Trial Outcomes & Findings for Nintedanib (BIBF 1120) vs Placebo in Refractory Metastatic Colorectal Cancer (LUME-Colon 1) (NCT NCT02149108)

Last Updated: 2017-07-21

Results Overview

PFS by central review assessment was defined as the time from the date of randomisation to the date of disease progression according to Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1 or death from any cause, whichever occurred first. Median, 95% Confidence Interval were calculated from an unadjusted Kaplan-Meier curve for each treatment arm.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

768 participants

Primary outcome timeframe

From randomisation until cut-off date 14JUN2016.

Results posted on

2017-07-21

Participant Flow

The "completed" patients were on treatment (2 patients on Placebo, 3 patients on Nintedanib) at the data cut-off date 14JUN2016. The "NOT Completed" patients were off-treatment (380 patients on Placebo, 383 patients on Nintedanib) at the data cut-off date 14JUN2016.

Participant milestones

Participant milestones
Measure	Placebo Placebo soft gelatin capsule matching that of Nintedanib twice daily (b.i.d.) administered orally of 21-day treatment course. If required the dose of placebo, could be reduced to 150 mg b.i.d. or 100 mg b.i.d. (according to the protocol-defined dose-reduction scheme). No dose increase was allowed after a dose reduction.	Nintedanib Nintedanib 200 mg twice daily (b.i.d.) administered orally in the form of a soft gelatin capsule of 21-day treatment course. If required the dose of Nintedanib, could be reduced to 150 mg b.i.d. or 100 mg b.i.d. (according to the protocol-defined dose-reduction scheme). No dose increase was allowed after a dose reduction.
Overall Study STARTED	382	386
Overall Study COMPLETED	2	3
Overall Study NOT COMPLETED	380	383

Reasons for withdrawal

Reasons for withdrawal
Measure	Placebo Placebo soft gelatin capsule matching that of Nintedanib twice daily (b.i.d.) administered orally of 21-day treatment course. If required the dose of placebo, could be reduced to 150 mg b.i.d. or 100 mg b.i.d. (according to the protocol-defined dose-reduction scheme). No dose increase was allowed after a dose reduction.	Nintedanib Nintedanib 200 mg twice daily (b.i.d.) administered orally in the form of a soft gelatin capsule of 21-day treatment course. If required the dose of Nintedanib, could be reduced to 150 mg b.i.d. or 100 mg b.i.d. (according to the protocol-defined dose-reduction scheme). No dose increase was allowed after a dose reduction.
Overall Study Not treated	1	2
Overall Study Progressive Disease (PD)	324	318
Overall Study Worsening/adverse event cancer disease	31	32
Overall Study Other Adverse Event (AE)	8	18
Overall Study Other not defined above	0	2
Overall Study Refusal to continue trial medication	15	11
Overall Study Lost to Follow-up	1	0

Baseline Characteristics

Nintedanib (BIBF 1120) vs Placebo in Refractory Metastatic Colorectal Cancer (LUME-Colon 1)

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Placebo n=382 Participants Placebo soft gelatin capsule matching that of Nintedanib twice daily (b.i.d.) administered orally of 21-day treatment course. If required the dose of placebo, could be reduced to 150 mg b.i.d. or 100 mg b.i.d. (according to the protocol-defined dose-reduction scheme). No dose increase was allowed after a dose reduction.	Nintedanib n=386 Participants Nintedanib 200 mg twice daily (b.i.d.) administered orally in the form of a soft gelatin capsule of 21-day treatment course. If required the dose of Nintedanib, could be reduced to 150 mg b.i.d. or 100 mg b.i.d. (according to the protocol-defined dose-reduction scheme). No dose increase was allowed after a dose reduction.	Total n=768 Participants Total of all reporting groups
Age, Continuous	61.1 Years STANDARD_DEVIATION 10.8 • n=99 Participants	61.0 Years STANDARD_DEVIATION 11.3 • n=107 Participants	61.1 Years STANDARD_DEVIATION 11.0 • n=206 Participants
Sex: Female, Male Female	164 Participants n=99 Participants	150 Participants n=107 Participants	314 Participants n=206 Participants
Sex: Female, Male Male	218 Participants n=99 Participants	236 Participants n=107 Participants	454 Participants n=206 Participants

PRIMARY outcome

Timeframe: From randomisation until cut-off date 14JUN2016.

Population: Randomised Set: This patient set included all patients who were randomised to receive treatment, whether treated or not.

Outcome measures

Outcome measures
Measure	Placebo n=382 Participants Placebo soft gelatin capsule matching that of Nintedanib twice daily (b.i.d.) administered orally of 21-day treatment course. If required the dose of placebo, could be reduced to 150 mg b.i.d. or 100 mg b.i.d. (according to the protocol-defined dose-reduction scheme). No dose increase was allowed after a dose reduction.	Nintedanib n=386 Participants Nintedanib 200 mg twice daily (b.i.d.) administered orally in the form of a soft gelatin capsule of 21-day treatment course. If required the dose of Nintedanib, could be reduced to 150 mg b.i.d. or 100 mg b.i.d. (according to the protocol-defined dose-reduction scheme). No dose increase was allowed after a dose reduction.
Progression-Free Survival (PFS) by Central Review Assessment	1.38 Months Interval 1.38 to 1.41	1.51 Months Interval 1.45 to 2.17

PRIMARY outcome

Timeframe: From randomisation until cut-off date 14JUN2016.

Population: Randomised Set: This patient set included all patients who were randomised to receive treatment, whether treated or not.

OS was defined as the time from randomisation to the time of death from any cause. Median, 95% Confidence Interval were calculated from an unadjusted Kaplan-Meier curve for each treatment arm.

Outcome measures

Outcome measures
Measure	Placebo n=382 Participants Placebo soft gelatin capsule matching that of Nintedanib twice daily (b.i.d.) administered orally of 21-day treatment course. If required the dose of placebo, could be reduced to 150 mg b.i.d. or 100 mg b.i.d. (according to the protocol-defined dose-reduction scheme). No dose increase was allowed after a dose reduction.	Nintedanib n=386 Participants Nintedanib 200 mg twice daily (b.i.d.) administered orally in the form of a soft gelatin capsule of 21-day treatment course. If required the dose of Nintedanib, could be reduced to 150 mg b.i.d. or 100 mg b.i.d. (according to the protocol-defined dose-reduction scheme). No dose increase was allowed after a dose reduction.
Overall Survival (OS)	6.05 Months Interval 5.22 to 6.97	6.44 Months Interval 5.98 to 7.1

SECONDARY outcome

Timeframe: From randomisation until cut-off date 14JUN2016.

Population: Randomised Set: This patient set included all patients who were randomised to receive treatment, whether treated or not.

Objective tumour response was defined as best overall response of CR or PR determined by central review assessment.

Outcome measures

Outcome measures
Measure	Placebo n=382 Participants Placebo soft gelatin capsule matching that of Nintedanib twice daily (b.i.d.) administered orally of 21-day treatment course. If required the dose of placebo, could be reduced to 150 mg b.i.d. or 100 mg b.i.d. (according to the protocol-defined dose-reduction scheme). No dose increase was allowed after a dose reduction.	Nintedanib n=386 Participants Nintedanib 200 mg twice daily (b.i.d.) administered orally in the form of a soft gelatin capsule of 21-day treatment course. If required the dose of Nintedanib, could be reduced to 150 mg b.i.d. or 100 mg b.i.d. (according to the protocol-defined dose-reduction scheme). No dose increase was allowed after a dose reduction.
Objective Tumour Response (Complete Response (CR)) + Partial Response (PR) by Central Review Assessment	0 Percentage of participants	0 Percentage of participants

SECONDARY outcome

Timeframe: From randomisation until cut-off date 14JUN2016.

