An Open-label Trial of the Long-term Safety and Tolerability of Nintedanib Per os, on Top of Standard of Care, Over at Least 3 Years, in Children and Adolescents With Clinically Significant Fibrosing Interstitial Lung Disease (InPedILD®-ON)
Phase: PHASE3
Conditions: Lung Diseases, Interstitial
Sponsor: Boehringer Ingelheim

 
 
001-MCS-40-106_RD-03 (19.0) / Saved on: 03 Nov 2020 
Clinical Trial Protocol 
TITLE PAGE 
Document Number: 
c34797766 / 228892_978711_6.0 
EU Trial No.  
Universal Trial Number 
2024-515743-27-00 
U1111-1305-7514  
BI Trial No. 
1199-0378 
BI Investigational 
Medicinal Product(s) 
Ofev®, nintedanib 
Title 
An open-label trial of the long-term safety and tolerability of 
nintedanib per os, on top of standard of care, over at least 3 years, 
in children and adolescents with clinically significant fibrosing 
Interstitial Lung Disease (InPedILD®-ON) 
Lay Title 
A study to evaluate long-term safety of nintedanib in children and 
adolescents with interstitial lung disease (InPedILD®-ON) 
Clinical Phase 
III 
Clinical Trial Leader 
Coordinating 
Investigator 
Current Version and 
Date 
Version 6.0, 27 Nov 2024 
Original Protocol 
Date 
17 Jun 2021 
Page 1 of 202 
Proprietary confidential information. 
© 2024 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved. 
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission. 

Boehringer Ingelheim 
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BI Trial No.: 1199-0378 
c34797766 / 228892_978711_6.0  Clinical Trial Protocol 
 
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CLINICAL TRIAL PROTOCOL SYNOPSIS 
Company name 
Boehringer Ingelheim  
Original Protocol date 
17 Jun 2021  
Revision date 
27 Nov 2024 
BI trial number 
1199-0378 
Title of trial 
An open-label trial of the long-term safety and tolerability of 
nintedanib per os, on top of standard of care, over at least 3 years, in 
children and adolescents with clinically significant fibrosing 
Interstitial Lung Disease (InPedILD®-ON) 
Coordinating 
Investigator 
Trial site(s) 
Multi-centre trial conducted in approximately 23 countries 
Clinical phase 
III 
Trial rationale 
The rationale of this open label trial is to collect additional safety and 
efficacy data of nintedanib in children and adolescents with clinically 
significant fibrosing ILD for at least 3 years (applies to patients 
rolling over from the parent trial) or until alternative treatment 
options become available or are made available (e.g., via marketing 
authorization, via compassionate use or via similar process) (applies 
to new patients and to roll-over patients after 3 years). 
Trial objective(s) 
The main objective of the trial is to assess the safety and tolerability 
of long-term treatment with nintedanib in pediatric patients with 
clinically significant fibrosing ILD. 
Trial endpoints 
The primary endpoint is the incidence of treatment emergent adverse 
events over the whole trial. 
Trial design 
Open label trial 
Total number of patients 
entered  
Approximately 50 to 60 patients 
Number of patients per 
treatment group 
Not applicable 
Diagnosis 
Clinically significant fibrosing ILD 
Main inclusion and 
exclusion criteria 
 
Patients who have completed the 1199-0337 (InPedILD®) study and 
did not prematurely discontinue trial treatment 
or 
Patients (children and adolescents ≥6 and ≤17 years old except in 
France (adolescents ≥12 and ≤17 years old)) with clinically 
significant fibrosing ILD who meet the following eligibility criteria:  
Main inclusion criteria: 
Evidence of fibrosing ILD on HRCT within 12 months of Visit 1, 
FVC % predicted ≥25% at Visit 2 and clinically significant disease at 
Visit 2 based on either clinical markers of disease severity or 

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27 Nov 2024 
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evidence of clinical progression over time. 
Main exclusion criteria: 
AST and/or ALT and/or bilirubin >1.5 x ULN, and/or eGFR <30 
mL/min/1.73m2, and/or underlying chronic liver disease (Child Pugh 
A, B or C hepatic impairment) at Visit 1; significant pulmonary 
arterial hypertension, any cardiovascular disease excluded by 
protocol, history of thrombotic event within 12 months of Visit 1, 
bleeding risk. 
Test product(s) 
nintedanib 
 
dose 
150 mg b.i.d. (300 mg daily), 100 mg b.i.d. (200 mg daily), 3x25 mg 
b.i.d. (150 mg daily), 2x25 mg b.i.d. (100 mg daily) or 25 mg b.i.d. 
(50 mg daily). 
The dose assigned is based on patient’s weight. Dose reduction is 
possible to manage adverse events. The lowest possible dose is 25 mg 
b.i.d. (50 mg daily). 
 
mode of 
administration 
Per os 
Comparator product(s) 
Not applicable 
 
dose 
Not applicable 
 
mode of 
administration 
Not applicable 
Duration of treatment 
Treatment duration for each patient will be variable. 
 
For roll-over patients: at least 3 years; or until alternative treatment 
options become or are made available (e.g., via marketing 
authorization, via compassionate use, or via similar process) to the 
patient outside of the clinical trial. 
 
For new patients: until the overall end of the trial (with expected 
minimum treatment duration of 76 weeks). 
 
Exception: patients aged 21 years must complete the trial before their 
22nd birthday. 
Consequently, a treatment duration of at least 3 years might not be 
reached by some patients aged 21. 
 
The overall end of trial will take place approximately when last roll-
over patient is expected to reach 3 years of treatment 
 
) ensuring that nintedanib or alternative treatment 
options (e.g., via marketing authorization, via compassionate use, or 
via similar process) will be available for all remaining patients (roll-
over or new patients) outside the trial at this time. 
Statistical methods 
Descriptive statistics will be provided for adverse events 
 
. 
 

Boehringer Ingelheim 
27 Nov 2024 
BI Trial No.: 1199-0378 
c34797766 / 228892_978711_6.0   
 
Clinical Trial Protocol 
 
 
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 FLOW CHART V1-V11 
Trial Periods 
Screening 
Treatment3 
Visits  
11 
2 
34 
3a3&4 
4 
4a3 
5 
5a3 
6 
6a3 
7 
7a3 
8 
8a3 
9 
9a3 
10 
10a3 
11 
11a3 
Weeks2 
-4 
 
2 
 
12 
 
24 
 
36 
 
52 
 
64 
 
76 
 
88 
 
104 
 
Days2 
≤28d before
D1 
D12 
15 
 
85 
 
169 
 
253 
 
365 
 
449 
 
533 
 
617 
 
729 
 
Time window for visits (days) 
  
none 
±3 
 
±3 
  
±3 
  
±7 
  
±7 
  
±7 
  
 ±7 
  
±7 
  
±7 
  
Informed consent and assent5 
X 
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
HRCT sent to central review6 
X 
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Biopsy sent to central review7 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Demographics 
X 
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Medical history 
X 
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Baseline conditions8,  
X 
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X30 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination, Vital 
signs9 
X 
X 
X 
 
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
Height (standing and sitting)10 
X 
X 
  
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
Leg length 
  
X 
  
  
X 
  
X 
  
X 
  
X 
  
  
  
X 
  
  
  
X 
  
Weight10 
X 
X 
X 
 
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
12 lead-ECG (at rest)11 
X 
(X) 
  
  
  
  
X 
  
  
  
X 
  
  
  
X 
  
  
  
X 
  
Safety Laboratory (blood and 
urine)12 
X9 
X 
X 
(X) 
X 
(X) 
X 
(X) 
X 
(X) 
X 
(X) 
X 
(X) 
X 
(X) 
X 
(X) 
X 
(X) 
Pregnancy tests13 
X 
X 
X 
 
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
Dispense urine pregnancy test 
with Diary Card (if applicable)13 
  
X13 
 X13 
 
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
Review Diary Card for urine 
pregnancy test (if applicable)13 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
  
X 
  
  
X 
  
X 
  
X 
  
X 
  
 
  
 
  
 
  
 
  

Boehringer Ingelheim 
27 Nov 2024 
BI Trial No.: 1199-0378 
c34797766 / 228892_978711_6.0   
 
Clinical Trial Protocol 
 
 
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Trial Periods 
Screening 
Treatment3 
Visits  
11 
2 
34 
3a3&4 
4 
4a3 
5 
5a3 
6 
6a3 
7 
7a3 
8 
8a3 
9 
9a3 
10 
10a3 
11 
11a3 
Weeks2 
-4 
 
2 
 
12 
 
24 
 
36 
 
52 
 
64 
 
76 
 
88 
 
104 
 
Days2 
≤28d before
D1 
D12 
15 
 
85 
 
169 
 
253 
 
365 
 
449 
 
533 
 
617 
 
729 
 
Time window for visits (days) 
  
none 
±3 
 
±3 
  
±3 
  
±7 
  
±7 
  
±7 
  
 ±7 
  
±7 
  
±7 
  
  
X 
X 
X 
 
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
FVC15 
X 
X 
X 
 
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
DLCO15 
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
  
  
  
  
  
  
  
  
 X 
  
  
  
  
  
  
  
 X  
  
Review of in-/ exclusion criteria 
X 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
IRT call/ notification17 
X 
X 
X 
 
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
Administer trial drug 
  
X 
X18 
  
X18 
  
X18 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X14  
 
X18 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X18 
  
X18 
  
X18 
  
  
  
  
  
  
  
  
  
  
  
  
  
Dispense trial drug 
  
X 
X 
 
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
Collect trial drugs 
  
  
X 
 
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
Compliance check/ drug 
accountability 
  
  
X 
 
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
Criteria for dose reduction/ 
interruption check 
  
 X29 
X 
 
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
  
  
X 
  
  
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
  
  
  
  
X 
  
  
  
X 
  
  
  
 X 
  
  
  
 X 
  
  
X 
  
  
  
  
X 
  
  
  
X 
  
  
  
X  
  
  
  
X  
  
  
X 
X 
 
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
  
X 
X 
 
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
  
X 
X 
 
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  

Boehringer Ingelheim 
27 Nov 2024 
BI Trial No.: 1199-0378 
c34797766 / 228892_978711_6.0   
 
Clinical Trial Protocol 
 
 
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Trial Periods 
Screening 
Treatment3 
Visits  
11 
2 
34 
3a3&4 
4 
4a3 
5 
5a3 
6 
6a3 
7 
7a3 
8 
8a3 
9 
9a3 
10 
10a3 
11 
11a3 
Weeks2 
-4 
 
2 
 
12 
 
24 
 
36 
 
52 
 
64 
 
76 
 
88 
 
104 
 
Days2 
≤28d before
D1 
D12 
15 
 
85 
 
169 
 
253 
 
365 
 
449 
 
533 
 
617 
 
729 
 
Time window for visits (days) 
  
none 
±3 
 
±3 
  
±3 
  
±7 
  
±7 
  
±7 
  
 ±7 
  
±7 
  
±7 
  
Bone imaging (if applicable)21 
 
ON REGULAR BASIS (Q12W to Q48W)21 
Dental examination22 
 
ON REGULAR BASIS (Q12W to Q24W)22 
Dental imaging23 
 
ON REGULAR BASIS (Q24W to Q48W)23 
All AEs/ SAEs/AESIs 
X 
X 
X 
 
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
Concomitant therapy  
 
X 
X 
X 
 
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
Vital status data25 
  
  
  
