n=8 Participants Subjects were required to be treated on a stable (up to 30 months) dose of nintedanib 150 milligram (mg) twice a day (BID) administered per prescribing instructions and to continue on this dose throughout the trial. Patients who recently started nintedanib 150 mg BID and have started by the day of randomization must be on nintedanib 150 mg BID a minimum of 10 days by the first day of pulmonary rehabilitation. Patients that have had an interruption in nintedanib treatment or a temporary dose reduction can be entered into the trial when they have returned to a dose of 150 mg BID and their condition is determined to be stable by the investigator and temporary dose reductions to treat adverse events is permitted during the trial. In addition patients received a standard pulmonary rehabilitation regimen two or three times weekly for 12 weeks. The pulmonary rehabilitation should follow the facility's standard regimen as long as the regimen meets basic standards.
Absolute Change From Baseline of Forced Vital Capacity (FVC) at 12 and 24 Weeks Change from baseline at week 12	-152.86 Milliliter (mL) Standard Deviation 261.90	-87.50 Milliliter (mL) Standard Deviation 277.32
Absolute Change From Baseline of Forced Vital Capacity (FVC) at 12 and 24 Weeks Change from baseline at week 24	76.00 Milliliter (mL) Standard Deviation 356.13	-86.67 Milliliter (mL) Standard Deviation 168.62

SECONDARY outcome

Timeframe: Baseline (day 1), week 12 (day 85) and week 24 (day 169).

Population: Randomized set (RS): This patient set includes all randomized patients, whether treated with pulmonary rehabilitation or not. Patients with no data available at week 12 or week 24 were excluded from their respective analyses.

Absolute change from baseline of forced vital capacity (FVC) % predicted at 12 and 24 weeks. 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. For predicted normal values, different sites may use different prediction formulas, based on the method used to measure diffusing capacity of the lung for carbon monoxide (DLco). In any case, the method used must be in compliance with the European Respiratory Society (ERS)/American Thoracic Society (ATS) guideline on DLco measurements, and the prediction formula appropriate for that method.

Outcome measures

Measure	Nintedanib 150 mg n=7 Participants Subjects were required to be treated on a stable (up to 30 months) dose of nintedanib 150 milligram (mg) twice a day (BID) administered per prescribing instructions and to continue on this dose throughout the trial. Patients who recently started nintedanib 150 mg BID and have started by the day of randomization must be on nintedanib 150 mg BID a minimum of 10 days by the first day of pulmonary rehabilitation. Patients that have had an interruption in nintedanib treatment or a temporary dose reduction can be entered into the trial when they have returned to a dose of 150 mg BID and their condition is determined to be stable by the investigator and temporary dose reductions to treat adverse events is permitted during the trial.	Nintedanib 150 mg + Pulmonary Rehabilitation n=8 Participants Subjects were required to be treated on a stable (up to 30 months) dose of nintedanib 150 milligram (mg) twice a day (BID) administered per prescribing instructions and to continue on this dose throughout the trial. Patients who recently started nintedanib 150 mg BID and have started by the day of randomization must be on nintedanib 150 mg BID a minimum of 10 days by the first day of pulmonary rehabilitation. Patients that have had an interruption in nintedanib treatment or a temporary dose reduction can be entered into the trial when they have returned to a dose of 150 mg BID and their condition is determined to be stable by the investigator and temporary dose reductions to treat adverse events is permitted during the trial. In addition patients received a standard pulmonary rehabilitation regimen two or three times weekly for 12 weeks. The pulmonary rehabilitation should follow the facility's standard regimen as long as the regimen meets basic standards.
Absolute Change From Baseline of Forced Vital Capacity (FVC) % Predicted at 12 and 24 Weeks Change from baseline at week 12	-3.84 Percent predicted Standard Deviation 7.93	-1.50 Percent predicted Standard Deviation 7.42
Absolute Change From Baseline of Forced Vital Capacity (FVC) % Predicted at 12 and 24 Weeks Change from baseline at week 24	3.63 Percent predicted Standard Deviation 11.69	-1.93 Percent predicted Standard Deviation 4.44

SECONDARY outcome

Timeframe: Baseline (day 1), week 12 (day 85) and week 24 (day 169).

Population: Randomized set (RS): This patient set includes all randomized patients, whether treated with pulmonary rehabilitation or not. Patients with no data available at week 12 or week 24 were excluded from their respective analyses.

Relative change (unitless) from baseline of forced vital capacity (FVC) at 12 and 24 weeks. 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. FVC is measured in milliliter (mL). Its relative change from baseline at 12 (24) weeks is calculated as: (FVC measured at 12 (24) weeks - FVC measured at baseline)/ FVC measured at baseline *100%.

Outcome measures

Measure	Nintedanib 150 mg n=7 Participants Subjects were required to be treated on a stable (up to 30 months) dose of nintedanib 150 milligram (mg) twice a day (BID) administered per prescribing instructions and to continue on this dose throughout the trial. Patients who recently started nintedanib 150 mg BID and have started by the day of randomization must be on nintedanib 150 mg BID a minimum of 10 days by the first day of pulmonary rehabilitation. Patients that have had an interruption in nintedanib treatment or a temporary dose reduction can be entered into the trial when they have returned to a dose of 150 mg BID and their condition is determined to be stable by the investigator and temporary dose reductions to treat adverse events is permitted during the trial.	Nintedanib 150 mg + Pulmonary Rehabilitation n=8 Participants Subjects were required to be treated on a stable (up to 30 months) dose of nintedanib 150 milligram (mg) twice a day (BID) administered per prescribing instructions and to continue on this dose throughout the trial. Patients who recently started nintedanib 150 mg BID and have started by the day of randomization must be on nintedanib 150 mg BID a minimum of 10 days by the first day of pulmonary rehabilitation. Patients that have had an interruption in nintedanib treatment or a temporary dose reduction can be entered into the trial when they have returned to a dose of 150 mg BID and their condition is determined to be stable by the investigator and temporary dose reductions to treat adverse events is permitted during the trial. In addition patients received a standard pulmonary rehabilitation regimen two or three times weekly for 12 weeks. The pulmonary rehabilitation should follow the facility's standard regimen as long as the regimen meets basic standards.
Relative Change From Baseline of Forced Vital Capacity (FVC) at 12 and 24 Weeks Change from baseline at week 12	-3.68 Percent change Standard Deviation 9.35	-2.60 Percent change Standard Deviation 9.02
Relative Change From Baseline of Forced Vital Capacity (FVC) at 12 and 24 Weeks Change from baseline at week 24	2.80 Percent change Standard Deviation 10.12	-2.16 Percent change Standard Deviation 4.64

SECONDARY outcome

Timeframe: Baseline (day 1), week 12 (day 85) and week 24 (day 169).