Population: Randomised Set: This patient set included all patients who were randomised to receive treatment, whether treated or not.

Disease control was defined as best overall response of CR, PR, or Stable Disease (SD).

Outcome measures

Outcome measures
Measure	Placebo n=382 Participants Placebo soft gelatin capsule matching that of Nintedanib twice daily (b.i.d.) administered orally of 21-day treatment course. If required the dose of placebo, could be reduced to 150 mg b.i.d. or 100 mg b.i.d. (according to the protocol-defined dose-reduction scheme). No dose increase was allowed after a dose reduction.	Nintedanib n=386 Participants Nintedanib 200 mg twice daily (b.i.d.) administered orally in the form of a soft gelatin capsule of 21-day treatment course. If required the dose of Nintedanib, could be reduced to 150 mg b.i.d. or 100 mg b.i.d. (according to the protocol-defined dose-reduction scheme). No dose increase was allowed after a dose reduction.
Disease Control (Complete Response + Partial Response + Stable Disease) by Central Review Assessment	10.5 Percentage of participants Interval 3.68 to 6.67	25.6 Percentage of participants Interval 3.65 to 4.11

Adverse Events

Placebo

Serious events: 133 serious events

Other events: 309 other events

Deaths: 0 deaths

Nintedanib

Serious events: 149 serious events

Other events: 351 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Boehringer Ingelheim Call Center

Boehringer Ingelheim

Phone: 1-800-243-0127

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee 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