  
  
  
(X)25 
  
  
  
(X)25 
  
  
  
(X)25 
  
  
  
(X)25 
  
 
 
 

Boehringer Ingelheim 
27 Nov 2024 
BI Trial No.: 1199-0378 
c34797766 / 228892_978711_6.0   
 
Clinical Trial Protocol 
 
 
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FLOW CHART V12 - END OF STUDY 
Trial Periods 
Treatment3 
Follow-up 
Visits  
12 
12a3 
13 
13a3 
14 
14a3 
15 
15a3 
X 
Xa3 
EoT24, 30 
F-up25 
/EoS26, 30 
Weeks2 
116 
 
128 
 
140 
 
156 
 
156 + 
Q12w 
 
  
EoT 
+4wks 
Days2 
813 
 
897 
 
981 
 
1093 
 
1093+ Q84 
 
  
EoT 
+28 
Time window for visits (days) 
±7 
  
 ±7 
  
±7 
  
±7 
  
±7 
 
  
+7 
 
 
 
 
 
 
 
 
 
 
 
X30 
X30 
Physical examination, Vital 
signs9 
X 
  
X 
  
X 
  
X 
  
X 
 
X 
X 
Height (standing and sitting)10 
X 
  
X 
  
X 
  
X 
  
X 
 
X 
(X)26 
Leg length 
  
  
X 
  
  
  
X 
  
X /Q24w 
 
X 
 
Weight10 
X 
  
X 
  
X 
  
X 
  
X 
 
X 
(X) 26 
12 lead-ECG (at rest)11 
  
  
X 
  
  
  
X 
  
X /Q24w 
 
X 
 
Safety Laboratory (blood and 
urine)12 
X 
(X) 
X 
(X) 
X 
(X) 
X 
(X) 
X 
(X) 
X 
(X)26 
Pregnancy tests13 
X 
  
X 
  
X 
  
X 
  
X 
 
X 
X 
Dispense urine pregnancy test 
with Diary Card (if applicable)13 
X 
  
X 
  
X 
  
X 
  
X 
 
 
 
Review Diary Card for urine 
pregnancy test (if applicable)13 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
  
X 
  
X 
  
X 
  
X 
  
X 
 
X 
X 
FVC15 
X 
  
X 
  
X 
  
X 
  
X 
 
X 
X 
  
  
  
  
  
  
X 
  
 
 
X 
 
IRT call/ notification17 
X 
  
X 
  
X 
  
X 
  
X 
 
 X 
 
Dispense trial drug 
X 
  
X 
  
X 
  
X 
  
X 
 
  
 
Collect trial drugs 
X 
  
X 
  
X 
  
X 
  
X 
 
X  
 
Compliance check/ drug 
X 
  
X 
  
X 
  
X 
  
X 
 
X 
 

Boehringer Ingelheim 
27 Nov 2024 
BI Trial No.: 1199-0378 
c34797766 / 228892_978711_6.0   
 
Clinical Trial Protocol 
 
 
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Trial Periods 
Treatment3 
Follow-up 
Visits  
12 
12a3 
13 
13a3 
14 
14a3 
15 
15a3 
X 
Xa3 
EoT24, 30 
F-up25 
/EoS26, 30 
Weeks2 
116 
 
128 
 
140 
 
156 
 
156 + 
Q12w 
 
  
EoT 
+4wks 
Days2 
813 
 
897 
 
981 
 
1093 
 
1093+ Q84 
 
  
EoT 
+28 
Time window for visits (days) 
±7 
  
 ±7 
  
±7 
  
±7 
  
±7 
 
  
+7 
accountability 
Criteria for dose reduction/ 
interruption check 
X 
  
X 
  
X 
  
X 
  
X 
 
 
 
  
  
 X  
  
  
  
 X  
  
X/Q24w 
 
X  
 
  
  
X 
  
  
  
X 
  
X/Q24w 
 
X  
 
X 
  
X 
  
X 
  
X 
  
X 
 
X  
 
X 
  
X 
  
X 
  
X 
  
X 
 
X 
X 
X 
  
X 
  
X 
  
X 
  
X 
 
X 
X 
Bone imaging (if applicable)21 
ON REGULAR BASIS (Q12W to Q48W)21 
X24 
 
Dental examination22 
ON REGULAR BASIS (Q12W to Q24W)22 
X24 
 
Dental imaging23 
ON REGULAR BASIS (Q24W to Q48W)23 
X24 
 
All AEs/ SAEs/AESIs 
X 
  
X 
  
X 
  
X 
  
X 
 
X 
X27 
Concomitant therapy  
 
X 
  
X 
  
X 
  
X 
  
X 
 
X 
X 
Vital status data25 
  
  
(X)25 
  
  
  
(X)25 
  
X/Q24w 
 
  
(X)25 
Completion of patient 
participation28 
 
 
 
 
 
 
(X)28 
 
(X/Q24)28 
 
 
X28 
 
 
 

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27 Nov 2024 
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1. For new patients, the interval between Visit 1 and Visit 2 should be ≤28 days. The interval between Visit 1 and Visit 2 could be >28 days in case the assessments 
required to check inclusion and exclusion criteria cannot be completed within 28 days (e.g. in case the available HRCT scan fails to meet the required image acquisition 
specification, laboratory test results show out-of-range values requiring retest, etc.) but the screening period (from informed consent signature to Visit 2) must not be 
longer than 12 weeks.  
For roll-over patients, Visit 1 and Visit 2 should occur the same day as EoT in InPedILD® 1199-0337 trial. In this case, all common procedures (e.g. physical 
examination, vital signs, height, leg length, weight, pregnancy test, ECG, 
, spirometry and some laboratory tests) will be performed once. If a patient is unable to 
roll-over on the day of EoT in 1199-0337 InPedILD® due to medical reason or in case the site is not ready to be initiated, the patient can be permitted to roll-over within 
8 weeks following EoT. The interval between EoT and Visit1/Visit 2 or Visit 1 and Visit 2 may be extended at the discretion of Sponsor on a case-by-case basis. 
2. Weeks and Days from the Day 1 (day of Visit 2). 
3. During treatment period: 
- 
Intermediate lab tests (“a” Visit) will be done as needed for additional safety monitoring at the discretion of the investigator, or as recommended by the Safety 
Monitoring Committee (SMC). Blood and urine sampling may be collected at the investigational site, primary care physician (GP, Pediatrician or Pulmonologist) or 
external laboratory preferably with specific study kits sent to the central laboratory for analysis or analysed locally. 
- 
Additional visits/ Phone calls (if appropriate) have to be included, in case of dose change (reduction or re-escalation) or in case of capsule’s size change. Please refer 
to Section 6.2.2.  
- 
Additional visits may be needed for following safety assessments: bone imaging, dental examination and dental imaging. Please refer to footnotes 21, 22, 23. 
- 
Patients aged 21 years must complete the trial while being 21 years old. They should perform EoT visit and EoS visit (28 days after) before their 22nd birthday.  
4. For new patients: Visit 3 applicable. For new patients in Norway, the Visit 3a is also applicable and should be performed at Week 6 (Day 43)  
For roll-over patients < 26 weeks (switching from InPedILD® to open label extension trial before Visit 7 (week 26)): Visit 3 applicable. 
For roll-over patients > 26 weeks (switching from InPedILD® to open label extension trial at Visit 7 (week 26) or after): Visit 3 not applicable. 
5. Informed consent, and assent where applicable, will be obtained before any procedure related to the study. When it is obtained before Visit 1, e.g. to allow shipment of 
images for central review, all Adverse Events (AEs) and Concomitant Treatments occurring/given after the informed consent (and assent where applicable) was given, 
have to be recorded, including those that occurred between informed consent and Visit 1. Upon obtaining informed consent, the patient/parent(s)/legal guardian will be 
instructed on procedures to be followed until the next study visit. 
6. For new patients who didn’t previously participate in InPedILD® only - Central review of High-Resolution Computed Tomography (HRCT) for meeting inclusion 
criteria. One HRCT should not be older than 12 months. If the patient does not have an HRCT within 12 months of Visit 1 or the available HRCT scan fails to meet the 
required image acquisition specification (see image acquisition guideline in the ISF), a new HRCT can be performed at discretion of the investigator for the purposes of 
participation in the trial, provided the patient meets all other in-/exclusion criteria. For details about HRCT review, see Section 3.3.2.1. 

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27 Nov 2024 
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7. For new patients who didn’t previously participate in InPedILD® only - Central review of previous documented biopsy for meeting inclusion criteria. For details 
about biopsy review, see Section 3.3.2.1. 
8. Medical conditions that are occurring concomitantly at Visit 1 will be recorded as baseline conditions in the electronic Case Report Form eCRF.  
9. Measurements of vital signs should precede blood sampling, 
 
10. At each time point, height and sitting height will be assessed three times and each assessment will be recorded into the patient’s files and transcribed into the eCRF. An 
average of the 3 measurements will be calculated.  
For new patients who didn’t previously participate in InPedILD®: height and weight assessed in the 2 years prior to screening (Visit 1) will also be collected, if 
available. 
11. Electrocardiogram (ECG) at rest (if possible, prior to blood sampling) will be performed at Visit 1 and at visits specified in the Flow Chart thereafter (every 24 weeks).  
For new patients, it will be repeated at Visit 2 prior to treatment allocation only if abnormal at Visit 1. 
12. For new patients, the safety laboratory tests of Visit 1 must be repeated if interval between Visit 1 and Visit 2 is longer than 6 weeks.  
13. Pregnancy testing should be conducted in all female patients, even pre-menarche, every 4 weeks. Pregnancy blood test will be conducted at each scheduled visit until 
EoT. At the Follow-up/EoS Visit, the pregnancy test will be conducted on urines (if acceptable). Additionally, urine pregnancy test should be repeated at home or at a 
local laboratory / local doctor, every 4-6 weeks if applicable, between clinic visits until the end of the trial. If urine test is not acceptable to local authorities, a blood test 
will be done at a local laboratory. In case of premature treatment discontinuation, when patient continues with visits off treatment, the pregnancy tests at home (for 
female patients) are only required to be continued every 4 weeks for the 3 months after last trial drug intake. 
From Visit 2 for roll-over patients > 26 weeks and from Visit 3 for new patients and for roll-over patients < 26 weeks, urine dipstick pregnancy tests will be 
provided with pregnancy test diary card when needed. Use of pregnancy test diary card will be explained with the patient / parent(s)/legal guardian and training will be 
repeated as needed. The pregnancy test diary card will be used to support the record of the date and result of test(s) between consecutive visits. Pregnancy test diary card 
will be reviewed at clinic visits. In case a positive test is reported the sponsor should be contacted immediately. Refer to Section 3.3.4.1 for further instructions. Refer to 
Section 5.2.7.2.3. for detailed information on event reporting in case of pregnancy. 
14. 
 