Population: Randomized set (RS): This patient set includes all randomized patients, whether treated with pulmonary rehabilitation or not. Patients with no data available at week 12 or week 24 were excluded from their respective analyses.

Relative change (unitless) from baseline of forced vital capacity (FVC) % predicted at 12 and 24 weeks. 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. For predicted normal values, different sites may use different prediction formulas, based on the method used to measure diffusing capacity of the lung for carbon monoxide (DLco). In any case, the method used must be in compliance with the European Respiratory Society (ERS)/American Thoracic Society (ATS) guideline on DLco measurements, and the prediction formula appropriate for that method. The relative change from baseline of FVC % predicted at 12 (24) weeks is calculated as: (FVC % Predicted measured at 12 (24) weeks - FVC % Predicted measured at baseline)/ FVC % Predicted measured at baseline *100%.

Outcome measures

Measure	Nintedanib 150 mg n=7 Participants Subjects were required to be treated on a stable (up to 30 months) dose of nintedanib 150 milligram (mg) twice a day (BID) administered per prescribing instructions and to continue on this dose throughout the trial. Patients who recently started nintedanib 150 mg BID and have started by the day of randomization must be on nintedanib 150 mg BID a minimum of 10 days by the first day of pulmonary rehabilitation. Patients that have had an interruption in nintedanib treatment or a temporary dose reduction can be entered into the trial when they have returned to a dose of 150 mg BID and their condition is determined to be stable by the investigator and temporary dose reductions to treat adverse events is permitted during the trial.	Nintedanib 150 mg + Pulmonary Rehabilitation n=8 Participants Subjects were required to be treated on a stable (up to 30 months) dose of nintedanib 150 milligram (mg) twice a day (BID) administered per prescribing instructions and to continue on this dose throughout the trial. Patients who recently started nintedanib 150 mg BID and have started by the day of randomization must be on nintedanib 150 mg BID a minimum of 10 days by the first day of pulmonary rehabilitation. Patients that have had an interruption in nintedanib treatment or a temporary dose reduction can be entered into the trial when they have returned to a dose of 150 mg BID and their condition is determined to be stable by the investigator and temporary dose reductions to treat adverse events is permitted during the trial. In addition patients received a standard pulmonary rehabilitation regimen two or three times weekly for 12 weeks. The pulmonary rehabilitation should follow the facility's standard regimen as long as the regimen meets basic standards.
Relative Change From Baseline of Forced Vital Capacity (FVC) % Predicted at 12 and 24 Weeks Change from baseline at week 12	-3.68 Percent change Standard Deviation 9.35	-2.60 Percent change Standard Deviation 9.02
Relative Change From Baseline of Forced Vital Capacity (FVC) % Predicted at 12 and 24 Weeks Change from baseline at week 24	2.80 Percent change Standard Deviation 10.12	-2.16 Percent change Standard Deviation 4.64

SECONDARY outcome

Timeframe: Baseline (day 1), week 12 (day 85) and week 24 (day 169).

Population: Randomized set (RS): This patient set includes all randomized patients, whether treated with pulmonary rehabilitation or not. Patients with no data available at week 12 or week 24 were excluded from their respective analyses.

Absolute categorical change of forced vital capacity (FVC)% predicted up to 12 and 24 weeks, the following three categories were defined: decrease by >5%, increase by >5%, and change within ≤5%. 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. For predicted normal values, different sites may use different prediction formulas, based on the method used to measure diffusing capacity of the lung for carbon monoxide (DLco). In any case, the method used must be in compliance with the European Respiratory Society (ERS)/American Thoracic Society(ATS) guideline on DLco measurements, and the prediction formula appropriate for that method.

Outcome measures

Measure	Nintedanib 150 mg n=7 Participants Subjects were required to be treated on a stable (up to 30 months) dose of nintedanib 150 milligram (mg) twice a day (BID) administered per prescribing instructions and to continue on this dose throughout the trial. Patients who recently started nintedanib 150 mg BID and have started by the day of randomization must be on nintedanib 150 mg BID a minimum of 10 days by the first day of pulmonary rehabilitation. Patients that have had an interruption in nintedanib treatment or a temporary dose reduction can be entered into the trial when they have returned to a dose of 150 mg BID and their condition is determined to be stable by the investigator and temporary dose reductions to treat adverse events is permitted during the trial.	Nintedanib 150 mg + Pulmonary Rehabilitation n=8 Participants Subjects were required to be treated on a stable (up to 30 months) dose of nintedanib 150 milligram (mg) twice a day (BID) administered per prescribing instructions and to continue on this dose throughout the trial. Patients who recently started nintedanib 150 mg BID and have started by the day of randomization must be on nintedanib 150 mg BID a minimum of 10 days by the first day of pulmonary rehabilitation. Patients that have had an interruption in nintedanib treatment or a temporary dose reduction can be entered into the trial when they have returned to a dose of 150 mg BID and their condition is determined to be stable by the investigator and temporary dose reductions to treat adverse events is permitted during the trial. In addition patients received a standard pulmonary rehabilitation regimen two or three times weekly for 12 weeks. The pulmonary rehabilitation should follow the facility's standard regimen as long as the regimen meets basic standards.
Absolute Categorical Change of Forced Vital Capacity (FVC)% Predicted up to 12 and 24 Weeks (Decrease by >5%, Increase by >5%, and Change Within ≤5%) Change from baseline at week 12 · Decrease by >5%	4 Participants	2 Participants
Absolute Categorical Change of Forced Vital Capacity (FVC)% Predicted up to 12 and 24 Weeks (Decrease by >5%, Increase by >5%, and Change Within ≤5%) Change from baseline at week 12 · Within 5% change	2 Participants	5 Participants
Absolute Categorical Change of Forced Vital Capacity (FVC)% Predicted up to 12 and 24 Weeks (Decrease by >5%, Increase by >5%, and Change Within ≤5%) Change from baseline at week 12 · Increase by >5%	1 Participants	1 Participants
Absolute Categorical Change of Forced Vital Capacity (FVC)% Predicted up to 12 and 24 Weeks (Decrease by >5%, Increase by >5%, and Change Within ≤5%) Change from baseline at week 24 · Decrease by >5%	1 Participants	1 Participants
Absolute Categorical Change of Forced Vital Capacity (FVC)% Predicted up to 12 and 24 Weeks (Decrease by >5%, Increase by >5%, and Change Within ≤5%) Change from baseline at week 24 · Within 5% change	2 Participants	2 Participants
Absolute Categorical Change of Forced Vital Capacity (FVC)% Predicted up to 12 and 24 Weeks (Decrease by >5%, Increase by >5%, and Change Within ≤5%) Change from baseline at week 24 · Increase by >5%	2 Participants	0 Participants