Serious adverse events
Measure	Placebo n=381 participants at risk Placebo soft gelatin capsule matching that of Nintedanib twice daily (b.i.d.) administered orally of 21-day treatment course. If required the dose of placebo, could be reduced to 150 mg b.i.d. or 100 mg b.i.d. (according to the protocol-defined dose-reduction scheme). No dose increase was allowed after a dose reduction.	Nintedanib n=384 participants at risk Nintedanib 200 mg twice daily (b.i.d.) administered orally in the form of a soft gelatin capsule of 21-day treatment course. If required the dose of Nintedanib, could be reduced to 150 mg b.i.d. or 100 mg b.i.d. (according to the protocol-defined dose-reduction scheme). No dose increase was allowed after a dose reduction.
Blood and lymphatic system disorders Anaemia	0.26% 1/381 • From first drug administration until 28 days after last drug administration, up to 22.7 months. 1. patient who was randomised to the Placebo was not treated. Consequently, number of subjects that started is 382 but only 381 reported that includes only treated patients. 2. patients were randomised to the Nintedanib were not treated. Consequently, number of subjects that started is 386 but only 384 reported that includes only treated patients.	0.52% 2/384 • From first drug administration until 28 days after last drug administration, up to 22.7 months. 1. patient who was randomised to the Placebo was not treated. Consequently, number of subjects that started is 382 but only 381 reported that includes only treated patients. 2. patients were randomised to the Nintedanib were not treated. Consequently, number of subjects that started is 386 but only 384 reported that includes only treated patients.
Cardiac disorders Atrial fibrillation	0.52% 2/381 • From first drug administration until 28 days after last drug administration, up to 22.7 months. 1. patient who was randomised to the Placebo was not treated. Consequently, number of subjects that started is 382 but only 381 reported that includes only treated patients. 2. patients were randomised to the Nintedanib were not treated. Consequently, number of subjects that started is 386 but only 384 reported that includes only treated patients.	0.00% 0/384 • From first drug administration until 28 days after last drug administration, up to 22.7 months. 1. patient who was randomised to the Placebo was not treated. Consequently, number of subjects that started is 382 but only 381 reported that includes only treated patients. 2. patients were randomised to the Nintedanib were not treated. Consequently, number of subjects that started is 386 but only 384 reported that includes only treated patients.
Cardiac disorders Atrioventricular block complete	0.26% 1/381 • From first drug administration until 28 days after last drug administration, up to 22.7 months. 1. patient who was randomised to the Placebo was not treated. Consequently, number of subjects that started is 382 but only 381 reported that includes only treated patients. 2. patients were randomised to the Nintedanib were not treated. Consequently, number of subjects that started is 386 but only 384 reported that includes only treated patients.	0.00% 0/384 • From first drug administration until 28 days after last drug administration, up to 22.7 months. 1. patient who was randomised to the Placebo was not treated. Consequently, number of subjects that started is 382 but only 381 reported that includes only treated patients. 2. patients were randomised to the Nintedanib were not treated. Consequently, number of subjects that started is 386 but only 384 reported that includes only treated patients.
Cardiac disorders Bradycardia	0.00% 0/381 • From first drug administration until 28 days after last drug administration, up to 22.7 months. 1. patient who was randomised to the Placebo was not treated. Consequently, number of subjects that started is 382 but only 381 reported that includes only treated patients. 2. patients were randomised to the Nintedanib were not treated. Consequently, number of subjects that started is 386 but only 384 reported that includes only treated patients.	0.26% 1/384 • From first drug administration until 28 days after last drug administration, up to 22.7 months. 1. patient who was randomised to the Placebo was not treated. Consequently, number of subjects that started is 382 but only 381 reported that includes only treated patients. 2. patients were randomised to the Nintedanib were not treated. Consequently, number of subjects that started is 386 but only 384 reported that includes only treated patients.
Cardiac disorders Cardiac arrest	0.26% 1/381 • From first drug administration until 28 days after last drug administration, up to 22.7 months. 1. patient who was randomised to the Placebo was not treated. Consequently, number of subjects that started is 382 but only 381 reported that includes only treated patients. 2. patients were randomised to the Nintedanib were not treated. Consequently, number of subjects that started is 386 but only 384 reported that includes only treated patients.	0.00% 0/384 • From first drug administration until 28 days after last drug administration, up to 22.7 months. 1. patient who was randomised to the Placebo was not treated. Consequently, number of subjects that started is 382 but only 381 reported that includes only treated patients. 2. patients were randomised to the Nintedanib were not treated. Consequently, number of subjects that started is 386 but only 384 reported that includes only treated patients.
Cardiac disorders Cardiac failure	0.00% 0/381 • From first drug administration until 28 days after last drug administration, up to 22.7 months. 1. patient who was randomised to the Placebo was not treated. Consequently, number of subjects that started is 382 but only 381 reported that includes only treated patients. 2. patients were randomised to the Nintedanib were not treated. Consequently, number of subjects that started is 386 but only 384 reported that includes only treated patients.	0.26% 1/384 • From first drug administration until 28 days after last drug administration, up to 22.7 months. 1. patient who was randomised to the Placebo was not treated. Consequently, number of subjects that started is 382 but only 381 reported that includes only treated patients. 2. patients were randomised to the Nintedanib were not treated. Consequently, number of subjects that started is 386 but only 384 reported that includes only treated patients.
Ear and labyrinth disorders Vertigo	0.00% 0/381 • From first drug administration until 28 days after last drug administration, up to 22.7 months. 1. patient who was randomised to the Placebo was not treated. Consequently, number of subjects that started is 382 but only 381 reported that includes only treated patients. 2. patients were randomised to the Nintedanib were not treated. Consequently, number of subjects that started is 386 but only 384 reported that includes only treated patients.	0.26% 1/384 • From first drug administration until 28 days after last drug administration, up to 22.7 months. 1. patient who was randomised to the Placebo was not treated. Consequently, number of subjects that started is 382 but only 381 reported that includes only treated patients. 2. patients were randomised to the Nintedanib were not treated. Consequently, number of subjects that started is 386 but only 384 reported that includes only treated patients.
Gastrointestinal disorders Abdominal distension	1.0% 4/381 • From first drug administration until 28 days after last drug administration, up to 22.7 months. 1. patient who was randomised to the Placebo was not treated. Consequently, number of subjects that started is 382 but only 381 reported that includes only treated patients. 2. patients were randomised to the Nintedanib were not treated. Consequently, number of subjects that started is 386 but only 384 reported that includes only treated patients.	0.52% 2/384 • From first drug administration until 28 days after last drug administration, up to 22.7 months. 1. patient who was randomised to the Placebo was not treated. Consequently, number of subjects that started is 382 but only 381 reported that includes only treated patients. 2. patients were randomised to the Nintedanib were not treated. Consequently, number of subjects that started is 386 but only 384 reported that includes only treated patients.
Gastrointestinal disorders Abdominal hernia	0.00% 0/381 • From first drug administration until 28 days after last drug administration, up to 22.7 months. 1. patient who was randomised to the Placebo was not treated. Consequently, number of subjects that started is 382 but only 381 reported that includes only treated patients. 2. patients were randomised to the Nintedanib were not treated. Consequently, number of subjects that started is 386 but only 384 reported that includes only treated patients.	0.26% 1/384 • From first drug administration until 28 days after last drug administration, up to 22.7 months. 1. patient who was randomised to the Placebo was not treated. Consequently, number of subjects that started is 382 but only 381 reported that includes only treated patients. 2. patients were randomised to the Nintedanib were not treated. Consequently, number of subjects that started is 386 but only 384 reported that includes only treated patients.