15. For new patients: Order of lung function measurements: 1. FVC followed by patient’s rest; 2. DLCO.  
For roll-over patients, DLCO not applicable. 
For all patients: after Visit 2 FVC measurements to be done at the same time each visit (+/- 90 min), with reference time at Visit 2. 
16. 
 
17. Interactive Response Technology (IRT) should be notified upon obtaining informed consent.  

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18. 
Please refer to Appendix 10.1 for details. 
19. 
20. 
21. Bone imaging. Please refer to Section 5.2.5 and to the image acquisition guideline available in the ISF for details. For patients aged 19 and older, please see additional 
information at the end of the footnote. 
For new patients: Bone imaging is required for all new patients who qualified for assignment of nintedanib treatment at Visit 2 as baseline. If it’s not possible to conduct the 
baseline bone imaging at Visit 2, the procedure can be done in the 2 weeks immediately after the visit (until D15).  
Imaging follow-up will be conducted only in patients with open physes at predefined time points. Imaging follow-up will be conducted, if applicable, at 12 weeks, 24 weeks, 
36 weeks, 52 weeks, 76 weeks, 104 weeks, 128 weeks, 156 weeks, and every 24 weeks thereafter until the end of study or closure of the physes. If it’s not possible to conduct 
the follow-up at the predefined time points, the procedure can be done within 1 week before and after this time point with always minimum of 10 weeks (during the first 
year)/22 weeks (thereafter) and always maximum of 16 weeks (during the first year)/28 weeks (thereafter) between 2 procedures.  
For roll-over patients: Bone imaging procedure is not applicable for patients with closed physes at the end of InPedILD®. For all other roll-over patients, previous MRIs/x-
rays of epiphyseal growth plates within 12 weeks (for roll-over patients with treatment duration less than 52 weeks in InPedILD®) and within 24 weeks (for roll-over patients 
with treatment duration more than 52 weeks in InPedILD®) prior Visit 2 should be used as baseline in the analyses of bone imaging (for scheduling of follow-up procedures 
see next paragraph). If a previous MRI/x-ray as outlined above, is not available, an MRI/x-ray should be conducted at Visit 2. If it’s not possible to conduct it at Visit 2, the 
procedure can be done in the 2 weeks immediately after the visit (until D15). 
Irrespective of scheduled visits, imaging follow-up will be conducted only in patients with open physes, every 12 weeks in the year after the start of the trial medication in the 
parent trial (when applicable) and every 24 weeks thereafter until the end of the study or closure of the physes.  
If it’s not possible to conduct the follow-up at the predefined time points, the procedure can be done within 2 weeks before and 4 weeks after this time point with always a 
minimum of 10 weeks (during the first year after the start of the trial medication in the parent trial)/22 weeks (thereafter) and always a maximum of 16 weeks (during the first 
year after the start of the trial medication in the parent trial)/28 weeks (thereafter) between 2 procedures.  
Preponement or postponement of one follow-up procedure by 2 months to the planned timepoint will be allowed once to align this procedure and the subsequent ones with 
the regular clinic visits planned in the protocol. After this alignment, the acceptable time window will be +/-1 week for this procedure (as for new patients). 
For patients aged 19 and older, bone imaging follow-up procedures will be performed around every 48 weeks (instead of around every 24 weeks) until the end of the study 
or closure of the physes. 

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For all patients, if the follow-up procedure cannot be conducted at least every 16 weeks (during the first year)/28 weeks (thereafter), the study treatment of this individual 
patient needs to be interrupted upon discussion with the sponsor (except for the one-time alignment with clinic visits mentioned above for roll-over patients).  
For all patients, timepoints may be adapted on a case-by-case basis after discussion with the sponsor if appropriate for patient’s safety.  
 
22. Clinical dental examination. Please refer to Section 5.2.6. 
For new patients: Clinical dental examination is required according to protocol requirements in all new patients who qualified for assignment of nintedanib treatment at 
Visit 2 as baseline. If it’s not possible to conduct the baseline clinical dental examination at Visit 2, the procedure can be done in the 2 weeks immediately after the visit (until 
D15).  
Follow-up will be conducted, if applicable, at 12 weeks, 24 weeks, 36 weeks, 52 weeks, 76 weeks, 104 weeks, 128 weeks, 156 weeks, and every 24 weeks thereafter until the 
end of the study. If it’s not possible to conduct the follow-up at the predefined time points, the procedure can be done within 1 week before and after this time point with 
always maximum of 16 weeks (during the first year)/28 weeks (thereafter) between 2 procedures.  
For roll-over patients: Previous dental examination at 1199-0337 EoT or within 12 weeks prior Visit 2 should be used as baseline in the analyses of clinical dental 
examinations (for scheduling of follow-up procedures see next paragraph). If a previous dental examination is not available, this examination should be conducted at Visit 2. 
If it’s not possible to conduct the dental examination at Visit 2, the procedure can be done in the 2 weeks immediately after the visit (until D15).  
Irrespective of scheduled visits, follow-up will be conducted, every 12 weeks in the year after the start of the trial medication in the parent trial (when applicable) and every 
24 weeks thereafter until the end of the study.  
If it’s not possible to conduct the follow-up at the predefined time point, the procedure can be done within 2 weeks before and in the 4 weeks after this time point with always 
a maximum of 16 weeks (during the first year after the start of the trial medication in the parent trial)/28 weeks (thereafter) between 2 procedures. 
Preponement or postponement of one follow-up procedure by 2 months to the planned timepoint will be allowed once to align this procedure and the subsequent ones with 
the regular clinic visits planned in the protocol. After this alignment, the acceptable time window will be +/-1 week for this procedure (as for new patients). 
For all patients, if the follow-up procedure cannot be conducted at least every 16 weeks (during the first year)/28 weeks (thereafter year), the study treatment of this 
individual patient needs to be interrupted upon discussion with the sponsor (except at the one-time alignment with clinic visits mentioned above for roll-over patients). 
For all patients, timepoints may be adapted on a case-by-case basis after discussion with the sponsor if appropriate for patient’s safety.  
23. Dental imaging. Please refer to Section 5.2.6 and to the image acquisition guideline available in the ISF for details.  
For new patients: Dental imaging is required according to protocol requirements in all patients who qualified for assignment of nintedanib treatment at baseline (Visit 2). If 
it’s not possible to conduct the dental imaging on the day of the Visit 2, the procedure can be done in the 2 weeks immediately after the visit (until D15). 
Follow-up will be conducted, if applicable, at 24 weeks, 52 weeks,104 weeks, 156 weeks, and every 48 weeks thereafter until the end of the study. If it’s not possible to 
conduct the follow-up at the predefined time points, the procedure can be done within 1 week before and after this time point with always a minimum of 22 weeks (during the 
first year)/46 weeks (thereafter) and always a maximum of 28 weeks (during the first year)/52 weeks (thereafter) between 2 procedures. 

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For roll-over patients: Previous dental imaging at 1199-0337 EoT or within 24 weeks prior EoT/Visit 1/Visit 2 should be used as baseline in the analyses of dental imaging 
(for scheduling of follow-up procedures see next paragraph). If a previous dental imaging is not available, this dental imaging should be conducted at Visit 2. If it’s not 
possible to conduct the dental imaging on the day of the Visit 2, the procedure can be done in the 2 weeks immediately after the visit (until D15). 
Irrespective of scheduled visits, follow-up will be conducted, every 24 weeks in the year after the start of the trial medication in the parent trial (when applicable) and every 
48 weeks thereafter until the end of the study. 
If it’s not possible to conduct the follow-up at the predefined time point, the procedure can be done within 2 weeks before or 4 weeks after this time point with always a 
minimum of 22 weeks (during the first year after the start of the trial medication in the parent trial)/46 weeks (thereafter) and always a maximum of 28 weeks (during the first 
year after the start of the trial medication in the parent trial)/52 weeks (thereafter) between 2 procedures. 
Preponement or postponement of one follow-up procedure by 2 months to the planned timepoint will be allowed once to align this procedure and the subsequent ones with 
the regular clinic visits planned in the protocol. After this alignment, the acceptable time window will be +/-1 week for this procedure (as for new patients). 
For all patients, if the follow-up procedure cannot be conducted at least every 28 weeks (during the first year)/52 weeks (thereafter), the study treatment of this individual 
patient needs to be interrupted upon discussion with the sponsor (except for the one-time alignment with clinic visits mentioned above for roll-over patients). 
For all patients, timepoints may be adapted on a case-by-case basis after discussion with the sponsor if appropriate for patient’s safety. 
 
24. Patients who discontinue trial treatment prematurely should undergo the End of Treatment (EoT) visit as soon as possible. 
At the EoT visit:  
• 
the MRI/x-ray should not be repeated if the last MRI/x-ray was conducted within 24 weeks,  
• 
the dental examination will not be repeated if the last examination was conducted within 12 weeks and  
• 
the dental imaging will not be repeated if the last examination was conducted within 24 weeks.  
If EoT occurs before Visit 15 (week 156), roll-over patients will be asked to remain in the study and to return to all regularly scheduled visits until week 156. New 
patients who prematurely discontinued trial drug will be asked to remain in the study and to return to all regularly scheduled visits until the overall end of trial. 
At future off-treatment visits, all assessments 
, and IRT call/notification will be performed. The first visit after the EoT 
visit will be skipped if the EoT visit occurs within 4 weeks prior to scheduled visit but if MRI/x-ray and/or dental examinations/imaging were planned at this visit, then 
they should be performed as planned. Only one additional regular follow-up for bone imaging and for dental imaging procedures will be needed after the EOT visit if 
there is no pathological finding. If there is a pathological finding, follow-up procedures will be conducted on individual basis upon discussion with the sponsor and with 
the investigator. Follow–up procedures for clinical dental examination will be conducted as initially planned by the protocol. Urine pregnancy tests at home (for female 
patients) are only required to be continued every 4 weeks for the 3 months after last trial drug intake. 
25. For patients who discontinue trial treatment prematurely and are not able to complete the scheduled visits, a follow-up (FU) visit should be planned 28 days after EoT. 
If the EoT visit has been delayed and has been done 28 days or more after the treatment discontinuation, the follow-up (FU) visit can be skipped. 