SECONDARY outcome

Timeframe: Baseline (day 1), week 12 (day 85) and week 24 (day 169).

Population: Randomized set (RS): This patient set includes all randomized patients, whether treated with pulmonary rehabilitation or not. Patients with no data available at week 12 or week 24 were excluded from their respective analyses.

Absolute categorical change of forced vital capacity (FVC)% predicted up to 12 and 24 weeks, the following three categories were defined: decrease by >10%, increase by >10%, and change within ≤10%. 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. For predicted normal values, different sites may use different prediction formulas, based on the method used to measure diffusing capacity of the lung for carbon monoxide (DLco). In any case, the method used must be in compliance with the European Respiratory Society (ERS)/American Thoracic Society(ATS) guideline on DLco measurements, and the prediction formula appropriate for that method.

Outcome measures

Measure	Nintedanib 150 mg n=7 Participants Subjects were required to be treated on a stable (up to 30 months) dose of nintedanib 150 milligram (mg) twice a day (BID) administered per prescribing instructions and to continue on this dose throughout the trial. Patients who recently started nintedanib 150 mg BID and have started by the day of randomization must be on nintedanib 150 mg BID a minimum of 10 days by the first day of pulmonary rehabilitation. Patients that have had an interruption in nintedanib treatment or a temporary dose reduction can be entered into the trial when they have returned to a dose of 150 mg BID and their condition is determined to be stable by the investigator and temporary dose reductions to treat adverse events is permitted during the trial.	Nintedanib 150 mg + Pulmonary Rehabilitation n=8 Participants Subjects were required to be treated on a stable (up to 30 months) dose of nintedanib 150 milligram (mg) twice a day (BID) administered per prescribing instructions and to continue on this dose throughout the trial. Patients who recently started nintedanib 150 mg BID and have started by the day of randomization must be on nintedanib 150 mg BID a minimum of 10 days by the first day of pulmonary rehabilitation. Patients that have had an interruption in nintedanib treatment or a temporary dose reduction can be entered into the trial when they have returned to a dose of 150 mg BID and their condition is determined to be stable by the investigator and temporary dose reductions to treat adverse events is permitted during the trial. In addition patients received a standard pulmonary rehabilitation regimen two or three times weekly for 12 weeks. The pulmonary rehabilitation should follow the facility's standard regimen as long as the regimen meets basic standards.
Absolute Categorical Change of Forced Vital Capacity (FVC)% Predicted up to 12 and 24 Weeks (Decrease by >10%, Increase by >10%, and Change Within ≤10%) Change from baseline at week 12 · Decrease by >10%	2 Participants	1 Participants
Absolute Categorical Change of Forced Vital Capacity (FVC)% Predicted up to 12 and 24 Weeks (Decrease by >10%, Increase by >10%, and Change Within ≤10%) Change from baseline at week 12 · Within 10% change	5 Participants	7 Participants
Absolute Categorical Change of Forced Vital Capacity (FVC)% Predicted up to 12 and 24 Weeks (Decrease by >10%, Increase by >10%, and Change Within ≤10%) Change from baseline at week 12 · Increase by >10%	0 Participants	0 Participants
Absolute Categorical Change of Forced Vital Capacity (FVC)% Predicted up to 12 and 24 Weeks (Decrease by >10%, Increase by >10%, and Change Within ≤10%) Change from baseline at week 24 · Decrease by >10%	0 Participants	0 Participants
Absolute Categorical Change of Forced Vital Capacity (FVC)% Predicted up to 12 and 24 Weeks (Decrease by >10%, Increase by >10%, and Change Within ≤10%) Change from baseline at week 24 · Within 10% change	4 Participants	3 Participants
Absolute Categorical Change of Forced Vital Capacity (FVC)% Predicted up to 12 and 24 Weeks (Decrease by >10%, Increase by >10%, and Change Within ≤10%) Change from baseline at week 24 · Increase by >10%	1 Participants	0 Participants

SECONDARY outcome

Timeframe: Baseline (day 1), week 12 (day 85) and week 24 (day 169).

Population: Randomized set (RS): This patient set includes all randomized patients, whether treated with pulmonary rehabilitation or not. Patients with no data available at week 12 or week 24 were excluded from their respective analyses.