Gastrointestinal disorders Abdominal pain	1.0% 4/381 • From first drug administration until 28 days after last drug administration, up to 22.7 months. 1. patient who was randomised to the Placebo was not treated. Consequently, number of subjects that started is 382 but only 381 reported that includes only treated patients. 2. patients were randomised to the Nintedanib were not treated. Consequently, number of subjects that started is 386 but only 384 reported that includes only treated patients.	1.6% 6/384 • From first drug administration until 28 days after last drug administration, up to 22.7 months. 1. patient who was randomised to the Placebo was not treated. Consequently, number of subjects that started is 382 but only 381 reported that includes only treated patients. 2. patients were randomised to the Nintedanib were not treated. Consequently, number of subjects that started is 386 but only 384 reported that includes only treated patients.
Gastrointestinal disorders Abdominal pain lower	0.26% 1/381 • From first drug administration until 28 days after last drug administration, up to 22.7 months. 1. patient who was randomised to the Placebo was not treated. Consequently, number of subjects that started is 382 but only 381 reported that includes only treated patients. 2. patients were randomised to the Nintedanib were not treated. Consequently, number of subjects that started is 386 but only 384 reported that includes only treated patients.	0.00% 0/384 • From first drug administration until 28 days after last drug administration, up to 22.7 months. 1. patient who was randomised to the Placebo was not treated. Consequently, number of subjects that started is 382 but only 381 reported that includes only treated patients. 2. patients were randomised to the Nintedanib were not treated. Consequently, number of subjects that started is 386 but only 384 reported that includes only treated patients.
Gastrointestinal disorders Abdominal pain upper	0.26% 1/381 • From first drug administration until 28 days after last drug administration, up to 22.7 months. 1. patient who was randomised to the Placebo was not treated. Consequently, number of subjects that started is 382 but only 381 reported that includes only treated patients. 2. patients were randomised to the Nintedanib were not treated. Consequently, number of subjects that started is 386 but only 384 reported that includes only treated patients.	0.26% 1/384 • From first drug administration until 28 days after last drug administration, up to 22.7 months. 1. patient who was randomised to the Placebo was not treated. Consequently, number of subjects that started is 382 but only 381 reported that includes only treated patients. 2. patients were randomised to the Nintedanib were not treated. Consequently, number of subjects that started is 386 but only 384 reported that includes only treated patients.
Gastrointestinal disorders Ascites	1.0% 4/381 • From first drug administration until 28 days after last drug administration, up to 22.7 months. 1. patient who was randomised to the Placebo was not treated. Consequently, number of subjects that started is 382 but only 381 reported that includes only treated patients. 2. patients were randomised to the Nintedanib were not treated. Consequently, number of subjects that started is 386 but only 384 reported that includes only treated patients.	0.26% 1/384 • From first drug administration until 28 days after last drug administration, up to 22.7 months. 1. patient who was randomised to the Placebo was not treated. Consequently, number of subjects that started is 382 but only 381 reported that includes only treated patients. 2. patients were randomised to the Nintedanib were not treated. Consequently, number of subjects that started is 386 but only 384 reported that includes only treated patients.
Gastrointestinal disorders Constipation	0.26% 1/381 • From first drug administration until 28 days after last drug administration, up to 22.7 months. 1. patient who was randomised to the Placebo was not treated. Consequently, number of subjects that started is 382 but only 381 reported that includes only treated patients. 2. patients were randomised to the Nintedanib were not treated. Consequently, number of subjects that started is 386 but only 384 reported that includes only treated patients.	0.52% 2/384 • From first drug administration until 28 days after last drug administration, up to 22.7 months. 1. patient who was randomised to the Placebo was not treated. Consequently, number of subjects that started is 382 but only 381 reported that includes only treated patients. 2. patients were randomised to the Nintedanib were not treated. Consequently, number of subjects that started is 386 but only 384 reported that includes only treated patients.
Gastrointestinal disorders Diarrhoea	0.52% 2/381 • From first drug administration until 28 days after last drug administration, up to 22.7 months. 1. patient who was randomised to the Placebo was not treated. Consequently, number of subjects that started is 382 but only 381 reported that includes only treated patients. 2. patients were randomised to the Nintedanib were not treated. Consequently, number of subjects that started is 386 but only 384 reported that includes only treated patients.	0.52% 2/384 • From first drug administration until 28 days after last drug administration, up to 22.7 months. 1. patient who was randomised to the Placebo was not treated. Consequently, number of subjects that started is 382 but only 381 reported that includes only treated patients. 2. patients were randomised to the Nintedanib were not treated. Consequently, number of subjects that started is 386 but only 384 reported that includes only treated patients.
Gastrointestinal disorders Dysphagia	0.26% 1/381 • From first drug administration until 28 days after last drug administration, up to 22.7 months. 1. patient who was randomised to the Placebo was not treated. Consequently, number of subjects that started is 382 but only 381 reported that includes only treated patients. 2. patients were randomised to the Nintedanib were not treated. Consequently, number of subjects that started is 386 but only 384 reported that includes only treated patients.	0.52% 2/384 • From first drug administration until 28 days after last drug administration, up to 22.7 months. 1. patient who was randomised to the Placebo was not treated. Consequently, number of subjects that started is 382 but only 381 reported that includes only treated patients. 2. patients were randomised to the Nintedanib were not treated. Consequently, number of subjects that started is 386 but only 384 reported that includes only treated patients.
Gastrointestinal disorders Enterocutaneous fistula	0.00% 0/381 • From first drug administration until 28 days after last drug administration, up to 22.7 months. 1. patient who was randomised to the Placebo was not treated. Consequently, number of subjects that started is 382 but only 381 reported that includes only treated patients. 2. patients were randomised to the Nintedanib were not treated. Consequently, number of subjects that started is 386 but only 384 reported that includes only treated patients.	0.26% 1/384 • From first drug administration until 28 days after last drug administration, up to 22.7 months. 1. patient who was randomised to the Placebo was not treated. Consequently, number of subjects that started is 382 but only 381 reported that includes only treated patients. 2. patients were randomised to the Nintedanib were not treated. Consequently, number of subjects that started is 386 but only 384 reported that includes only treated patients.
Gastrointestinal disorders Fistula of small intestine	0.26% 1/381 • From first drug administration until 28 days after last drug administration, up to 22.7 months. 1. patient who was randomised to the Placebo was not treated. Consequently, number of subjects that started is 382 but only 381 reported that includes only treated patients. 2. patients were randomised to the Nintedanib were not treated. Consequently, number of subjects that started is 386 but only 384 reported that includes only treated patients.	0.00% 0/384 • From first drug administration until 28 days after last drug administration, up to 22.7 months. 1. patient who was randomised to the Placebo was not treated. Consequently, number of subjects that started is 382 but only 381 reported that includes only treated patients. 2. patients were randomised to the Nintedanib were not treated. Consequently, number of subjects that started is 386 but only 384 reported that includes only treated patients.
Gastrointestinal disorders Gastrointestinal haemorrhage	0.26% 1/381 • From first drug administration until 28 days after last drug administration, up to 22.7 months. 1. patient who was randomised to the Placebo was not treated. Consequently, number of subjects that started is 382 but only 381 reported that includes only treated patients. 2. patients were randomised to the Nintedanib were not treated. Consequently, number of subjects that started is 386 but only 384 reported that includes only treated patients.	0.00% 0/384 • From first drug administration until 28 days after last drug administration, up to 22.7 months. 1. patient who was randomised to the Placebo was not treated. Consequently, number of subjects that started is 382 but only 381 reported that includes only treated patients. 2. patients were randomised to the Nintedanib were not treated. Consequently, number of subjects that started is 386 but only 384 reported that includes only treated patients.
Gastrointestinal disorders Gastrointestinal hypomotility	0.00% 0/381 • From first drug administration until 28 days after last drug administration, up to 22.7 months. 1. patient who was randomised to the Placebo was not treated. Consequently, number of subjects that started is 382 but only 381 reported that includes only treated patients. 2. patients were randomised to the Nintedanib were not treated. Consequently, number of subjects that started is 386 but only 384 reported that includes only treated patients.	0.26% 1/384 • From first drug administration until 28 days after last drug administration, up to 22.7 months. 1. patient who was randomised to the Placebo was not treated. Consequently, number of subjects that started is 382 but only 381 reported that includes only treated patients. 2. patients were randomised to the Nintedanib were not treated. Consequently, number of subjects that started is 386 but only 384 reported that includes only treated patients.