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In addition, every attempt will be made to get information on vital status, when applicable, at 24, 52, 76, 104, 128, 156, and every 24 weeks thereafter until the end of the 
study and for new patients at EoS. Please see Section 5.2.7.2.1  
26. End of Study (EoS), synonym for individual patient’s end of trial. Height, weight or safety laboratory test will be repeated at EoS visit in case of clinically relevant 
change at EoT. In exceptional cases, when the patient is not able to come at site for medical reason, the EoS visit can be replaced by a phone call. If the EoT visit has 
been delayed and has been done 28 days or more after the treatment discontinuation, the EoS visit can be skipped.  
27. After the individual patient’s end of the trial the investigator should report only any occurrence of cancer, study treatment related Serious Adverse Events (SAEs) and 
study treatment related Adverse Event of Special Interests (AESIs) of which the investigator may become aware of by any means of communication, e.g. phone call. 
Those AEs should be reported on the BI SAE form, but not on the eCRF. Please see Section 5.2.7.2.1.  
28. For patients who discontinue permanently trial treatment before Visit 15 and who accepted to attend further scheduled visits as per protocol, then the patient’s trial 
completion will be at initial planned date of Visit 15 (at week 156) for roll-over patients and at the overall end of trial for new patients. Completion of trial participation 
will be conducted at EoT visit, if FU/EoS visit is skipped due to delayed EoT for more than 28 days. 
29. For roll-over patients only 
 
 
In the event of force majeure or other disruptive circumstances (e.g. pandemic, war) the investigational plan as per this clinical trial protocol may 
not be feasible at a site. With the consent/assent of the patient/parent(s)/legal guardian, sponsor and investigator may implement risk mitigation 
measures and modifications to CTP standard procedures as described in Section 10.9. See also Section 4.1.4, Section 6.1 and ISF for details.  

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TABLE OF CONTENTS 
TITLE PAGE ........................................................................................................................... 1 
CLINICAL TRIAL PROTOCOL SYNOPSIS ..................................................................... 2 
FLOW CHART V1-V11 .......................................................................................................... 4 
FLOW CHART V12 - END OF STUDY ............................................................................... 7 
 
TABLE OF CONTENTS ...................................................................................................... 16 
ABBREVIATIONS AND DEFINITIONS ........................................................................... 21 
1. 
INTRODUCTION ............................................................................................... 26 
1.1 
MEDICAL BACKGROUND ............................................................................. 26 
1.2 
DRUG PROFILE ................................................................................................ 27 
1.3 
RATIONALE FOR PERFORMING THE TRIAL ......................................... 30 
1.4 
BENEFIT - RISK ASSESSMENT..................................................................... 30 
1.4.1 
Benefits ................................................................................................................. 30 
1.4.2 
Risks ..................................................................................................................... 31 
1.4.3 
Discussion ............................................................................................................. 37 
2. 
TRIAL OBJECTIVES AND ENDPOINTS ...................................................... 38 
2.1 
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS........ 38 
2.1.1 
Main objectives .................................................................................................... 38 
2.1.2 
Primary endpoint(s) ............................................................................................ 38 
2.1.3 
Secondary endpoint(s) ........................................................................................ 38 
3. 
DESCRIPTION OF DESIGN AND TRIAL POPULATION ......................... 40 
3.1 
OVERALL TRIAL DESIGN ............................................................................. 40 
3.2 
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S) ...................................................................................... 43 
3.3 
SELECTION OF TRIAL POPULATION ....................................................... 43 
3.3.1 
Main diagnosis for trial entry ............................................................................ 44 
3.3.2 
Inclusion criteria ................................................................................................. 44 
3.3.2.1 
Evidence of fibrosing ILD for new patients: ........................................................ 45 
3.3.3 
Exclusion criteria ................................................................................................ 46 
3.3.4 
Discontinuation of patients from treatment or assessments ........................... 49 
3.3.4.1 
Discontinuation of trial treatment ......................................................................... 49 

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3.3.4.2 
Withdrawal of consent to trial participation ......................................................... 50 
3.3.4.3 
Discontinuation of the trial by the sponsor ........................................................... 51 
4. 
TREATMENTS ................................................................................................... 52 
4.1 
INVESTIGATIONAL TREATMENTS ........................................................... 52 
4.1.1 
Identity of the Investigational Medicinal Products .......................................... 52 
4.1.2 
Selection of doses in the trial and dose modifications ...................................... 53 
4.1.3 
Method of assigning patients to treatment groups ........................................... 55 
4.1.4 
Drug assignment and administration of doses for each patient...................... 55 
4.1.5 
Blinding and procedures for unblinding ........................................................... 56 
4.1.5.1 
Blinding ................................................................................................................. 56 
4.1.5.2 
Unblinding and breaking the code ........................................................................ 57 
4.1.6 
Packaging, labelling, and re-supply................................................................... 57 
4.1.7 
Storage conditions ............................................................................................... 57 
4.1.8 
Drug accountability............................................................................................. 57 
4.2 
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS ................................................................................................ 58 
4.2.1 
Other treatments and emergency procedures .................................................. 58 
4.2.1.1 
Management of diarrhoea ..................................................................................... 59 
4.2.1.2 
Management of liver enzyme elevations .............................................................. 61 
4.2.1.3 
Management of acute ILD exacerbations ............................................................. 62 
4.2.2 
Restrictions .......................................................................................................... 62 
4.2.2.1 
Restrictions regarding concomitant treatment ...................................................... 62 
4.2.2.2 
Restrictions on diet and life style .......................................................................... 64 
4.2.2.3 
Contraception requirements .................................................................................. 64 
4.3 
TREATMENT COMPLIANCE ........................................................................ 64 
5. 
ASSESSMENTS .................................................................................................. 66 
5.1 
ASSESSMENT OF EFFICACY ........................................................................ 66 
5.1.1 
Assessment of FVC.............................................................................................. 66 
5.2 
ASSESSMENT OF SAFETY ............................................................................. 68 
5.2.1 
Physical examination .......................................................................................... 68 
5.2.1.1 
Body weight .......................................................................................................... 69 
5.2.1.2 
Height, leg length .................................................................................................. 69 
5.2.2 
Vital signs ............................................................................................................. 70 
5.2.3 
Safety laboratory parameters ............................................................................ 70 
5.2.4 
Electrocardiogram .............................................................................................. 73 
5.2.5 
Assessment of pathological findings of epiphyseal growth plate .................... 73 
5.2.6 
Assessment of pathological findings on dental examination or imaging........ 74 
5.2.7 
Assessment of adverse events ............................................................................. 75 

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5.2.7.1 
Definitions of AEs ................................................................................................ 75 
5.2.7.1.1 
Adverse event ........................................................................................................ 75 
5.2.7.1.2 
Serious adverse event ............................................................................................ 76 
5.2.7.1.3 
AEs considered “Always Serious” ........................................................................ 76 
5.2.7.1.4 
Adverse events of special interest ......................................................................... 77 
5.2.7.1.5 
Intensity (severity) of AEs .................................................................................... 77 
5.2.7.1.6 
Causal relationship of AEs .................................................................................... 78 
5.2.7.2 
Adverse event collection and reporting ................................................................ 79 
5.2.7.2.1 
AE Collection ........................................................................................................ 79 
5.2.7.2.2 
AE reporting to the sponsor and timelines ............................................................ 79 
5.2.7.2.3 
Pregnancy .............................................................................................................. 80 
5.2.7.2.4 
Safety monitoring and adverse events with additional information collection ..... 80 
5.5 
BIOBANKING .................................................................................................... 82 
5.6 
OTHER ASSESSMENTS................................................................................... 82 
5.6.4 
Assessment of DLCO ............................................................................................. 84 
5.6.6 
Assessment of HRCT .......................................................................................... 85 
5.7 
APPROPRIATENESS OF MEASUREMENTS .............................................. 86 
6. 
INVESTIGATIONAL PLAN............................................................................. 87 
6.1 
VISIT SCHEDULE ............................................................................................. 87 
6.2 
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS ................. 88 
6.2.1 
Screening and run-in period(s) .......................................................................... 88 
6.2.2 
Treatment period(s) ............................................................................................ 90 
6.2.3 
Follow-up period and trial completion............................................................ 100 

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7. 
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE102 
7.1 
NULL AND ALTERNATIVE HYPOTHESES ............................................. 102 
7.2 
PLANNED ANALYSES ................................................................................... 102 
7.2.1 
General considerations ..................................................................................... 102 
7.2.2 
Handling of Intercurrent Events ..................................................................... 103 
7.2.3 
Primary objective analyses ............................................................................... 104 
7.2.3.1 
Sensitivity Analyses ............................................................................................ 104 
7.2.3.2 
Subgroup Analyses ............................................................................................. 104 
7.2.3.3 
Supplementary Analyses ..................................................................................... 104 
7.2.4 
Secondary objective analyses ........................................................................... 104 
7.2.6 
Safety analyses ................................................................................................... 104 
7.2.8 
Interim Analyses ............................................................................................... 105 
7.3 
HANDLING OF MISSING DATA ................................................................. 106 
7.4 
RANDOMISATION ......................................................................................... 106 
7.5 
DETERMINATION OF SAMPLE SIZE ....................................................... 106 
8. 
INFORMED CONSENT, TRIAL RECORDS, DATA PROTECTION, 
PUBLICATION POLICY, AND ADMINISTRATIVE STRUCTURE ...... 107 
8.1 
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED 
CONSENT ......................................................................................................... 107 
8.2 
DATA QUALITY ASSURANCE .................................................................... 108 
8.3 
RECORDS ......................................................................................................... 109 
8.3.1 
Source documents ............................................................................................. 109 
8.3.2 
Direct access to source data and documents ................................................... 110 
8.3.3 
Storage period of records ................................................................................. 111 
8.4 
EXPEDITED REPORTING OF ADVERSE EVENTS ................................ 111 
8.5 
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY ...... 111 
8.5.1 
Collection, storage and future use of biological samples and corresponding 
data ..................................................................................................................... 111 
8.6 
TRIAL MILESTONES..................................................................................... 112 
8.7 
ADMINISTRATIVE STRUCTURE OF THE TRIAL ................................. 112 
9. 
REFERENCES .................................................................................................. 115 
9.1 
PUBLISHED REFERENCES .......................................................................... 115 
9.2 
UNPUBLISHED REFERENCES .................................................................... 117 
10. 
APPENDICES ................................................................................................... 119 

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10.1 
........... 119 
10.2 
FAN SEVERITY SCORE ................................................................................ 120 
10.3 
ESTIMATED GLOMERULAR FILTRATION RATE ................................ 121 
10.4 
EQUATIONS FOR DLCO ADJUSTMENT FOR HAEMOGLOBIN ........... 123 
10.5 
RECOMMENDATIONS FOR AMBULATORY (OFFICE) BLOOD 
PRESSURE MEASUREMENTS IN CHILDREN AND ADOLESCENTS 124 
10.9 
VISIT MODIFICATION IN EXCEPTIONAL CIRCUMSTANCES ......... 149 
11. 
DESCRIPTION OF GLOBAL AMENDMENT(S) ....................................... 152 
11.1 
GLOBAL AMENDMENT 1 ............................................................................ 152 
11.2 
GLOBAL AMENDMENT 2 ............................................................................ 169 
11.3 
GLOBAL AMENDMENT 3 ............................................................................ 178 
11.4 
GLOBAL AMENDMENT 4 ............................................................................ 197 
11.5 
GLOBAL AMENDMENT 5 ............................................................................ 200 
 