Change from baseline in daily accelerometer activity from baseline at 12 and 24 weeks: Score of average Steps/day. Categories were defined as follows:

Steps (total daily value) 0 = 0 to 1900 steps/day

1. = 1901 to 3700 steps/day

2. = 3701 to 5500 steps/day

3. = 5501 to 7300 steps/day

4. = >7301 steps/day

Outcome measures

Measure	Nintedanib 150 mg n=5 Participants Subjects were required to be treated on a stable (up to 30 months) dose of nintedanib 150 milligram (mg) twice a day (BID) administered per prescribing instructions and to continue on this dose throughout the trial. Patients who recently started nintedanib 150 mg BID and have started by the day of randomization must be on nintedanib 150 mg BID a minimum of 10 days by the first day of pulmonary rehabilitation. Patients that have had an interruption in nintedanib treatment or a temporary dose reduction can be entered into the trial when they have returned to a dose of 150 mg BID and their condition is determined to be stable by the investigator and temporary dose reductions to treat adverse events is permitted during the trial.	Nintedanib 150 mg + Pulmonary Rehabilitation n=6 Participants Subjects were required to be treated on a stable (up to 30 months) dose of nintedanib 150 milligram (mg) twice a day (BID) administered per prescribing instructions and to continue on this dose throughout the trial. Patients who recently started nintedanib 150 mg BID and have started by the day of randomization must be on nintedanib 150 mg BID a minimum of 10 days by the first day of pulmonary rehabilitation. Patients that have had an interruption in nintedanib treatment or a temporary dose reduction can be entered into the trial when they have returned to a dose of 150 mg BID and their condition is determined to be stable by the investigator and temporary dose reductions to treat adverse events is permitted during the trial. In addition patients received a standard pulmonary rehabilitation regimen two or three times weekly for 12 weeks. The pulmonary rehabilitation should follow the facility's standard regimen as long as the regimen meets basic standards.
Change From Baseline in Daily Accelerometer Activity From Baseline at 12 and 24 Weeks: Score of Average Steps/Day Change from baseline at week 24	-0.8 Score on a scale Standard Deviation 1.7	0.0 Score on a scale Standard Deviation 0.0
Change From Baseline in Daily Accelerometer Activity From Baseline at 12 and 24 Weeks: Score of Average Steps/Day Change from baseline at week 12	0.4 Score on a scale Standard Deviation 0.9	0.5 Score on a scale Standard Deviation 0.5

SECONDARY outcome

Timeframe: Baseline (day 1), week 12 (day 85) and week 24 (day 169).

Population: Randomized set (RS): This patient set includes all randomized patients, whether treated with pulmonary rehabilitation or not. Patients with no data available at week 12 or week 24 were excluded from their respective analyses.

Change from baseline in daily accelerometer activity from baseline at 12 and 24 weeks: Score of average vector magnitude units (VMU)/day. Categories were defined as follows:

VMU (daily VMU/min) 0 = 0 to 50 VMU/min

1. = 51 to 110 VMU/min

2. = 111 to 190 VMU/min

3. = 191 to 270 VMU/min

4. = 271 to 440 VMU/min

5. = >441 VMU/min

Outcome measures

Measure	Nintedanib 150 mg n=5 Participants Subjects were required to be treated on a stable (up to 30 months) dose of nintedanib 150 milligram (mg) twice a day (BID) administered per prescribing instructions and to continue on this dose throughout the trial. Patients who recently started nintedanib 150 mg BID and have started by the day of randomization must be on nintedanib 150 mg BID a minimum of 10 days by the first day of pulmonary rehabilitation. Patients that have had an interruption in nintedanib treatment or a temporary dose reduction can be entered into the trial when they have returned to a dose of 150 mg BID and their condition is determined to be stable by the investigator and temporary dose reductions to treat adverse events is permitted during the trial.	Nintedanib 150 mg + Pulmonary Rehabilitation n=6 Participants Subjects were required to be treated on a stable (up to 30 months) dose of nintedanib 150 milligram (mg) twice a day (BID) administered per prescribing instructions and to continue on this dose throughout the trial. Patients who recently started nintedanib 150 mg BID and have started by the day of randomization must be on nintedanib 150 mg BID a minimum of 10 days by the first day of pulmonary rehabilitation. Patients that have had an interruption in nintedanib treatment or a temporary dose reduction can be entered into the trial when they have returned to a dose of 150 mg BID and their condition is determined to be stable by the investigator and temporary dose reductions to treat adverse events is permitted during the trial. In addition patients received a standard pulmonary rehabilitation regimen two or three times weekly for 12 weeks. The pulmonary rehabilitation should follow the facility's standard regimen as long as the regimen meets basic standards.
Change From Baseline in Daily Accelerometer Activity From Baseline at 12 and 24 Weeks: Score of Average Vector Magnitude Units (VMU)/Day Change from baseline at week 12	0.4 Score on a scale Standard Deviation 0.9	0.3 Score on a scale Standard Deviation 0.8
Change From Baseline in Daily Accelerometer Activity From Baseline at 12 and 24 Weeks: Score of Average Vector Magnitude Units (VMU)/Day Change from baseline at week 24	-0.5 Score on a scale Standard Deviation 1.7	-0.5 Score on a scale Standard Deviation 0.7