Gastrointestinal disorders Ileus	0.52% 2/381 • From first drug administration until 28 days after last drug administration, up to 22.7 months. 1. patient who was randomised to the Placebo was not treated. Consequently, number of subjects that started is 382 but only 381 reported that includes only treated patients. 2. patients were randomised to the Nintedanib were not treated. Consequently, number of subjects that started is 386 but only 384 reported that includes only treated patients.	1.3% 5/384 • From first drug administration until 28 days after last drug administration, up to 22.7 months. 1. patient who was randomised to the Placebo was not treated. Consequently, number of subjects that started is 382 but only 381 reported that includes only treated patients. 2. patients were randomised to the Nintedanib were not treated. Consequently, number of subjects that started is 386 but only 384 reported that includes only treated patients.
Gastrointestinal disorders Incarcerated inguinal hernia	0.00% 0/381 • From first drug administration until 28 days after last drug administration, up to 22.7 months. 1. patient who was randomised to the Placebo was not treated. Consequently, number of subjects that started is 382 but only 381 reported that includes only treated patients. 2. patients were randomised to the Nintedanib were not treated. Consequently, number of subjects that started is 386 but only 384 reported that includes only treated patients.	0.52% 2/384 • From first drug administration until 28 days after last drug administration, up to 22.7 months. 1. patient who was randomised to the Placebo was not treated. Consequently, number of subjects that started is 382 but only 381 reported that includes only treated patients. 2. patients were randomised to the Nintedanib were not treated. Consequently, number of subjects that started is 386 but only 384 reported that includes only treated patients.
Gastrointestinal disorders Intestinal obstruction	1.6% 6/381 • From first drug administration until 28 days after last drug administration, up to 22.7 months. 1. patient who was randomised to the Placebo was not treated. Consequently, number of subjects that started is 382 but only 381 reported that includes only treated patients. 2. patients were randomised to the Nintedanib were not treated. Consequently, number of subjects that started is 386 but only 384 reported that includes only treated patients.	1.6% 6/384 • From first drug administration until 28 days after last drug administration, up to 22.7 months. 1. patient who was randomised to the Placebo was not treated. Consequently, number of subjects that started is 382 but only 381 reported that includes only treated patients. 2. patients were randomised to the Nintedanib were not treated. Consequently, number of subjects that started is 386 but only 384 reported that includes only treated patients.
Gastrointestinal disorders Intestinal prolapse	0.00% 0/381 • From first drug administration until 28 days after last drug administration, up to 22.7 months. 1. patient who was randomised to the Placebo was not treated. Consequently, number of subjects that started is 382 but only 381 reported that includes only treated patients. 2. patients were randomised to the Nintedanib were not treated. Consequently, number of subjects that started is 386 but only 384 reported that includes only treated patients.	0.26% 1/384 • From first drug administration until 28 days after last drug administration, up to 22.7 months. 1. patient who was randomised to the Placebo was not treated. Consequently, number of subjects that started is 382 but only 381 reported that includes only treated patients. 2. patients were randomised to the Nintedanib were not treated. Consequently, number of subjects that started is 386 but only 384 reported that includes only treated patients.
Gastrointestinal disorders Large intestinal obstruction	0.00% 0/381 • From first drug administration until 28 days after last drug administration, up to 22.7 months. 1. patient who was randomised to the Placebo was not treated. Consequently, number of subjects that started is 382 but only 381 reported that includes only treated patients. 2. patients were randomised to the Nintedanib were not treated. Consequently, number of subjects that started is 386 but only 384 reported that includes only treated patients.	0.26% 1/384 • From first drug administration until 28 days after last drug administration, up to 22.7 months. 1. patient who was randomised to the Placebo was not treated. Consequently, number of subjects that started is 382 but only 381 reported that includes only treated patients. 2. patients were randomised to the Nintedanib were not treated. Consequently, number of subjects that started is 386 but only 384 reported that includes only treated patients.
Gastrointestinal disorders Large intestinal stenosis	0.00% 0/381 • From first drug administration until 28 days after last drug administration, up to 22.7 months. 1. patient who was randomised to the Placebo was not treated. Consequently, number of subjects that started is 382 but only 381 reported that includes only treated patients. 2. patients were randomised to the Nintedanib were not treated. Consequently, number of subjects that started is 386 but only 384 reported that includes only treated patients.	0.26% 1/384 • From first drug administration until 28 days after last drug administration, up to 22.7 months. 1. patient who was randomised to the Placebo was not treated. Consequently, number of subjects that started is 382 but only 381 reported that includes only treated patients. 2. patients were randomised to the Nintedanib were not treated. Consequently, number of subjects that started is 386 but only 384 reported that includes only treated patients.
Gastrointestinal disorders Large intestine perforation	0.00% 0/381 • From first drug administration until 28 days after last drug administration, up to 22.7 months. 1. patient who was randomised to the Placebo was not treated. Consequently, number of subjects that started is 382 but only 381 reported that includes only treated patients. 2. patients were randomised to the Nintedanib were not treated. Consequently, number of subjects that started is 386 but only 384 reported that includes only treated patients.	0.52% 2/384 • From first drug administration until 28 days after last drug administration, up to 22.7 months. 1. patient who was randomised to the Placebo was not treated. Consequently, number of subjects that started is 382 but only 381 reported that includes only treated patients. 2. patients were randomised to the Nintedanib were not treated. Consequently, number of subjects that started is 386 but only 384 reported that includes only treated patients.
Gastrointestinal disorders Lower gastrointestinal haemorrhage	0.52% 2/381 • From first drug administration until 28 days after last drug administration, up to 22.7 months. 1. patient who was randomised to the Placebo was not treated. Consequently, number of subjects that started is 382 but only 381 reported that includes only treated patients. 2. patients were randomised to the Nintedanib were not treated. Consequently, number of subjects that started is 386 but only 384 reported that includes only treated patients.	0.00% 0/384 • From first drug administration until 28 days after last drug administration, up to 22.7 months. 1. patient who was randomised to the Placebo was not treated. Consequently, number of subjects that started is 382 but only 381 reported that includes only treated patients. 2. patients were randomised to the Nintedanib were not treated. Consequently, number of subjects that started is 386 but only 384 reported that includes only treated patients.
Gastrointestinal disorders Mallory-Weiss syndrome	0.26% 1/381 • From first drug administration until 28 days after last drug administration, up to 22.7 months. 1. patient who was randomised to the Placebo was not treated. Consequently, number of subjects that started is 382 but only 381 reported that includes only treated patients. 2. patients were randomised to the Nintedanib were not treated. Consequently, number of subjects that started is 386 but only 384 reported that includes only treated patients.	0.00% 0/384 • From first drug administration until 28 days after last drug administration, up to 22.7 months. 1. patient who was randomised to the Placebo was not treated. Consequently, number of subjects that started is 382 but only 381 reported that includes only treated patients. 2. patients were randomised to the Nintedanib were not treated. Consequently, number of subjects that started is 386 but only 384 reported that includes only treated patients.
Gastrointestinal disorders Nausea	1.0% 4/381 • From first drug administration until 28 days after last drug administration, up to 22.7 months. 1. patient who was randomised to the Placebo was not treated. Consequently, number of subjects that started is 382 but only 381 reported that includes only treated patients. 2. patients were randomised to the Nintedanib were not treated. Consequently, number of subjects that started is 386 but only 384 reported that includes only treated patients.	0.78% 3/384 • From first drug administration until 28 days after last drug administration, up to 22.7 months. 1. patient who was randomised to the Placebo was not treated. Consequently, number of subjects that started is 382 but only 381 reported that includes only treated patients. 2. patients were randomised to the Nintedanib were not treated. Consequently, number of subjects that started is 386 but only 384 reported that includes only treated patients.