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ABBREVIATIONS AND DEFINITIONS 
ABCA3 
ATP Binding Cassette Subfamily A Member 3 
AC 
Adjudication Committee 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
ALCOA 
Attributable, Legible, Contemporaneous, Original, Accurate  
ALT 
Alanine Aminotransferase 
AMP 
Auxiliary Medicinal Products 
AP 
Alkaline Phosphatase 
aPTT 
Activated Partial Thromboplastin Time 
AST 
Aspartate Aminotransferase 
ATP 
Adenosine Triphosphate 
ATS / ERS 
American Thoracic Society / European Respiratory Society 
AUC 
Area under the Curve 
b.i.d. 
bis in die (twice daily dosing) 
ß-HCG 
Beta- Human Chorionic Gonadotropin 
BI 
Boehringer Ingelheim 
CA 
Competent Authority 
chILD 
Childhood Interstitial Lung Disease 
cHP 
Chronic Hypersensitivity Pneumonitis 
CNS 
Central Nervous System 
COHb 
Carboxyhaemoglobin 
COVID-19 
Coronavirus Disease 2019 
CRA 
Clinical Research Associate 
CRF 
Case Report Form, paper or electronic (sometimes referred to as “eCRF”) 
CRO 
Contract Research Organisation 
CSF1R 
Colony-Stimulating Factor 1 Receptor 
CT 
Computed Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CT Leader 
Clinical Trial Leader 
CT Manager 
Clinical Trial Manager 

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CTP 
Clinical Trial Protocol 
CYP3A4 
Cytochrome P450 3A4 
Δ 
Delta, i.e. difference 
d 
Day(s) 
DBL 
Database Lock 
DILI 
Drug Induced Liver Injury 
DLCO 
Diffusing Capacity of the Lung for Carbon Monoxide 
DM 
Dermatomyositis 
DMC 
Data Monitoring Committee 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
eDC 
Electronic Data Capture 
EDTA 
Ethylenediamine-Tetraacetic Acid 
EoS 
End of Study (corresponds with End of Trial) 
EoT 
End of Treatment 
EudraCT 
European Union Drug Regulating Authorities Clinical Trials Database 
FGFR 
Fibroblast Growth Factor Receptor 
FUP 
Follow-up 
FVC 
Forced Vital Capacity 
GCP 
Good Clinical Practice 
GFR 
Glomerular Filtration Rate 
GGT 
Gamma-Glutamyl Transferase 
GI 
Gastro-Intestinal 
GLI 
Global Lung Initiative 
GMP 
Good Manufacturing Practice 
HA 
Health Authority 
Hb 
Haemoglobin 
HP 
Hypersensitivity Pneumonitis 
HRCT 
High-Resolution Computed Tomography 
HSCT 
Haematopoietic Stem Cell Transplant 

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i.v 
Intravenous 
IB 
Investigator’s Brochure 
ICH 
International Council on Harmonisation 
IEC 
Independent Ethics Committee 
ILD 
Interstitial Lung Disease 
IMP 
Investigational Medicinal Product 
INR 
International Normalized Ratio 
IPD 
Important Protocol Deviation 
IPF 
Idiopathic Pulmonary Fibrosis 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
ISF 
Investigator Site File 
IUD 
Intrauterine Device 
IUS 
Intrauterine Hormone-Releasing System 
Lck 
Lymphocyte-specific Tyrosine-protein Kinase 
LFT 
Liver Function Test 
LPLT 
Last patient last treatment 
Lyn 
Tyrosine-protein Kinase Lyn 
MACE 
Major Adverse Cardiovascular Events 
MCTD 
Mixed Connective Tissue Disease 
MCV 
Mean Corpuscular Volume 
MedDRA 
Medical Dictionary for Drug Regulatory Activities 
MRI 
Magnetic Resonance Imaging 
n.a. 
Not Applicable 
NSIP 
Non-Specific Interstitial Pneumonia 
OPU 
Operative Unit 
PIP 
Pediatric Investigational Plan 
PAH 
Pulmonary Arterial Hypertension 
PBMC 
Peripheral Blood Monocytic Cells 
PDGFR 
Platelet-Derived Growth Factor Receptor 
PF-ILD 
Progressive Fibrosing Interstitial Lung Disease 

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P-gp 
Permeability Glycoprotein 
PM 
Polymyositis 
PT 
Prothrombin Time 
PTM 
Planned Time 
Q 
Quaque i.e. every 
q.d. 
quaque die (once a day) 
RA 
Regulatory Authority 
RA-ILD 
Rheumatoid Arthritis associated ILD 
RBC 
Red Blood Count 
REP 
Residual effect period 
SAE 
Serious Adverse Event 
SARS-CoV2 
Severe Acute Respiratory Syndrome Coronavirus 2 
SFTPC 
Surfactant Protein Deficiency 
SI 
International System of units 
SMC 
Safety Monitoring Committee 
SMQ 
Standard MedDRA Query 
SOP 
Standard Operating Procedure 
Src 
Proto-oncogene Tyrosine-protein Kinase 
SSc-ILD 
Systemic Sclerosis associated ILD 
SUSAR 
Suspected Unexpected Serious Adverse Reactions 
TKI 
Tyrosine Kinase Inhibitor 
TMF 
Trial Master File 
TS 
Treated Set 
TSAP 
Trial Statistical Analysis Plan 
ULN 
Upper limit of normal 
US 
United States 
VEGFR 
Vascular Endothelial Growth Factor receptor 

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WOCBP 
Woman of childbearing potential 

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1. 
INTRODUCTION 
1.1 
MEDICAL BACKGROUND 
Childhood interstitial lung disease ‘chILD’ syndrome’ is a term used to describe diffuse lung 
disease in children with non-specific respiratory symptoms. It consists of a heterogeneous 
group of rare respiratory diseases associated with varying morbidity and mortality [R09-
5337]. Although many of the ILDs present in children can also be found in adults, some 
chILDs are specific to paediatric populations and involve different pathophysiology.  
 
While the pathophysiology underlying most of the pediatric ILD have not been fully 
characterized, according to the expert opinion, the following diagnoses were considered to be 
most likely associated with chronic fibrosis and as such potentially amenable to anti-fibrotic 
treatments:  
surfactant protein deficiency (SFTPC and ABCA3 mutations [i.e. recessive disorder, 
suspected pathogenic variants or deletion/disruption]); 
chronic hypersensitivity pneumonitis (cHP); 
toxic/radiation and drug induced pneumonitis; 
post haematopoietic stem cell transplant (HSCT) fibrosis; 
connective tissue disease related disorders (e.g. juvenile rheumatoid arthritis [RA]/ juvenile 
idiopathic arthritis, SSc, dermatomyositis/polymyositis [DM/PM]; mixed connective tissue 
disease [MCTD]), sarcoidosis. 
 
There are no currently approved therapies for the treatment of ILD in children. Clinical 
management is focused on supportive care (e.g. oxygen therapy, ventilator support). 
Therapeutic treatment is primarily based on anecdotal evidence, such as case series and 
clinical observation. Based on the mode of action of nintedanib and its demonstrated effects 
in adult IPF and other chronic fibrosing ILDs with progressive phenotype, the use of 
nintedanib in fibrotic ILDs in children was considered to be of potential benefit.  
As the underlying diseases associated with the clinically significant fibrosing Interstitial Lung 
Disease may be multiple, different regimes of immunosuppressives/ supportive symptomatic 
therapy are considered as standard of care for the treatment of ILD in children.  
 
In the Phase III trial, InPedILD® (BI trial 1199-0337; EudraCT no. 2018-004530-14), the 
parent trial to this open label study, the dose-exposure relationship and safety of nintedanib in 
children and adolescents with fibrosing ILD was investigated and information on the efficacy 
was collected as well. In the parent trial, following completion of the 24-week blinded, 
placebo-controlled treatment period (Part A) patients entered a variable, open label treatment 
period (Part B). Once 30 patients (including at least 20 patients of age 12-17 years) 
completed PK at week 26, or prematurely discontinued, the first database lock was 
announced (DBL1).  
 
As, the benefit/risk assessment based on the data of the InPedILD® trial justified further 
exposure to nintedanib, all patients still on treatment were offered to participate in this open 
label trial InPedILD®-ON (BI trial 1199-0378). Rollover of eligible patients from InPedILD® 

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study to the current trial was planned to occur without treatment interruption, whenever 
possible [c26450188].  
1.2 
DRUG PROFILE 
Mode of action  
Nintedanib is a tyrosine kinase inhibitor (TKI) targeting fibroblast growth factor receptor 
(FGFR) 1–3, platelet-derived growth factor receptor (PDGFR) α and β, and vascular 
endothelial growth factor receptor (VEGFR 1–3) involved in fibrotic mechanisms active in 
patients with fibrosing interstitial lung diseases. In addition, nintedanib inhibits lymphocyte-
specific tyrosine-protein kinase (Lck), tyrosine-protein kinase lyn (Lyn), proto-oncogene 
tyrosine-protein kinase (Src) [P08-08684] and colony-stimulating factor 1 receptor (CSF1R) 
kinases [P18-00197]. Nintedanib binds competitively to the Adenosine Triphosphate (ATP) 
binding pocket of these kinases and blocks the intracellular signalling cascades, which have 
been demonstrated to be involved in the pathogenesis of fibrotic tissue remodelling in 
interstitial lung diseases.  
 
Nintedanib inhibited migration, proliferation and transformation of human lung and skin 
fibroblasts from patients with IPF and SSc-ILD and the release of extracellular matrix protein 
[P14-07999, P14-17410, P15-06100, P14-02860, P16-05905, P17-06049, P18-05607]. In 
addition nintedanib attenuated cellular processes assumed to be involved in the initiation and 
progression of fibrosis, the release of pro-fibrotic mediators from peripheral blood monocytic 
cells (PBMC) [P17-06052] and the polarisation of macrophages to alternatively activated 
pro-fibrotic macrophages [P17-06049]. Nintedanib was effective in attenuating the 
progressive fibrotic lung pathology in animal models of lung fibrosis independent of the 
initial trigger, chemical, environmental, immunologic or transcriptional [P17-03310, P14-
02860, P15-06100, P17-10564, P18-02512] suggesting a preclinical rationale to treat patients 
with lung fibrosis related to different underlying diseases. 
 
Key pharmacokinetic characteristics 
The pharmacokinetic characteristics of nintedanib have been evaluated in adults, for which a 
summary is provided in the following paragraph. For a more detailed description of the 
nintedanib profile in ILD please refer to the current Investigator’s Brochure (IB) Nintedanib 
in Idiopathic Pulmonary Fibrosis, Systemic Sclerosis, Progressive Fibrosing Interstitial Lung 
Disease [c01783972]. 
 
A soft gelatin capsule formulation of nintedanib is used in humans. After oral administration, 
nintedanib is absorbed quickly and has an absolute bioavailability of slightly below 5% in 
healthy volunteers. 
 
Nintedanib displayed a high volume of distribution and a high total plasma clearance; the 
terminal half-life of nintedanib is in the range of 10 to 15 h. Nintedanib is mainly eliminated 
via faeces. The major metabolites are BIBF 1202 and its glucuronide. Nintedanib is a 
substrate and a weak inhibitor of P-gp. 
 