Adverse Events

Nintedanib 150 mg

Serious events: 3 serious events

Other events: 4 other events

Deaths: 0 deaths

Nintedanib 150 mg + Pulmonary Rehabilitation

Serious events: 2 serious events

Other events: 6 other events

Deaths: 1 deaths

Serious adverse events

Measure	Nintedanib 150 mg n=9 participants at risk Subjects were required to be treated on a stable (up to 30 months) dose of nintedanib 150 milligram (mg) twice a day (BID) administered per prescribing instructions and to continue on this dose throughout the trial. Patients who recently started nintedanib 150 mg BID and have started by the day of randomization must be on nintedanib 150 mg BID a minimum of 10 days by the first day of pulmonary rehabilitation. Patients that have had an interruption in nintedanib treatment or a temporary dose reduction can be entered into the trial when they have returned to a dose of 150 mg BID and their condition is determined to be stable by the investigator and temporary dose reductions to treat adverse events is permitted during the trial.	Nintedanib 150 mg + Pulmonary Rehabilitation n=10 participants at risk Subjects were required to be treated on a stable (up to 30 months) dose of nintedanib 150 milligram (mg) twice a day (BID) administered per prescribing instructions and to continue on this dose throughout the trial. Patients who recently started nintedanib 150 mg BID and have started by the day of randomization must be on nintedanib 150 mg BID a minimum of 10 days by the first day of pulmonary rehabilitation. Patients that have had an interruption in nintedanib treatment or a temporary dose reduction can be entered into the trial when they have returned to a dose of 150 mg BID and their condition is determined to be stable by the investigator and temporary dose reductions to treat adverse events is permitted during the trial. In addition patients received a standard pulmonary rehabilitation regimen two or three times weekly for 12 weeks. The pulmonary rehabilitation should follow the facility's standard regimen as long as the regimen meets basic standards.
Hepatobiliary disorders Cholecystitis acute	11.1% 1/9 • From first Nintedanib drug intake on/after randomization (or re-start of nintedanib if interruption) to the last Nintedanib drug intake plus 28 days plus one day. Up to 263 days. Randomized set (RS): This patient set includes all randomized patients, whether treated with pulmonary rehabilitation or not.	0.00% 0/10 • From first Nintedanib drug intake on/after randomization (or re-start of nintedanib if interruption) to the last Nintedanib drug intake plus 28 days plus one day. Up to 263 days. Randomized set (RS): This patient set includes all randomized patients, whether treated with pulmonary rehabilitation or not.
Infections and infestations Influenza	11.1% 1/9 • From first Nintedanib drug intake on/after randomization (or re-start of nintedanib if interruption) to the last Nintedanib drug intake plus 28 days plus one day. Up to 263 days. Randomized set (RS): This patient set includes all randomized patients, whether treated with pulmonary rehabilitation or not.	0.00% 0/10 • From first Nintedanib drug intake on/after randomization (or re-start of nintedanib if interruption) to the last Nintedanib drug intake plus 28 days plus one day. Up to 263 days. Randomized set (RS): This patient set includes all randomized patients, whether treated with pulmonary rehabilitation or not.
Injury, poisoning and procedural complications Fall	0.00% 0/9 • From first Nintedanib drug intake on/after randomization (or re-start of nintedanib if interruption) to the last Nintedanib drug intake plus 28 days plus one day. Up to 263 days. Randomized set (RS): This patient set includes all randomized patients, whether treated with pulmonary rehabilitation or not.	10.0% 1/10 • From first Nintedanib drug intake on/after randomization (or re-start of nintedanib if interruption) to the last Nintedanib drug intake plus 28 days plus one day. Up to 263 days. Randomized set (RS): This patient set includes all randomized patients, whether treated with pulmonary rehabilitation or not.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Lung cancer metastatic	0.00% 0/9 • From first Nintedanib drug intake on/after randomization (or re-start of nintedanib if interruption) to the last Nintedanib drug intake plus 28 days plus one day. Up to 263 days. Randomized set (RS): This patient set includes all randomized patients, whether treated with pulmonary rehabilitation or not.	10.0% 1/10 • From first Nintedanib drug intake on/after randomization (or re-start of nintedanib if interruption) to the last Nintedanib drug intake plus 28 days plus one day. Up to 263 days. Randomized set (RS): This patient set includes all randomized patients, whether treated with pulmonary rehabilitation or not.
Respiratory, thoracic and mediastinal disorders Idiopathic pulmonary fibrosis	11.1% 1/9 • From first Nintedanib drug intake on/after randomization (or re-start of nintedanib if interruption) to the last Nintedanib drug intake plus 28 days plus one day. Up to 263 days. Randomized set (RS): This patient set includes all randomized patients, whether treated with pulmonary rehabilitation or not.	10.0% 1/10 • From first Nintedanib drug intake on/after randomization (or re-start of nintedanib if interruption) to the last Nintedanib drug intake plus 28 days plus one day. Up to 263 days. Randomized set (RS): This patient set includes all randomized patients, whether treated with pulmonary rehabilitation or not.