Gastrointestinal disorders Pancreatitis	0.00% 0/381 • From first drug administration until 28 days after last drug administration, up to 22.7 months. 1. patient who was randomised to the Placebo was not treated. Consequently, number of subjects that started is 382 but only 381 reported that includes only treated patients. 2. patients were randomised to the Nintedanib were not treated. Consequently, number of subjects that started is 386 but only 384 reported that includes only treated patients.	0.26% 1/384 • From first drug administration until 28 days after last drug administration, up to 22.7 months. 1. patient who was randomised to the Placebo was not treated. Consequently, number of subjects that started is 382 but only 381 reported that includes only treated patients. 2. patients were randomised to the Nintedanib were not treated. Consequently, number of subjects that started is 386 but only 384 reported that includes only treated patients.
Gastrointestinal disorders Proctalgia	0.26% 1/381 • From first drug administration until 28 days after last drug administration, up to 22.7 months. 1. patient who was randomised to the Placebo was not treated. Consequently, number of subjects that started is 382 but only 381 reported that includes only treated patients. 2. patients were randomised to the Nintedanib were not treated. Consequently, number of subjects that started is 386 but only 384 reported that includes only treated patients.	0.00% 0/384 • From first drug administration until 28 days after last drug administration, up to 22.7 months. 1. patient who was randomised to the Placebo was not treated. Consequently, number of subjects that started is 382 but only 381 reported that includes only treated patients. 2. patients were randomised to the Nintedanib were not treated. Consequently, number of subjects that started is 386 but only 384 reported that includes only treated patients.
Gastrointestinal disorders Rectal haemorrhage	0.00% 0/381 • From first drug administration until 28 days after last drug administration, up to 22.7 months. 1. patient who was randomised to the Placebo was not treated. Consequently, number of subjects that started is 382 but only 381 reported that includes only treated patients. 2. patients were randomised to the Nintedanib were not treated. Consequently, number of subjects that started is 386 but only 384 reported that includes only treated patients.	0.26% 1/384 • From first drug administration until 28 days after last drug administration, up to 22.7 months. 1. patient who was randomised to the Placebo was not treated. Consequently, number of subjects that started is 382 but only 381 reported that includes only treated patients. 2. patients were randomised to the Nintedanib were not treated. Consequently, number of subjects that started is 386 but only 384 reported that includes only treated patients.
Gastrointestinal disorders Rectal obstruction	0.00% 0/381 • From first drug administration until 28 days after last drug administration, up to 22.7 months. 1. patient who was randomised to the Placebo was not treated. Consequently, number of subjects that started is 382 but only 381 reported that includes only treated patients. 2. patients were randomised to the Nintedanib were not treated. Consequently, number of subjects that started is 386 but only 384 reported that includes only treated patients.	0.26% 1/384 • From first drug administration until 28 days after last drug administration, up to 22.7 months. 1. patient who was randomised to the Placebo was not treated. Consequently, number of subjects that started is 382 but only 381 reported that includes only treated patients. 2. patients were randomised to the Nintedanib were not treated. Consequently, number of subjects that started is 386 but only 384 reported that includes only treated patients.
Gastrointestinal disorders Rectal tenesmus	0.00% 0/381 • From first drug administration until 28 days after last drug administration, up to 22.7 months. 1. patient who was randomised to the Placebo was not treated. Consequently, number of subjects that started is 382 but only 381 reported that includes only treated patients. 2. patients were randomised to the Nintedanib were not treated. Consequently, number of subjects that started is 386 but only 384 reported that includes only treated patients.	0.26% 1/384 • From first drug administration until 28 days after last drug administration, up to 22.7 months. 1. patient who was randomised to the Placebo was not treated. Consequently, number of subjects that started is 382 but only 381 reported that includes only treated patients. 2. patients were randomised to the Nintedanib were not treated. Consequently, number of subjects that started is 386 but only 384 reported that includes only treated patients.
Gastrointestinal disorders Small intestinal obstruction	0.00% 0/381 • From first drug administration until 28 days after last drug administration, up to 22.7 months. 1. patient who was randomised to the Placebo was not treated. Consequently, number of subjects that started is 382 but only 381 reported that includes only treated patients. 2. patients were randomised to the Nintedanib were not treated. Consequently, number of subjects that started is 386 but only 384 reported that includes only treated patients.	0.26% 1/384 • From first drug administration until 28 days after last drug administration, up to 22.7 months. 1. patient who was randomised to the Placebo was not treated. Consequently, number of subjects that started is 382 but only 381 reported that includes only treated patients. 2. patients were randomised to the Nintedanib were not treated. Consequently, number of subjects that started is 386 but only 384 reported that includes only treated patients.
Gastrointestinal disorders Subileus	0.26% 1/381 • From first drug administration until 28 days after last drug administration, up to 22.7 months. 1. patient who was randomised to the Placebo was not treated. Consequently, number of subjects that started is 382 but only 381 reported that includes only treated patients. 2. patients were randomised to the Nintedanib were not treated. Consequently, number of subjects that started is 386 but only 384 reported that includes only treated patients.	0.00% 0/384 • From first drug administration until 28 days after last drug administration, up to 22.7 months. 1. patient who was randomised to the Placebo was not treated. Consequently, number of subjects that started is 382 but only 381 reported that includes only treated patients. 2. patients were randomised to the Nintedanib were not treated. Consequently, number of subjects that started is 386 but only 384 reported that includes only treated patients.
Gastrointestinal disorders Vomiting	0.52% 2/381 • From first drug administration until 28 days after last drug administration, up to 22.7 months. 1. patient who was randomised to the Placebo was not treated. Consequently, number of subjects that started is 382 but only 381 reported that includes only treated patients. 2. patients were randomised to the Nintedanib were not treated. Consequently, number of subjects that started is 386 but only 384 reported that includes only treated patients.	1.3% 5/384 • From first drug administration until 28 days after last drug administration, up to 22.7 months. 1. patient who was randomised to the Placebo was not treated. Consequently, number of subjects that started is 382 but only 381 reported that includes only treated patients. 2. patients were randomised to the Nintedanib were not treated. Consequently, number of subjects that started is 386 but only 384 reported that includes only treated patients.
General disorders Asthenia	0.79% 3/381 • From first drug administration until 28 days after last drug administration, up to 22.7 months. 1. patient who was randomised to the Placebo was not treated. Consequently, number of subjects that started is 382 but only 381 reported that includes only treated patients. 2. patients were randomised to the Nintedanib were not treated. Consequently, number of subjects that started is 386 but only 384 reported that includes only treated patients.	1.0% 4/384 • From first drug administration until 28 days after last drug administration, up to 22.7 months. 1. patient who was randomised to the Placebo was not treated. Consequently, number of subjects that started is 382 but only 381 reported that includes only treated patients. 2. patients were randomised to the Nintedanib were not treated. Consequently, number of subjects that started is 386 but only 384 reported that includes only treated patients.
General disorders Chest pain	0.00% 0/381 • From first drug administration until 28 days after last drug administration, up to 22.7 months. 1. patient who was randomised to the Placebo was not treated. Consequently, number of subjects that started is 382 but only 381 reported that includes only treated patients. 2. patients were randomised to the Nintedanib were not treated. Consequently, number of subjects that started is 386 but only 384 reported that includes only treated patients.	0.26% 1/384 • From first drug administration until 28 days after last drug administration, up to 22.7 months. 1. patient who was randomised to the Placebo was not treated. Consequently, number of subjects that started is 382 but only 381 reported that includes only treated patients. 2. patients were randomised to the Nintedanib were not treated. Consequently, number of subjects that started is 386 but only 384 reported that includes only treated patients.