For adults, nintedanib is available in two dose strengths corresponding to 100 mg and 150 
mg. In the paediatric trial, a third dose strength of 25 mg is available, and nintedanib is 

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administered in doses of 150, 100, 75, or 50 mg bid depending on predefined weight 
categories. 
 
Drug interactions 
Patients taking potent P-gp inhibitors (e.g. ketoconazole, erythromycin or cyclosporine) 
should be monitored closely for tolerability of nintedanib. Management of side effects may 
require interruption, dose reduction, or discontinuation of therapy with nintedanib (see 
Section 4.1.2 and Table 4.2.1:1) [U10-1991, U13-1504, U13-1506, U13-1925, c02153150]. 
 
Potent P-gp inducers (e.g. rifampicin, carbamazepine, phenytoin, and St. John’s Wort) may 
decrease exposure to nintedanib. Selection of an alternate concomitant medication with no or 
minimal P-gp induction potential should be considered [U13-1478, U13-1506, c02153150]. 
For specific restrictions of concomitant medication please refer to Section 4.2.2.1. 
 
Residual Effect Period 
The Residual Effect Period (REP) of nintedanib for the pediatric programme is 28 days.  
 
Data from non-clinical studies 
The antifibrotic effects of nintedanib have been demonstrated in various animal models of 
lung fibrosis, resembling features of idiopathic pulmonary fibrosis (IPF) [P17-03310, P18-
05618], hypersensitivity pneumonitis (HP) [P18-08230], silicosis [P17-03310], systemic 
sclerosis associated ILD (SSc-ILD) [P17-10564] and rheumatoid arthritis associated ILD 
(RA-ILD) [P18-02512]. 
 
Single dose toxicity studies in rats and mice indicated low acute toxic potential of nintedanib. 
In repeat dose toxicology studies in rats, adverse events (e.g. thickening of epiphyseal plates, 
lesions of the incisors) were mostly related to the mechanism of action of nintedanib (i.e. 
VEGFR-2 inhibition). Changes occurring during bone growth phases were reversible after 
discontinuation, while alterations in tooth structure and function were irreversible. These 
findings are considered class effects and may be particularly relevant for growing children 
with regards to development and growth of skeleton and teeth. Diarrhoea and vomiting, 
accompanied by reduced food consumption and loss of body weight, were observed in 
toxicity studies in non-rodents. There was no evidence of liver enzyme increases in rats, 
dogs, and cynomolgus monkeys. Mild liver enzyme increases were only observed in rhesus 
monkeys. 
 
Nintedanib is non-mutagenic. Embryo-foetal lethality and teratogenic effects in rats were 
observed at dose level resulting in plasma drug concentrations comparable or below those in 
humans. 
 
Data from clinical studies 
Nintedanib (trade name: Ofev) is approved for the treatment of IPF and for the treatment of 
SSc-ILD in the US, EU, Japan and a large number of additional countries. Nintedanib is 
recently also approved in the US, EU, Japan, Canada and a number of other countries for the 
treatment of (chronic) fibrosing ILDs with a progressive phenotype. 

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Results from the IPF and SSc-ILD programme in adults show nintedanib to be associated 
with statistically significant and clinically meaningful slowing of the progressive decline in 
lung function as measured by FVC over 1 year.  
 
In the phase III study performed to investigate the efficacy and safety of nintedanib in adult 
subjects with non-IPF chronic fibrosing ILDs that were progressive despite management 
deemed appropriate in clinical practice (Trial 1199.247, INBUILD®) [P17-10582], nintedanib 
significantly reduced the progression of fibrosing ILD, as measured by the annual rate of 
decline in FVC over 52 weeks compared with placebo in both in the overall population and in 
the co-primary population of subjects with a usual interstitial pneumonia (UIP)-like fibrotic 
pattern on HRCT. Compared with placebo, relative reductions of the annual rate of decline in 
FVC over 52 weeks of 57% in the overall population, 61% in patients with HRCT with UIP-
like fibrotic pattern was observed. Consistent results were obtained in the complementary 
population of patients with HRCT with other fibrotic patterns [P19-08802]. Although the 
INBUILD® trial was not powered to study individual ILDs, subgroup analyses suggested that 
nintedanib had a consistent effect on FVC decline across diagnostic groups. The effect of 
nintedanib versus placebo on reducing the rate of FVC decline (mL/year) was consistent 
across subgroups by ILD diagnosis in the overall population [P20-02333]. 
 
The most commonly reported AEs were gastrointestinal disorders. Of those, the most 
frequent events were diarrhoea, nausea, and vomiting. Most of these events were of mild or 
moderate intensity, reported as non-serious, and were managed by symptomatic treatment 
and/or temporary interruption and/or reduction of the nintedanib dose. Diarrhoea, nausea, 
vomiting, which may lead to dehydration and/or electrolyte disturbances, and abdominal pain 
are considered adverse reactions of nintedanib treatment in adults. More patients in the 
nintedanib group than in the placebo group reported weight and appetite decrease as AEs. 
Weight decrease and appetite decrease are considered adverse drug reactions of nintedanib 
treatment. 
 
Cases of drug-induced liver injury (DILI) have been observed with nintedanib treatment in 
adults. The majority of hepatic events occur within the first three months of treatment, 
therefore hepatic transaminase and bilirubin levels should be investigated upon the initiation 
of treatment with nintedanib, at regular intervals during the first three months of treatment 
and periodically thereafter or as clinically indicated. 
 
Considering that VEGFR inhibition might potentially be associated with an increased risk of 
bleeding, patients at known risk for bleeding or who required fibrinolysis, full-dose 
therapeutic anticoagulation, or high dose antiplatelet therapy have been excluded from 
participation in the nintedanib trials, and initiation of any of these therapies during the course 
of the trials required discontinuation of the study medication. 
 
For a more detailed description of the nintedanib profile, please refer to the current 
Investigator’s Brochure (IB) Nintedanib in Idiopathic Pulmonary Fibrosis, Systemic Sclerosis 
and Progressive Fibrosing Interstitial Lung Disease [c01783972]. 

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1.3 
RATIONALE FOR PERFORMING THE TRIAL 
The rationale of this open label trial is to collect additional safety and efficacy data of 
nintedanib in children and adolescents with clinically significant fibrosing ILD for at least 3 
years (applies to patients rolling-over from parent trial) or until alternative treatment options 
become or are made available (e.g., via marketing authorization, via compassionate use, via 
similar process) (applies to new patients and to roll-over patients after 3 years). 
Alternative therapies outside of the trial would be alternative drugs shown to have positive 
benefit-risk assessment, any new therapy which would be available on the market for this 
indication or most probably the availability of nintedanib via marketing authorization, or via 
compassionate use or via similar process, as offered/provided by the sponsor (depending on 
local laws). 
It is expected that availability of nintedanib via marketing authorization, or via 
compassionate use or via similar process, as offered/provided by the sponsor (depending on 
local laws) occurs in most countries 
 However, roll-over 
patients should stay in the trial for at least 3 years and new patients should stay in the trial 
until the end of trial (with the exception of patients > 22 years of age) to ensure collection of 
patient data for a prolonged period of time. 
 
At individual level, this trial is aimed to provide nintedanib treatment for all patients who 
have completed InPedILD®, the parent trial, and who may have experienced benefit from the 
trial medication according to investigator judgement and wish to receive treatment.  
In addition to patients rolled over from the InPedILD® study, in order to address the high 
unmet medical need for safe and efficacious treatment of this devastating condition, newly 
identified children and adolescents with clinically significant fibrosing ILD will enter this 
trial if they meet the eligibility criteria of the protocol.  
Consequently, the patient population will include two cohorts: roll-over patients who have 
completed InPedILD® (and did not prematurely discontinue trial medication in InPedILD®) 
and newly recruited patients who meet the eligibility criteria of the current protocol including 
patients who discontinued treatment in InPedILD® but are again eligible (for details refer to 
section 3.1). 
1.4 
BENEFIT - RISK ASSESSMENT 
1.4.1 
Benefits  
Although the classification of paediatric interstitial lung disease is distinct from that of adult 
ILD, similar to adults with progressive fibrosing ILD, some patients with children’s 
interstitial lung disease (chILD) develop chronic lung fibrosis that is associated with 
significant morbidity and mortality. However, there are currently no approved therapies for 
the treatment of fibrosing interstitial lung disease in children. Building on the scientific 
working hypothesis of the progressive fibrosing ILD programme that lung fibrosis can 
become progressive, self-sustaining independent of the original clinical association or trigger, 
it is postulated that targeted antifibrotic therapy may also provide therapeutic benefit in 
children with fibrosing lung disease. Based on the mode of action and demonstrated effect in 
various pre-clinical models of ILD, treatment of fibrosing ILDs with nintedanib in children 

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and adolescents is expected to lead to similar clinical benefit as in adults with fibrotic lung 
diseases. 
In addition, this open label trial only started when the review of the first InPedILD® results 
had been completed and once the positive benefit/risk assessment justifies the start of this 
follow up open label study. The benefit/ risk was be assessed favorable if nintedanib-treated 
patients showed a comparable exposure to that observed in adults and the safety and 
tolerability of nintedanib was considered acceptable.  
All patients will receive active treatment with nintedanib in this trial. 
1.4.2 
Risks 
Currently, except in the ongoing parent trial, there is no experience with nintedanib treatment 
in the paediatric population. However, the known risks of use of nintedanib in adults can be 
expected in children and adolescents as well. The most frequently reported adverse reactions 
associated with the use of nintedanib in adults relate to the gastrointestinal system (i.e. 
diarrhoea, nausea, vomiting, abdominal pain), decreased appetite and hepatic enzyme 
increase. These events are mostly non-serious and are reversible with dose reductions or drug 
discontinuation. Less frequent and important adverse reactions include bleeding and drug 
induced liver injury (DILI) which may result in fatal outcome. 
 
Additional potential risks specific to the pediatric population based on the mechanism of 
action of nintedanib have also been identified in preclinical animal studies, like a potential 
impact in maturation and growth, in bone development and in tooth development (please see 
Table 1.4.2:1). 
 
The most frequently reported adverse reactions associated with the use of nintedanib in 
adults, and the potential risks specific to the paediatric population, already identified for the 
parent trial, will be carefully monitored in the same way as in the parent trial. The same 
mitigation strategy as the one in place in the InPedILD® trial, outlined below, will apply for 
each potential risk /adverse event in 1199-0378 trial. 
 
Based on the pharmacological mechanism, existing non-clinical, clinical and post-marketing 
data there is no indication that treatment with nintedanib may increase the risk for infection 
with SARS-CoV-2 or for worsening the disease course of COVID-19. However, patients with 
chronic fibrosing interstitial lung disease may be at risk of severe clinical courses due to 
underlying disease, associated co-morbidities and potential use of immunosuppressive co-
medications. 
 
The trial related risk to the COVID-19 pandemic situation is the general risk of travelling to 
site and being at site for assessments. Risk mitigation measures and modifications to CTP 
standard procedures have been defined and are permitted to ensure Investigational Medicine 
Product (IMP) supply to patients and required safety monitoring while reducing the risk of 
exposure to SARS-CoV-2 related to center visits and planned examinations. See Section 6.1 
and Appendix 10.9 for details. 
 