Other adverse events

Measure	Nintedanib 150 mg n=9 participants at risk Subjects were required to be treated on a stable (up to 30 months) dose of nintedanib 150 milligram (mg) twice a day (BID) administered per prescribing instructions and to continue on this dose throughout the trial. Patients who recently started nintedanib 150 mg BID and have started by the day of randomization must be on nintedanib 150 mg BID a minimum of 10 days by the first day of pulmonary rehabilitation. Patients that have had an interruption in nintedanib treatment or a temporary dose reduction can be entered into the trial when they have returned to a dose of 150 mg BID and their condition is determined to be stable by the investigator and temporary dose reductions to treat adverse events is permitted during the trial.	Nintedanib 150 mg + Pulmonary Rehabilitation n=10 participants at risk Subjects were required to be treated on a stable (up to 30 months) dose of nintedanib 150 milligram (mg) twice a day (BID) administered per prescribing instructions and to continue on this dose throughout the trial. Patients who recently started nintedanib 150 mg BID and have started by the day of randomization must be on nintedanib 150 mg BID a minimum of 10 days by the first day of pulmonary rehabilitation. Patients that have had an interruption in nintedanib treatment or a temporary dose reduction can be entered into the trial when they have returned to a dose of 150 mg BID and their condition is determined to be stable by the investigator and temporary dose reductions to treat adverse events is permitted during the trial. In addition patients received a standard pulmonary rehabilitation regimen two or three times weekly for 12 weeks. The pulmonary rehabilitation should follow the facility's standard regimen as long as the regimen meets basic standards.
Gastrointestinal disorders Abdominal pain	0.00% 0/9 • From first Nintedanib drug intake on/after randomization (or re-start of nintedanib if interruption) to the last Nintedanib drug intake plus 28 days plus one day. Up to 263 days. Randomized set (RS): This patient set includes all randomized patients, whether treated with pulmonary rehabilitation or not.	10.0% 1/10 • From first Nintedanib drug intake on/after randomization (or re-start of nintedanib if interruption) to the last Nintedanib drug intake plus 28 days plus one day. Up to 263 days. Randomized set (RS): This patient set includes all randomized patients, whether treated with pulmonary rehabilitation or not.
Gastrointestinal disorders Abdominal pain lower	11.1% 1/9 • From first Nintedanib drug intake on/after randomization (or re-start of nintedanib if interruption) to the last Nintedanib drug intake plus 28 days plus one day. Up to 263 days. Randomized set (RS): This patient set includes all randomized patients, whether treated with pulmonary rehabilitation or not.	0.00% 0/10 • From first Nintedanib drug intake on/after randomization (or re-start of nintedanib if interruption) to the last Nintedanib drug intake plus 28 days plus one day. Up to 263 days. Randomized set (RS): This patient set includes all randomized patients, whether treated with pulmonary rehabilitation or not.
Gastrointestinal disorders Colitis microscopic	0.00% 0/9 • From first Nintedanib drug intake on/after randomization (or re-start of nintedanib if interruption) to the last Nintedanib drug intake plus 28 days plus one day. Up to 263 days. Randomized set (RS): This patient set includes all randomized patients, whether treated with pulmonary rehabilitation or not.	10.0% 1/10 • From first Nintedanib drug intake on/after randomization (or re-start of nintedanib if interruption) to the last Nintedanib drug intake plus 28 days plus one day. Up to 263 days. Randomized set (RS): This patient set includes all randomized patients, whether treated with pulmonary rehabilitation or not.
Gastrointestinal disorders Constipation	0.00% 0/9 • From first Nintedanib drug intake on/after randomization (or re-start of nintedanib if interruption) to the last Nintedanib drug intake plus 28 days plus one day. Up to 263 days. Randomized set (RS): This patient set includes all randomized patients, whether treated with pulmonary rehabilitation or not.	10.0% 1/10 • From first Nintedanib drug intake on/after randomization (or re-start of nintedanib if interruption) to the last Nintedanib drug intake plus 28 days plus one day. Up to 263 days. Randomized set (RS): This patient set includes all randomized patients, whether treated with pulmonary rehabilitation or not.
Gastrointestinal disorders Diarrhoea	11.1% 1/9 • From first Nintedanib drug intake on/after randomization (or re-start of nintedanib if interruption) to the last Nintedanib drug intake plus 28 days plus one day. Up to 263 days. Randomized set (RS): This patient set includes all randomized patients, whether treated with pulmonary rehabilitation or not.	10.0% 1/10 • From first Nintedanib drug intake on/after randomization (or re-start of nintedanib if interruption) to the last Nintedanib drug intake plus 28 days plus one day. Up to 263 days. Randomized set (RS): This patient set includes all randomized patients, whether treated with pulmonary rehabilitation or not.
Gastrointestinal disorders Haemorrhoids	0.00% 0/9 • From first Nintedanib drug intake on/after randomization (or re-start of nintedanib if interruption) to the last Nintedanib drug intake plus 28 days plus one day. Up to 263 days. Randomized set (RS): This patient set includes all randomized patients, whether treated with pulmonary rehabilitation or not.	10.0% 1/10 • From first Nintedanib drug intake on/after randomization (or re-start of nintedanib if interruption) to the last Nintedanib drug intake plus 28 days plus one day. Up to 263 days. Randomized set (RS): This patient set includes all randomized patients, whether treated with pulmonary rehabilitation or not.
Gastrointestinal disorders Nausea	0.00% 0/9 • From first Nintedanib drug intake on/after randomization (or re-start of nintedanib if interruption) to the last Nintedanib drug intake plus 28 days plus one day. Up to 263 days. Randomized set (RS): This patient set includes all randomized patients, whether treated with pulmonary rehabilitation or not.	10.0% 1/10 • From first Nintedanib drug intake on/after randomization (or re-start of nintedanib if interruption) to the last Nintedanib drug intake plus 28 days plus one day. Up to 263 days. Randomized set (RS): This patient set includes all randomized patients, whether treated with pulmonary rehabilitation or not.
Gastrointestinal disorders Rectal haemorrhage	0.00% 0/9 • From first Nintedanib drug intake on/after randomization (or re-start of nintedanib if interruption) to the last Nintedanib drug intake plus 28 days plus one day. Up to 263 days. Randomized set (RS): This patient set includes all randomized patients, whether treated with pulmonary rehabilitation or not.	10.0% 1/10 • From first Nintedanib drug intake on/after randomization (or re-start of nintedanib if interruption) to the last Nintedanib drug intake plus 28 days plus one day. Up to 263 days. Randomized set (RS): This patient set includes all randomized patients, whether treated with pulmonary rehabilitation or not.