Other adverse events
Measure	Placebo n=381 participants at risk Placebo soft gelatin capsule matching that of Nintedanib twice daily (b.i.d.) administered orally of 21-day treatment course. If required the dose of placebo, could be reduced to 150 mg b.i.d. or 100 mg b.i.d. (according to the protocol-defined dose-reduction scheme). No dose increase was allowed after a dose reduction.	Nintedanib n=384 participants at risk Nintedanib 200 mg twice daily (b.i.d.) administered orally in the form of a soft gelatin capsule of 21-day treatment course. If required the dose of Nintedanib, could be reduced to 150 mg b.i.d. or 100 mg b.i.d. (according to the protocol-defined dose-reduction scheme). No dose increase was allowed after a dose reduction.
Blood and lymphatic system disorders Anaemia	5.8% 22/381 • From first drug administration until 28 days after last drug administration, up to 22.7 months. 1. patient who was randomised to the Placebo was not treated. Consequently, number of subjects that started is 382 but only 381 reported that includes only treated patients. 2. patients were randomised to the Nintedanib were not treated. Consequently, number of subjects that started is 386 but only 384 reported that includes only treated patients.	6.0% 23/384 • From first drug administration until 28 days after last drug administration, up to 22.7 months. 1. patient who was randomised to the Placebo was not treated. Consequently, number of subjects that started is 382 but only 381 reported that includes only treated patients. 2. patients were randomised to the Nintedanib were not treated. Consequently, number of subjects that started is 386 but only 384 reported that includes only treated patients.
Gastrointestinal disorders Abdominal pain	15.5% 59/381 • From first drug administration until 28 days after last drug administration, up to 22.7 months. 1. patient who was randomised to the Placebo was not treated. Consequently, number of subjects that started is 382 but only 381 reported that includes only treated patients. 2. patients were randomised to the Nintedanib were not treated. Consequently, number of subjects that started is 386 but only 384 reported that includes only treated patients.	16.9% 65/384 • From first drug administration until 28 days after last drug administration, up to 22.7 months. 1. patient who was randomised to the Placebo was not treated. Consequently, number of subjects that started is 382 but only 381 reported that includes only treated patients. 2. patients were randomised to the Nintedanib were not treated. Consequently, number of subjects that started is 386 but only 384 reported that includes only treated patients.
Gastrointestinal disorders Abdominal pain upper	5.5% 21/381 • From first drug administration until 28 days after last drug administration, up to 22.7 months. 1. patient who was randomised to the Placebo was not treated. Consequently, number of subjects that started is 382 but only 381 reported that includes only treated patients. 2. patients were randomised to the Nintedanib were not treated. Consequently, number of subjects that started is 386 but only 384 reported that includes only treated patients.	6.5% 25/384 • From first drug administration until 28 days after last drug administration, up to 22.7 months. 1. patient who was randomised to the Placebo was not treated. Consequently, number of subjects that started is 382 but only 381 reported that includes only treated patients. 2. patients were randomised to the Nintedanib were not treated. Consequently, number of subjects that started is 386 but only 384 reported that includes only treated patients.
Gastrointestinal disorders Constipation	15.0% 57/381 • From first drug administration until 28 days after last drug administration, up to 22.7 months. 1. patient who was randomised to the Placebo was not treated. Consequently, number of subjects that started is 382 but only 381 reported that includes only treated patients. 2. patients were randomised to the Nintedanib were not treated. Consequently, number of subjects that started is 386 but only 384 reported that includes only treated patients.	16.9% 65/384 • From first drug administration until 28 days after last drug administration, up to 22.7 months. 1. patient who was randomised to the Placebo was not treated. Consequently, number of subjects that started is 382 but only 381 reported that includes only treated patients. 2. patients were randomised to the Nintedanib were not treated. Consequently, number of subjects that started is 386 but only 384 reported that includes only treated patients.
Gastrointestinal disorders Diarrhoea	15.0% 57/381 • From first drug administration until 28 days after last drug administration, up to 22.7 months. 1. patient who was randomised to the Placebo was not treated. Consequently, number of subjects that started is 382 but only 381 reported that includes only treated patients. 2. patients were randomised to the Nintedanib were not treated. Consequently, number of subjects that started is 386 but only 384 reported that includes only treated patients.	45.6% 175/384 • From first drug administration until 28 days after last drug administration, up to 22.7 months. 1. patient who was randomised to the Placebo was not treated. Consequently, number of subjects that started is 382 but only 381 reported that includes only treated patients. 2. patients were randomised to the Nintedanib were not treated. Consequently, number of subjects that started is 386 but only 384 reported that includes only treated patients.
Gastrointestinal disorders Nausea	27.0% 103/381 • From first drug administration until 28 days after last drug administration, up to 22.7 months. 1. patient who was randomised to the Placebo was not treated. Consequently, number of subjects that started is 382 but only 381 reported that includes only treated patients. 2. patients were randomised to the Nintedanib were not treated. Consequently, number of subjects that started is 386 but only 384 reported that includes only treated patients.	42.4% 163/384 • From first drug administration until 28 days after last drug administration, up to 22.7 months. 1. patient who was randomised to the Placebo was not treated. Consequently, number of subjects that started is 382 but only 381 reported that includes only treated patients. 2. patients were randomised to the Nintedanib were not treated. Consequently, number of subjects that started is 386 but only 384 reported that includes only treated patients.
Gastrointestinal disorders Vomiting	18.6% 71/381 • From first drug administration until 28 days after last drug administration, up to 22.7 months. 1. patient who was randomised to the Placebo was not treated. Consequently, number of subjects that started is 382 but only 381 reported that includes only treated patients. 2. patients were randomised to the Nintedanib were not treated. Consequently, number of subjects that started is 386 but only 384 reported that includes only treated patients.	38.8% 149/384 • From first drug administration until 28 days after last drug administration, up to 22.7 months. 1. patient who was randomised to the Placebo was not treated. Consequently, number of subjects that started is 382 but only 381 reported that includes only treated patients. 2. patients were randomised to the Nintedanib were not treated. Consequently, number of subjects that started is 386 but only 384 reported that includes only treated patients.
General disorders Asthenia	12.1% 46/381 • From first drug administration until 28 days after last drug administration, up to 22.7 months. 1. patient who was randomised to the Placebo was not treated. Consequently, number of subjects that started is 382 but only 381 reported that includes only treated patients. 2. patients were randomised to the Nintedanib were not treated. Consequently, number of subjects that started is 386 but only 384 reported that includes only treated patients.	14.1% 54/384 • From first drug administration until 28 days after last drug administration, up to 22.7 months. 1. patient who was randomised to the Placebo was not treated. Consequently, number of subjects that started is 382 but only 381 reported that includes only treated patients. 2. patients were randomised to the Nintedanib were not treated. Consequently, number of subjects that started is 386 but only 384 reported that includes only treated patients.
General disorders Fatigue	23.4% 89/381 • From first drug administration until 28 days after last drug administration, up to 22.7 months. 1. patient who was randomised to the Placebo was not treated. Consequently, number of subjects that started is 382 but only 381 reported that includes only treated patients. 2. patients were randomised to the Nintedanib were not treated. Consequently, number of subjects that started is 386 but only 384 reported that includes only treated patients.	29.4% 113/384 • From first drug administration until 28 days after last drug administration, up to 22.7 months. 1. patient who was randomised to the Placebo was not treated. Consequently, number of subjects that started is 382 but only 381 reported that includes only treated patients. 2. patients were randomised to the Nintedanib were not treated. Consequently, number of subjects that started is 386 but only 384 reported that includes only treated patients.
General disorders Oedema peripheral	7.3% 28/381 • From first drug administration until 28 days after last drug administration, up to 22.7 months. 1. patient who was randomised to the Placebo was not treated. Consequently, number of subjects that started is 382 but only 381 reported that includes only treated patients. 2. patients were randomised to the Nintedanib were not treated. Consequently, number of subjects that started is 386 but only 384 reported that includes only treated patients.	5.7% 22/384 • From first drug administration until 28 days after last drug administration, up to 22.7 months. 1. patient who was randomised to the Placebo was not treated. Consequently, number of subjects that started is 382 but only 381 reported that includes only treated patients. 2. patients were randomised to the Nintedanib were not treated. Consequently, number of subjects that started is 386 but only 384 reported that includes only treated patients.
General disorders Pain	5.5% 21/381 • From first drug administration until 28 days after last drug administration, up to 22.7 months. 1. patient who was randomised to the Placebo was not treated. Consequently, number of subjects that started is 382 but only 381 reported that includes only treated patients. 2. patients were randomised to the Nintedanib were not treated. Consequently, number of subjects that started is 386 but only 384 reported that includes only treated patients.	2.3% 9/384 • From first drug administration until 28 days after last drug administration, up to 22.7 months. 1. patient who was randomised to the Placebo was not treated. Consequently, number of subjects that started is 382 but only 381 reported that includes only treated patients. 2. patients were randomised to the Nintedanib were not treated. Consequently, number of subjects that started is 386 but only 384 reported that includes only treated patients.
General disorders Pyrexia	11.8% 45/381 • From first drug administration until 28 days after last drug administration, up to 22.7 months. 1. patient who was randomised to the Placebo was not treated. Consequently, number of subjects that started is 382 but only 381 reported that includes only treated patients. 2. patients were randomised to the Nintedanib were not treated. Consequently, number of subjects that started is 386 but only 384 reported that includes only treated patients.	13.8% 53/384 • From first drug administration until 28 days after last drug administration, up to 22.7 months. 1. patient who was randomised to the Placebo was not treated. Consequently, number of subjects that started is 382 but only 381 reported that includes only treated patients. 2. patients were randomised to the Nintedanib were not treated. Consequently, number of subjects that started is 386 but only 384 reported that includes only treated patients.
Investigations Alanine aminotransferase increased	6.0% 23/381 • From first drug administration until 28 days after last drug administration, up to 22.7 months. 1. patient who was randomised to the Placebo was not treated. Consequently, number of subjects that started is 382 but only 381 reported that includes only treated patients. 2. patients were randomised to the Nintedanib were not treated. Consequently, number of subjects that started is 386 but only 384 reported that includes only treated patients.	23.4% 90/384 • From first drug administration until 28 days after last drug administration, up to 22.7 months. 1. patient who was randomised to the Placebo was not treated. Consequently, number of subjects that started is 382 but only 381 reported that includes only treated patients. 2. patients were randomised to the Nintedanib were not treated. Consequently, number of subjects that started is 386 but only 384 reported that includes only treated patients.