 
 

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Table 1.4.2:1 Overview of trial related risks  
Potential risks of 
clinical relevance for 
this trial 
Summary of data, 
rationale for the risk 
Mitigation strategy 
Investigational Medicinal Product Nintedanib [c01783972] 
Adverse reactions reported in adults: 
Gastrointestinal 
disorders (e.g. 
diarrhoea, nausea, 
vomiting, abdominal 
pain) 
Most frequent, mostly 
non-serious and reversible 
with dose reductions, 
temporary drug 
interruption or drug 
discontinuation. 
Increased awareness of 
symptoms and early 
management, guideline to 
manage diarrhoea (CTP Section 
4.2.1.1), regular monitoring by 
SMC. 
 
Decreased appetite 
 
Same as above. 
 
Weight check every 12-16 weeks, 
regular monitoring by SMC. 
 
Hepatic enzyme 
increased 
 
Same as above. 
 
Increased awareness of 
symptoms and early 
management, guideline to liver 
enzyme elevations (CTP Section 
4.2.1.2), regular monitoring by 
SMC, kits provided to conduct 
blood sampling at local 
laboratory/doctor/health care 
provider for intermediate liver 
function tests (LFTs) by central 
laboratory as needed (“a” visits). 
 
Drug-induced liver 
injury (DILI) 
 
Rare but severe event may 
result in fatal outcome, 
thus under constant 
surveillance by sponsors 
and regulators. 
 
Increased awareness and expedite 
reporting (Adverse Event of 
Special Interest (AESI)). 
Careful monitoring of liver 
function, guideline to liver 
enzyme elevations (CTP Section 
4.2.1.2). Timely detection, 
evaluation, and follow-up of 
laboratory alterations in selected 
liver laboratory parameters to 
ensure patients´ safety. 
Bleeding 
 
Less frequent compared to 
gastrointestinal disorders, 
Increased awareness and expedite 
reporting (AESI). 

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Potential risks of 
clinical relevance for 
this trial 
Summary of data, 
rationale for the risk 
Mitigation strategy 
may result in fatal 
outcome. 
 
Patients at known risk for 
bleeding or who required 
fibrinolysis, full-dose therapeutic 
anticoagulation, or high dose 
antiplatelet therapy are excluded 
from participation in the trial. 
Foetal harm 
 
Pre-clinical studies in 
animals have shown 
reproductive toxicity of 
this drug. [U07-1710, 
U07-1814].  
 
Pregnancy testing in all female 
patients, even pre-menarche, 
every 4 weeks. Pregnancy blood 
test at each scheduled visit until 
EoT, with urine pregnancy tests 
repeated at home or at a local 
laboratory / local doctor, every 4 
weeks between clinic visits until 
the end of the trial and at the 
EoS/Follow-up Visit (if 
acceptable). 
Females of childbearing potential 
are included only if sexual 
abstinence is standard practice, or 
if using a highly effective method 
of birth control in combination 
with a barrier method of birth 
control. 
Potential risks in adults relevant to the paediatric population  
Gastrointestinal 
perforation 
 
Based on mechanism of 
action and post-marketing 
data. 
Increased awareness and expedite 
reporting (AESI). 
Potential risks specific to the paediatric population, risk based on the nintedanib 
mechanism of action: 
Impact on maturation 
and growth 
 
VEGFR blockade results 
in decreased angiogenesis, 
which is essential for 
growth and development 
processes. 
Monitor potential effects on 
growth by: 
Height (standing and sitting) and 
leg length measurement every 
12-16 weeks. Regular evaluation 
by SMC. 
Impact on bone 
development and 
growth 
In animal models, 
nintedanib has been shown 
to alter the epiphyseal 
growth plates of large 
Monitor potential reversible 
effects on bone development and 
growth by: 

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Potential risks of 
clinical relevance for 
this trial 
Summary of data, 
rationale for the risk 
Mitigation strategy 
 
bones (femur and tibia). 
Changes seen in rodents 
were: in epiphyseal growth 
plates (thickening due to 
increased number of 
hypertrophic 
chondrocytes) and 
articular cartilage 
(swelling of chondrocytes 
in the basal layers). These 
changes were reported 
during bone growth and 
were reversible after 
discontinuation. 
 
Regular evaluation by radiology 
expert, with skeletal growth 
monitoring (MRIs or x-rays of 
epiphyseal growth plates) at 
baseline and regular follow-up 
conducted in patients with open 
physes at predefined time points 
until end of the study or closure 
of the physes (defined as 100% 
skeletal maturity) in patients with 
open physes. The follow-up bone 
imagings will be planned, 
irrespective of scheduled visits, 
in order to respect the frequency 
of around every 12 weeks for 
first year and around every 24 
weeks thereafter, taking in 
account, for roll-over patients, 
the participation in the parent 
trial. Please refer to Flow Chart 
footnotes and to CTP Section 
5.2.5 for more details. Expedited 
reporting of pathological findings 
identified on bone imaging 
(AESI). 
Regular evaluation by SMC. 
Not applicable for roll-over 
patients with closed physes at the 
end of parent trial 
Impact on dentition 
 
In animal models, 
nintedanib has been shown 
to impact tooth 
development. Tooth 
changes were major with 
altered tooth structure and 
function which were 
irreversible. (In rodents 
(more prominently in the 
rat than in the mouse), 
nintedanib induced a 
pharmacologically 
mediated dentopathy 
Monitor potential 
severe/irreversible effects on 
dentition by: 
Regular evaluation by dentist, 
with dental examination at 
baseline and regular follow-up 
conducted at predefined time 
points. The follow-up dental 
examinations will be planned, 
irrespective of scheduled visits, 
in order to respect the frequency 
of around every 12 weeks for 
first year and around every 24 

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Potential risks of 
clinical relevance for 
this trial 
Summary of data, 
rationale for the risk 
Mitigation strategy 
(degeneration and loss of 
odontoblasts and 
ameloblasts with 
consecutive structural 
changes of enamel and 
cementum) of the 
continuously growing 
incisors often 
accompanied by dental 
fractures, hemorrhages and 
necroses in the pulp). 
Changes occurred only 
during the growth phase of 
the teeth. 
weeks thereafter, taking in 
account, for roll-over patients, 
the participation in the parent 
trial. Please refer to Flow Chart 
footnotes and to CTP Section 
5.2.6 for more details. 
Expedited reporting of stunted 
growth identified on dental 
imaging (AESI). 
Regular evaluation by paediatric 
dentistry expert, with panoramic 
x-ray at baseline and and regular 
follow-up conducted at 
predefined time points. The 
follow-up dental imagings will be 
planned, irrespective of 
scheduled visits, in order to 
respect the frequency of around 
every 24 weeks for first year and 
around every 48 weeks thereafter, 
taking in account, for roll-over 
patients, the participation in the 
parent trial. Please refer to Flow 
Chart footnotes and to CTP 
Section 5.2.6 for more details. 
Regular evaluation by SMC. 
 
Trial procedures 
Radiation exposure  
 
Required to monitor 
potential risk associated 
with study drug and 
confirm patient eligibility. 
State of the art radiologic 
methods required, x-rays of 
epiphyseal growth plates only if 
MRI not possible in individual 
patients. 
Regular dental examination and 
panoramic x-ray at minimum 
time interval required to ensure 
safety. 
For new patients: HRCT at 
baseline required only if 
acceptable HRCT not available 
within 12 months of Visit 1.  

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Potential risks of 
clinical relevance for 
this trial 
Summary of data, 
rationale for the risk 
Mitigation strategy 
Bone MRI/x-ray required with 
always minimum 10 weeks (first 
year)/22 weeks (thereafter) and 
dental X-ray required with 
always minimum 22 weeks (first 
year)/46 weeks (thereafter) from 
the previous procedure, taking 
into account, for roll-over 
patients, the participation in the 
parent trial (except at the one 
time alignment of these safety 
procedures with clinic visits). 
Similarly, bone MRI/x-ray at 
EoT required only if previous 
MRI/x-ray not available within 
12 weeks in the first year, 24 
weeks thereafter. Timepoints 
may be adapted on a case-by-case 
basis after discussion with the 
sponsor if appropriate for 
patient’s safety. 
Panoramic x-ray at EoT required 
only if previous panoramic x-ray 
not available within 24 weeks. 
 
Others risks 
Risk of contracting a 
SARS CoV-2 
infection. 
 
Travelling to the site or 
being at the site for trial 
visit may potentially 
increase the risk of 
contracting a SARS CoV-
2 infection. 
The number of site visits is 
limited to the minimum required 
for the successful conduct of 
trial. 
Several measures are proposed 
for local implementation – if 
possible and needed - to ensure 
continued patient treatment, 
monitoring, and safety even if 
site visits are not possible (see 
Section 4.1, Section 6.2 and 

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Potential risks of 
clinical relevance for 
this trial 
Summary of data, 
rationale for the risk 
Mitigation strategy 
Appendix 10.9). 
 
Patients with co-morbidities associated with potentially increased risk to nintedanib will be 
excluded (see Section 3.3.3). 
 
An external Safety Monitoring Committee (SMC) will ensure monitoring of safety 
throughout the conduct of the study. Further details on SMC and other external committees in 
Section 7. 
1.4.3 
Discussion 
This open label trial only started recruiting once the first results of InPedILD® trial have been 
reviewed and justify the start of this open label trial by confirming that safety and tolerability 
of nintedanib is considered acceptable in the patient population of the InPedILD® trial. 
The planned trial procedures and the associated risks are deemed acceptable, as they allow 
for timely identification of potential risks, interruption or discontinuation of treatment if 
required to manage adverse events/ adverse drug reactions. 
Given the high unmet need for treatment options in paediatric fibrosing ILDs, the established 
clinical benefit and known safety profile of nintedanib in adults, as well as the expected 
benefit of nintedanib in the paediatric fibrosing ILD, the extrapolated benefit-risk of 
nintedanib in the target population is considered acceptable. 

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2. 
TRIAL OBJECTIVES AND ENDPOINTS 
2.1 
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS 
2.1.1 
Main objectives 
The trial will assess the safety and tolerability of long-term treatment with nintedanib in 
pediatric patients with clinically significant fibrosing ILD. 
 
The primary objective is to estimate the incidence of treatment emergent adverse events over 
the whole trial.  
2.1.2 
Primary endpoint(s) 
The primary endpoint is the incidence of treatment emergent adverse events over the whole 
trial. 
2.1.3 
Secondary endpoint(s) 
No secondary endpoints are defined. 

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3. 
DESCRIPTION OF DESIGN AND TRIAL POPULATION 
3.1 
OVERALL TRIAL DESIGN  
This is a multi-centre, multi-national, not randomised, open label clinical trial. 
 