Infections and infestations Mycoplasma infection	0.00% 0/9 • From first Nintedanib drug intake on/after randomization (or re-start of nintedanib if interruption) to the last Nintedanib drug intake plus 28 days plus one day. Up to 263 days. Randomized set (RS): This patient set includes all randomized patients, whether treated with pulmonary rehabilitation or not.	10.0% 1/10 • From first Nintedanib drug intake on/after randomization (or re-start of nintedanib if interruption) to the last Nintedanib drug intake plus 28 days plus one day. Up to 263 days. Randomized set (RS): This patient set includes all randomized patients, whether treated with pulmonary rehabilitation or not.
Infections and infestations Nasopharyngitis	11.1% 1/9 • From first Nintedanib drug intake on/after randomization (or re-start of nintedanib if interruption) to the last Nintedanib drug intake plus 28 days plus one day. Up to 263 days. Randomized set (RS): This patient set includes all randomized patients, whether treated with pulmonary rehabilitation or not.	0.00% 0/10 • From first Nintedanib drug intake on/after randomization (or re-start of nintedanib if interruption) to the last Nintedanib drug intake plus 28 days plus one day. Up to 263 days. Randomized set (RS): This patient set includes all randomized patients, whether treated with pulmonary rehabilitation or not.
Infections and infestations Sinusitis	22.2% 2/9 • From first Nintedanib drug intake on/after randomization (or re-start of nintedanib if interruption) to the last Nintedanib drug intake plus 28 days plus one day. Up to 263 days. Randomized set (RS): This patient set includes all randomized patients, whether treated with pulmonary rehabilitation or not.	0.00% 0/10 • From first Nintedanib drug intake on/after randomization (or re-start of nintedanib if interruption) to the last Nintedanib drug intake plus 28 days plus one day. Up to 263 days. Randomized set (RS): This patient set includes all randomized patients, whether treated with pulmonary rehabilitation or not.
Infections and infestations Upper respiratory tract infection	22.2% 2/9 • From first Nintedanib drug intake on/after randomization (or re-start of nintedanib if interruption) to the last Nintedanib drug intake plus 28 days plus one day. Up to 263 days. Randomized set (RS): This patient set includes all randomized patients, whether treated with pulmonary rehabilitation or not.	0.00% 0/10 • From first Nintedanib drug intake on/after randomization (or re-start of nintedanib if interruption) to the last Nintedanib drug intake plus 28 days plus one day. Up to 263 days. Randomized set (RS): This patient set includes all randomized patients, whether treated with pulmonary rehabilitation or not.
Investigations Alanine aminotransferase increased	11.1% 1/9 • From first Nintedanib drug intake on/after randomization (or re-start of nintedanib if interruption) to the last Nintedanib drug intake plus 28 days plus one day. Up to 263 days. Randomized set (RS): This patient set includes all randomized patients, whether treated with pulmonary rehabilitation or not.	0.00% 0/10 • From first Nintedanib drug intake on/after randomization (or re-start of nintedanib if interruption) to the last Nintedanib drug intake plus 28 days plus one day. Up to 263 days. Randomized set (RS): This patient set includes all randomized patients, whether treated with pulmonary rehabilitation or not.
Investigations Aspartate aminotransferase increased	11.1% 1/9 • From first Nintedanib drug intake on/after randomization (or re-start of nintedanib if interruption) to the last Nintedanib drug intake plus 28 days plus one day. Up to 263 days. Randomized set (RS): This patient set includes all randomized patients, whether treated with pulmonary rehabilitation or not.	0.00% 0/10 • From first Nintedanib drug intake on/after randomization (or re-start of nintedanib if interruption) to the last Nintedanib drug intake plus 28 days plus one day. Up to 263 days. Randomized set (RS): This patient set includes all randomized patients, whether treated with pulmonary rehabilitation or not.
Investigations Blood glucose increased	0.00% 0/9 • From first Nintedanib drug intake on/after randomization (or re-start of nintedanib if interruption) to the last Nintedanib drug intake plus 28 days plus one day. Up to 263 days. Randomized set (RS): This patient set includes all randomized patients, whether treated with pulmonary rehabilitation or not.	10.0% 1/10 • From first Nintedanib drug intake on/after randomization (or re-start of nintedanib if interruption) to the last Nintedanib drug intake plus 28 days plus one day. Up to 263 days. Randomized set (RS): This patient set includes all randomized patients, whether treated with pulmonary rehabilitation or not.
Investigations Gamma-glutamyltransferase increased	11.1% 1/9 • From first Nintedanib drug intake on/after randomization (or re-start of nintedanib if interruption) to the last Nintedanib drug intake plus 28 days plus one day. Up to 263 days. Randomized set (RS): This patient set includes all randomized patients, whether treated with pulmonary rehabilitation or not.	0.00% 0/10 • From first Nintedanib drug intake on/after randomization (or re-start of nintedanib if interruption) to the last Nintedanib drug intake plus 28 days plus one day. Up to 263 days. Randomized set (RS): This patient set includes all randomized patients, whether treated with pulmonary rehabilitation or not.
Investigations Lymphocyte percentage decreased	0.00% 0/9 • From first Nintedanib drug intake on/after randomization (or re-start of nintedanib if interruption) to the last Nintedanib drug intake plus 28 days plus one day. Up to 263 days. Randomized set (RS): This patient set includes all randomized patients, whether treated with pulmonary rehabilitation or not.	10.0% 1/10 • From first Nintedanib drug intake on/after randomization (or re-start of nintedanib if interruption) to the last Nintedanib drug intake plus 28 days plus one day. Up to 263 days. Randomized set (RS): This patient set includes all randomized patients, whether treated with pulmonary rehabilitation or not.
Investigations Mean platelet volume decreased	0.00% 0/9 • From first Nintedanib drug intake on/after randomization (or re-start of nintedanib if interruption) to the last Nintedanib drug intake plus 28 days plus one day. Up to 263 days. Randomized set (RS): This patient set includes all randomized patients, whether treated with pulmonary rehabilitation or not.	10.0% 1/10 • From first Nintedanib drug intake on/after randomization (or re-start of nintedanib if interruption) to the last Nintedanib drug intake plus 28 days plus one day. Up to 263 days. Randomized set (RS): This patient set includes all randomized patients, whether treated with pulmonary rehabilitation or not.
Investigations Neutrophil percentage increased	0.00% 0/9 • From first Nintedanib drug intake on/after randomization (or re-start of nintedanib if interruption) to the last Nintedanib drug intake plus 28 days plus one day. Up to 263 days. Randomized set (RS): This patient set includes all randomized patients, whether treated with pulmonary rehabilitation or not.	10.0% 1/10 • From first Nintedanib drug intake on/after randomization (or re-start of nintedanib if interruption) to the last Nintedanib drug intake plus 28 days plus one day. Up to 263 days. Randomized set (RS): This patient set includes all randomized patients, whether treated with pulmonary rehabilitation or not.