Investigations Aspartate aminotransferase increased	11.5% 44/381 • From first drug administration until 28 days after last drug administration, up to 22.7 months. 1. patient who was randomised to the Placebo was not treated. Consequently, number of subjects that started is 382 but only 381 reported that includes only treated patients. 2. patients were randomised to the Nintedanib were not treated. Consequently, number of subjects that started is 386 but only 384 reported that includes only treated patients.	23.4% 90/384 • From first drug administration until 28 days after last drug administration, up to 22.7 months. 1. patient who was randomised to the Placebo was not treated. Consequently, number of subjects that started is 382 but only 381 reported that includes only treated patients. 2. patients were randomised to the Nintedanib were not treated. Consequently, number of subjects that started is 386 but only 384 reported that includes only treated patients.
Investigations Blood alkaline phosphatase increased	5.8% 22/381 • From first drug administration until 28 days after last drug administration, up to 22.7 months. 1. patient who was randomised to the Placebo was not treated. Consequently, number of subjects that started is 382 but only 381 reported that includes only treated patients. 2. patients were randomised to the Nintedanib were not treated. Consequently, number of subjects that started is 386 but only 384 reported that includes only treated patients.	7.3% 28/384 • From first drug administration until 28 days after last drug administration, up to 22.7 months. 1. patient who was randomised to the Placebo was not treated. Consequently, number of subjects that started is 382 but only 381 reported that includes only treated patients. 2. patients were randomised to the Nintedanib were not treated. Consequently, number of subjects that started is 386 but only 384 reported that includes only treated patients.
Investigations Blood bilirubin increased	3.9% 15/381 • From first drug administration until 28 days after last drug administration, up to 22.7 months. 1. patient who was randomised to the Placebo was not treated. Consequently, number of subjects that started is 382 but only 381 reported that includes only treated patients. 2. patients were randomised to the Nintedanib were not treated. Consequently, number of subjects that started is 386 but only 384 reported that includes only treated patients.	6.8% 26/384 • From first drug administration until 28 days after last drug administration, up to 22.7 months. 1. patient who was randomised to the Placebo was not treated. Consequently, number of subjects that started is 382 but only 381 reported that includes only treated patients. 2. patients were randomised to the Nintedanib were not treated. Consequently, number of subjects that started is 386 but only 384 reported that includes only treated patients.
Investigations Weight decreased	3.4% 13/381 • From first drug administration until 28 days after last drug administration, up to 22.7 months. 1. patient who was randomised to the Placebo was not treated. Consequently, number of subjects that started is 382 but only 381 reported that includes only treated patients. 2. patients were randomised to the Nintedanib were not treated. Consequently, number of subjects that started is 386 but only 384 reported that includes only treated patients.	9.1% 35/384 • From first drug administration until 28 days after last drug administration, up to 22.7 months. 1. patient who was randomised to the Placebo was not treated. Consequently, number of subjects that started is 382 but only 381 reported that includes only treated patients. 2. patients were randomised to the Nintedanib were not treated. Consequently, number of subjects that started is 386 but only 384 reported that includes only treated patients.
Metabolism and nutrition disorders Decreased appetite	25.2% 96/381 • From first drug administration until 28 days after last drug administration, up to 22.7 months. 1. patient who was randomised to the Placebo was not treated. Consequently, number of subjects that started is 382 but only 381 reported that includes only treated patients. 2. patients were randomised to the Nintedanib were not treated. Consequently, number of subjects that started is 386 but only 384 reported that includes only treated patients.	33.3% 128/384 • From first drug administration until 28 days after last drug administration, up to 22.7 months. 1. patient who was randomised to the Placebo was not treated. Consequently, number of subjects that started is 382 but only 381 reported that includes only treated patients. 2. patients were randomised to the Nintedanib were not treated. Consequently, number of subjects that started is 386 but only 384 reported that includes only treated patients.
Musculoskeletal and connective tissue disorders Arthralgia	1.6% 6/381 • From first drug administration until 28 days after last drug administration, up to 22.7 months. 1. patient who was randomised to the Placebo was not treated. Consequently, number of subjects that started is 382 but only 381 reported that includes only treated patients. 2. patients were randomised to the Nintedanib were not treated. Consequently, number of subjects that started is 386 but only 384 reported that includes only treated patients.	5.5% 21/384 • From first drug administration until 28 days after last drug administration, up to 22.7 months. 1. patient who was randomised to the Placebo was not treated. Consequently, number of subjects that started is 382 but only 381 reported that includes only treated patients. 2. patients were randomised to the Nintedanib were not treated. Consequently, number of subjects that started is 386 but only 384 reported that includes only treated patients.
Musculoskeletal and connective tissue disorders Back pain	7.9% 30/381 • From first drug administration until 28 days after last drug administration, up to 22.7 months. 1. patient who was randomised to the Placebo was not treated. Consequently, number of subjects that started is 382 but only 381 reported that includes only treated patients. 2. patients were randomised to the Nintedanib were not treated. Consequently, number of subjects that started is 386 but only 384 reported that includes only treated patients.	8.6% 33/384 • From first drug administration until 28 days after last drug administration, up to 22.7 months. 1. patient who was randomised to the Placebo was not treated. Consequently, number of subjects that started is 382 but only 381 reported that includes only treated patients. 2. patients were randomised to the Nintedanib were not treated. Consequently, number of subjects that started is 386 but only 384 reported that includes only treated patients.
Nervous system disorders Headache	5.0% 19/381 • From first drug administration until 28 days after last drug administration, up to 22.7 months. 1. patient who was randomised to the Placebo was not treated. Consequently, number of subjects that started is 382 but only 381 reported that includes only treated patients. 2. patients were randomised to the Nintedanib were not treated. Consequently, number of subjects that started is 386 but only 384 reported that includes only treated patients.	6.5% 25/384 • From first drug administration until 28 days after last drug administration, up to 22.7 months. 1. patient who was randomised to the Placebo was not treated. Consequently, number of subjects that started is 382 but only 381 reported that includes only treated patients. 2. patients were randomised to the Nintedanib were not treated. Consequently, number of subjects that started is 386 but only 384 reported that includes only treated patients.
Psychiatric disorders Insomnia	5.8% 22/381 • From first drug administration until 28 days after last drug administration, up to 22.7 months. 1. patient who was randomised to the Placebo was not treated. Consequently, number of subjects that started is 382 but only 381 reported that includes only treated patients. 2. patients were randomised to the Nintedanib were not treated. Consequently, number of subjects that started is 386 but only 384 reported that includes only treated patients.	7.8% 30/384 • From first drug administration until 28 days after last drug administration, up to 22.7 months. 1. patient who was randomised to the Placebo was not treated. Consequently, number of subjects that started is 382 but only 381 reported that includes only treated patients. 2. patients were randomised to the Nintedanib were not treated. Consequently, number of subjects that started is 386 but only 384 reported that includes only treated patients.
Renal and urinary disorders Proteinuria	3.1% 12/381 • From first drug administration until 28 days after last drug administration, up to 22.7 months. 1. patient who was randomised to the Placebo was not treated. Consequently, number of subjects that started is 382 but only 381 reported that includes only treated patients. 2. patients were randomised to the Nintedanib were not treated. Consequently, number of subjects that started is 386 but only 384 reported that includes only treated patients.	8.9% 34/384 • From first drug administration until 28 days after last drug administration, up to 22.7 months. 1. patient who was randomised to the Placebo was not treated. Consequently, number of subjects that started is 382 but only 381 reported that includes only treated patients. 2. patients were randomised to the Nintedanib were not treated. Consequently, number of subjects that started is 386 but only 384 reported that includes only treated patients.
Respiratory, thoracic and mediastinal disorders Cough	12.6% 48/381 • From first drug administration until 28 days after last drug administration, up to 22.7 months. 1. patient who was randomised to the Placebo was not treated. Consequently, number of subjects that started is 382 but only 381 reported that includes only treated patients. 2. patients were randomised to the Nintedanib were not treated. Consequently, number of subjects that started is 386 but only 384 reported that includes only treated patients.	10.9% 42/384 • From first drug administration until 28 days after last drug administration, up to 22.7 months. 1. patient who was randomised to the Placebo was not treated. Consequently, number of subjects that started is 382 but only 381 reported that includes only treated patients. 2. patients were randomised to the Nintedanib were not treated. Consequently, number of subjects that started is 386 but only 384 reported that includes only treated patients.
Respiratory, thoracic and mediastinal disorders Dyspnoea	10.5% 40/381 • From first drug administration until 28 days after last drug administration, up to 22.7 months. 1. patient who was randomised to the Placebo was not treated. Consequently, number of subjects that started is 382 but only 381 reported that includes only treated patients. 2. patients were randomised to the Nintedanib were not treated. Consequently, number of subjects that started is 386 but only 384 reported that includes only treated patients.	9.1% 35/384 • From first drug administration until 28 days after last drug administration, up to 22.7 months. 1. patient who was randomised to the Placebo was not treated. Consequently, number of subjects that started is 382 but only 381 reported that includes only treated patients. 2. patients were randomised to the Nintedanib were not treated. Consequently, number of subjects that started is 386 but only 384 reported that includes only treated patients.
Skin and subcutaneous tissue disorders Rash	3.7% 14/381 • From first drug administration until 28 days after last drug administration, up to 22.7 months. 1. patient who was randomised to the Placebo was not treated. Consequently, number of subjects that started is 382 but only 381 reported that includes only treated patients. 2. patients were randomised to the Nintedanib were not treated. Consequently, number of subjects that started is 386 but only 384 reported that includes only treated patients.	5.2% 20/384 • From first drug administration until 28 days after last drug administration, up to 22.7 months. 1. patient who was randomised to the Placebo was not treated. Consequently, number of subjects that started is 382 but only 381 reported that includes only treated patients. 2. patients were randomised to the Nintedanib were not treated. Consequently, number of subjects that started is 386 but only 384 reported that includes only treated patients.
Vascular disorders Hypertension	3.9% 15/381 • From first drug administration until 28 days after last drug administration, up to 22.7 months. 1. patient who was randomised to the Placebo was not treated. Consequently, number of subjects that started is 382 but only 381 reported that includes only treated patients. 2. patients were randomised to the Nintedanib were not treated. Consequently, number of subjects that started is 386 but only 384 reported that includes only treated patients.	10.9% 42/384 • From first drug administration until 28 days after last drug administration, up to 22.7 months. 1. patient who was randomised to the Placebo was not treated. Consequently, number of subjects that started is 382 but only 381 reported that includes only treated patients. 2. patients were randomised to the Nintedanib were not treated. Consequently, number of subjects that started is 386 but only 384 reported that includes only treated patients.