Metabolism and nutrition disorders Abnormal loss of weight	0.00% 0/9 • From first Nintedanib drug intake on/after randomization (or re-start of nintedanib if interruption) to the last Nintedanib drug intake plus 28 days plus one day. Up to 263 days. Randomized set (RS): This patient set includes all randomized patients, whether treated with pulmonary rehabilitation or not.	10.0% 1/10 • From first Nintedanib drug intake on/after randomization (or re-start of nintedanib if interruption) to the last Nintedanib drug intake plus 28 days plus one day. Up to 263 days. Randomized set (RS): This patient set includes all randomized patients, whether treated with pulmonary rehabilitation or not.
Musculoskeletal and connective tissue disorders Back pain	11.1% 1/9 • From first Nintedanib drug intake on/after randomization (or re-start of nintedanib if interruption) to the last Nintedanib drug intake plus 28 days plus one day. Up to 263 days. Randomized set (RS): This patient set includes all randomized patients, whether treated with pulmonary rehabilitation or not.	0.00% 0/10 • From first Nintedanib drug intake on/after randomization (or re-start of nintedanib if interruption) to the last Nintedanib drug intake plus 28 days plus one day. Up to 263 days. Randomized set (RS): This patient set includes all randomized patients, whether treated with pulmonary rehabilitation or not.
Musculoskeletal and connective tissue disorders Intervertebral disc compression	0.00% 0/9 • From first Nintedanib drug intake on/after randomization (or re-start of nintedanib if interruption) to the last Nintedanib drug intake plus 28 days plus one day. Up to 263 days. Randomized set (RS): This patient set includes all randomized patients, whether treated with pulmonary rehabilitation or not.	10.0% 1/10 • From first Nintedanib drug intake on/after randomization (or re-start of nintedanib if interruption) to the last Nintedanib drug intake plus 28 days plus one day. Up to 263 days. Randomized set (RS): This patient set includes all randomized patients, whether treated with pulmonary rehabilitation or not.
Musculoskeletal and connective tissue disorders Rotator cuff syndrome	0.00% 0/9 • From first Nintedanib drug intake on/after randomization (or re-start of nintedanib if interruption) to the last Nintedanib drug intake plus 28 days plus one day. Up to 263 days. Randomized set (RS): This patient set includes all randomized patients, whether treated with pulmonary rehabilitation or not.	10.0% 1/10 • From first Nintedanib drug intake on/after randomization (or re-start of nintedanib if interruption) to the last Nintedanib drug intake plus 28 days plus one day. Up to 263 days. Randomized set (RS): This patient set includes all randomized patients, whether treated with pulmonary rehabilitation or not.
Musculoskeletal and connective tissue disorders Synovial cyst	11.1% 1/9 • From first Nintedanib drug intake on/after randomization (or re-start of nintedanib if interruption) to the last Nintedanib drug intake plus 28 days plus one day. Up to 263 days. Randomized set (RS): This patient set includes all randomized patients, whether treated with pulmonary rehabilitation or not.	0.00% 0/10 • From first Nintedanib drug intake on/after randomization (or re-start of nintedanib if interruption) to the last Nintedanib drug intake plus 28 days plus one day. Up to 263 days. Randomized set (RS): This patient set includes all randomized patients, whether treated with pulmonary rehabilitation or not.
Psychiatric disorders Agitation	0.00% 0/9 • From first Nintedanib drug intake on/after randomization (or re-start of nintedanib if interruption) to the last Nintedanib drug intake plus 28 days plus one day. Up to 263 days. Randomized set (RS): This patient set includes all randomized patients, whether treated with pulmonary rehabilitation or not.	10.0% 1/10 • From first Nintedanib drug intake on/after randomization (or re-start of nintedanib if interruption) to the last Nintedanib drug intake plus 28 days plus one day. Up to 263 days. Randomized set (RS): This patient set includes all randomized patients, whether treated with pulmonary rehabilitation or not.
Psychiatric disorders Confusional state	0.00% 0/9 • From first Nintedanib drug intake on/after randomization (or re-start of nintedanib if interruption) to the last Nintedanib drug intake plus 28 days plus one day. Up to 263 days. Randomized set (RS): This patient set includes all randomized patients, whether treated with pulmonary rehabilitation or not.	10.0% 1/10 • From first Nintedanib drug intake on/after randomization (or re-start of nintedanib if interruption) to the last Nintedanib drug intake plus 28 days plus one day. Up to 263 days. Randomized set (RS): This patient set includes all randomized patients, whether treated with pulmonary rehabilitation or not.
Respiratory, thoracic and mediastinal disorders Cough	11.1% 1/9 • From first Nintedanib drug intake on/after randomization (or re-start of nintedanib if interruption) to the last Nintedanib drug intake plus 28 days plus one day. Up to 263 days. Randomized set (RS): This patient set includes all randomized patients, whether treated with pulmonary rehabilitation or not.	0.00% 0/10 • From first Nintedanib drug intake on/after randomization (or re-start of nintedanib if interruption) to the last Nintedanib drug intake plus 28 days plus one day. Up to 263 days. Randomized set (RS): This patient set includes all randomized patients, whether treated with pulmonary rehabilitation or not.
Respiratory, thoracic and mediastinal disorders Oropharyngeal pain	11.1% 1/9 • From first Nintedanib drug intake on/after randomization (or re-start of nintedanib if interruption) to the last Nintedanib drug intake plus 28 days plus one day. Up to 263 days. Randomized set (RS): This patient set includes all randomized patients, whether treated with pulmonary rehabilitation or not.	0.00% 0/10 • From first Nintedanib drug intake on/after randomization (or re-start of nintedanib if interruption) to the last Nintedanib drug intake plus 28 days plus one day. Up to 263 days. Randomized set (RS): This patient set includes all randomized patients, whether treated with pulmonary rehabilitation or not.
Respiratory, thoracic and mediastinal disorders Sinus congestion	0.00% 0/9 • From first Nintedanib drug intake on/after randomization (or re-start of nintedanib if interruption) to the last Nintedanib drug intake plus 28 days plus one day. Up to 263 days. Randomized set (RS): This patient set includes all randomized patients, whether treated with pulmonary rehabilitation or not.	10.0% 1/10 • From first Nintedanib drug intake on/after randomization (or re-start of nintedanib if interruption) to the last Nintedanib drug intake plus 28 days plus one day. Up to 263 days. Randomized set (RS): This patient set includes all randomized patients, whether treated with pulmonary rehabilitation or not.
Skin and subcutaneous tissue disorders Skin irritation	0.00% 0/9 • From first Nintedanib drug intake on/after randomization (or re-start of nintedanib if interruption) to the last Nintedanib drug intake plus 28 days plus one day. Up to 263 days. Randomized set (RS): This patient set includes all randomized patients, whether treated with pulmonary rehabilitation or not.	10.0% 1/10 • From first Nintedanib drug intake on/after randomization (or re-start of nintedanib if interruption) to the last Nintedanib drug intake plus 28 days plus one day. Up to 263 days. Randomized set (RS): This patient set includes all randomized patients, whether treated with pulmonary rehabilitation or not.

Additional Information

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• 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.
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