 
Figure 3.1:1 Trial design 
The patient population will include two cohorts:  
Patients rolling over from the InPedILD® study:  
At the time point when the data from the InPedILD® trial are available, and a positive benefit 
risk assessment (by external independent SMC and internal BI Benefit Risk Committee) 
justifies the start of the current trial, all patients on study treatment (including those who 
temporarily interrupted treatment for less than 8 weeks) at the end of the parent trial 
InPedILD® will be offered participation in the current long-term study. These patients can be 
enrolled into 1199-0378 from Part A or from Part B. 
 
Patient’s individual benefit-risk to receive long-term treatment of nintedanib should be 
assessed by the investigator. The decision to participate in this study will be made by the 
patient/parent(s)/legal guardian following a discussion on this benefit-risk assessment with 
the investigator.  
 
Completed patients from the parent trial not able to roll-over into the extension trial within 12 
weeks following their End of Treatment Visit in the parent trial (i.e. time period between last 
dose of study drug in parent trial and first dose in extension trial is greater than 12 weeks) 
will formally not be considered as “roll-over” patient. These patients will be handled as new 
patients in 1199-0378, i.e. they have to follow the visit schedule for new patients but will 
have adapted inclusion/exclusion criteria (please refer to Section 3.3.2 and to Section 3.3.3). 
 
Patients who prematurely permanently discontinued treatment due to AE considered related 
to nintedanib in the InPedILD® trial will not be eligible for this open-label trial.  
150 mg b.i.d.,
100 mg b.i.d.,
75 mg b.i.d.,
50 mg b.i.d.,
25 mg b.i.d. ( if dose reduction)
Or placebo
Treatment period 
minimum 3 years
Follow-up
4 weeks
1199-0337
Treatment period
variable duration
Follow-up
4 weeks
Screening
- 4 weeks
Transition period
Starting dose based on weight and dose received 
at EoT visit in 1199-0337
150 mg b.i.d,
100 mg b.i.d.,
75 mg b.i.d.,
50 mg b.i.d.,
and 25 mg b.i.d.  if dose reduction
Stating dose based on weight
150 mg b.i.d.,
100 mg b.i.d.,
75 mg b.i.d.,
50 mg b.i.d.,
and 25 mg b.i.d.  if dose reduction
S
New patients
Patients from 
1199-0337

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Patients who permanently discontinued trial treatment due to AE considered related to 
placebo or for reasons other than drug-related AE and are willing to participate in study 
1199-0378 will potentially be eligible for this open-label trial. For those patients, the 
individual benefit risk and potential eligibility for participation in study 1199-0378 should be 
carefully assessed by the investigator and should be discussed with the sponsor. These 
patients will be handled as new patients in 1199-0378, i.e. they have to follow the visit 
schedule for new patients. 
 
Patients who have withdrawn consent to trial participation in InPedILD® will not be eligible 
for 1199-0378. 
 
Whenever feasible, for roll-over patients, the first visits (Visit 1 and Visit 2) of this open-
label trial should be on the same day as the End of Treatment visit of InPedILD®, the parent 
trial, to allow for continuous treatment. In this case, procedures performed at the EoT of 
InPedILD® should not be repeated if stated as planned at Visit 1 or Visit 2 in the 1199-0378 
trial (please refer to section 6.2.1 and Flow Chart). 
 
After signing Informed Consent, and if all eligibility criteria are met, patients will receive 
treatment with nintedanib at their last dose of study medication in the parent trial 150 mg 
b.i.d. (300 mg daily), 100 mg b.i.d. (200 mg daily), 3x25 mg b.i.d. (150 mg daily), 2x25 mg 
b.i.d. (100 mg daily) or 25 mg b.i.d. (50 mg daily) unless the patient’s weight has changed 
such that a different dose is required (please refer to Table 4.1.2: 1). 
For those patients with dose reduced in the parent trial, the dose can be increased based on 
the judgement of the investigator. Similar to the parent trial, dose reduction to the next lower 
dose is possible to manage adverse events. 
At the time point of start of this open label study, the treatment received by the patient in the 
parent trial in Part A remains blinded until the final DBL (DBL2) occurs for the parent trial. 
 
Patients newly enrolled in the study:  
Enrollment will also be open to newly identified children and adolescents with clinically 
significant fibrosing ILDs if they meet the eligibility criteria of the current protocol, or to 
patients who needed to discontinue trial treatment (due to AE considered related to placebo or 
for reason other than drug-related AE) in InPedILD® and again are eligible for treatment with 
nintedanib according to investigator’s assessment (and after discussion with the sponsor). 
All new patients recruited for the study will enter a 4-week screening period. After this first 
period, patients meeting in-/exclusion criteria will initiate their treatment period of the study. 
Starting dose assigned will be based on patient’s weight: 
150 mg b.i.d. (300 mg daily), 100 mg b.i.d. (200 mg daily), 3x25 mg b.i.d. (150 mg daily), 
2x25 mg b.i.d. (100 mg daily). 
 
For all patients, during treatment period, dose is adjusted based on patient’s weight. Dose 
reduction to the next lower dose is possible to manage adverse events. The lowest possible 
dose is 25 mg b.i.d. (50 mg daily). 
 
Roll-over patients will be requested to stay in the trial for at least 156 weeks (until Visit 15).  
At week 156, roll-over patients who can be treated with nintedanib or alternative treatment 
options outside the clinical trial will have their EoT Visit instead of Visit 15. 

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The remaining roll-over patients will continue in the trial until nintedanib or alternative 
treatment options can be made available to them outside the clinical trial. 
 
New patients will be requested to stay in the trial until the end of trial (with expected 
minimum treatment duration of 76 weeks),  
then patients will perform their EoT Visit and enter in the 28-days follow-up period off-
treatment until End of Study Visit (EOS). 
 
Exception: patients aged 21 years must complete the trial before their 22nd birthday. 
Consequently, a treatment duration of at least 3 years might not be reached by some patients 
aged 21. 
Patients completing trial while being 21 years old, even with a treatment duration less than 3 
years, will be considered as completed patients. 
 
The overall end of trial will take place approximately when last roll-over patient is expected 
to reach 3 years of treatment (
) ensuring nintedanib or 
alternative treatment options (e.g., via marketing authorization, via compassionate use, or via 
similar process) will be available for all remaining patients (roll-over or new patients) outside 
the trial at this time. 
 
At this time, all the remaining patients will perform their EoT Visit.  
For logistical reasons, it may be planned that EoT visit of all remaining patients will occur 
within 6 weeks before the planned date of Visit 15 of last roll-over patient. If regular 
scheduled visit is planned for a patient during this period of 6 weeks, then the patient will 
skip this regular visit and will perform directly the EoT visit instead. After the EoT visit, all 
remaining patients will enter a 4-week follow-up period. 
 
Trial medication will be stopped prematurely if a reason for withdrawal is met (refer to 
section 3.3.4).  
Roll-over patients will be considered as prematurely discontinued from trial treatment if they 
stop trial medication before week 156 (except at the age of 21). 
New patients will be considered as prematurely discontinued from trial treatment if they 
discontinue trial treatment before the overall end of trial (except at the age of 21). 
 
Patients who prematurely discontinue trial medication should come to the clinic to perform 
EoT as soon as possible after treatment discontinuation.  
Roll-over patients prematurely discontinued from trial treatment before week 156 will be 
asked to remain in the study and return to all regularly scheduled visits until Visit 15 
(individual planned date of week 156). 
New patients prematurely discontinued from trial treatment will be asked to remain in the 
study until the overall end of trial (expected to occur approximately when last roll-over 
patient is expected to reach 3 years of treatment). 
 
For patients who prematurely discontinued trial drug and who are unable to complete the 
scheduled visits, a follow-up (FU) visit should be planned for 28 days after EoT. In addition, 
every attempt will be made to collect information on vital status, when applicable, at weeks 

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24, 52, 76, 104, 128 and 156 and for new patients at EoS. These requests will be outlined in 
the parental-information form and discussed during administration of the informed consent 
(the same applies to the assent form, where applicable). 
 
If it is intended by a treatment discontinued patient to use available nintedanib outside the 
trial after trial treatment discontinuation, the patient should directly undergo the EoS visit 28 
days after the EOT visit (no vital status will be required for this patient). 
 
A patient will be considered lost to follow-up if the investigator is not able to contact the 
patient/parent(s)/legal guardian despite multiple attempts. Every effort must be made; at least 
2 telephone contacts plus 1 mailing should be documented. The site must notify the clinical 
monitor prior to designating a patient as lost to follow-up. 
3.2 
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S) 
All patients will receive active treatment as prolonged used of placebo would not be 
appropriate. The design as open label study with no comparison group is appropriate for 
assessing the long-term tolerability and safety of nintedanib in pediatric patients with 
fibrosing ILDs.  
This trial will follow the study InPedILD® to address EMA’s request on the collection of 
additional safety and efficacy data as discussed during the PIP negotiations.  
In addition to patients rolled over from the InPedILD® study, in order to address the high 
unmet medical need for safe and efficacious treatment of this devastating condition, newly 
identified children and adolescents with clinically significant fibrosing ILD from already 
participating centres will have the possibility to enter in this trial if they meet the eligibility 
criteria.  
3.3 
SELECTION OF TRIAL POPULATION 
It is anticipated that at least 30 patients on treatment at the end of the InPedILD® trial, from 
approximately 40 sites in about 21 countries, will consent to participate (and thus receive 
treatment (if eligible)) in this trial.  
In addition, considering enrolment of 2 patients/month across around 40 sites, approximately 
20 to 30 newly identified patients are expected to enter treatment in an estimated recruitment 
period of 18 months with a screen failure rate around 50%. Extension of the study population 
beyond that of the parent trial is aimed at addressing a high unmet medical need for safe and 
efficacious therapy for fibrosing ILDs in children and adolescents.  
 
Re-enrolment of screen failed patients will be permitted once. Patients who did not qualify 
for entering treatment during the early months of the recruitment period might qualify for 
entering treatment during the late months of the recruitment period of the study. A new 
informed consent/assent will be signed by the patient/parent(s)/legal guardian and the patient 

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will be assigned a new unique patient number. The previous patient number will be collected 
via the electronic Case Report Form (eCRF). 
 
A log of all patients enrolled into the trial (i.e. who have an informed consent signed) will be 
maintained in the Investigator Site File (ISF) irrespective of whether they have been treated 
with investigational drug or not. 
If retrospectively it is found that a patient has been entered in error (=did not meet all 
inclusion criteria or met one or more exclusion criteria), the sponsor or delegate should be 
contacted immediately. Based on an individual benefit-risk assessment by the investigator in 
discussion with the patient and its parents/legal guardian and discussion with the sponsor, a 
decision will be made whether continued trial participation is possible or not. 
3.3.1 
Main diagnosis for trial entry 
Main diagnosis for trial entry is identical with that of the parent trial i.e. clinically significant 
fibrosing ILD as defined by clinical and radiological criteria detailed below.  
 
For patients who rollover from the parent trial InPedILD®, eligibility of these patients will be 
established based on a limited number of criteria listed below. Exceptionally, patients that 
reached adult age during participation of 1199-0337 will be allowed to participate in 1199-
0378. 
For newly recruited patients, all eligibility criteria based on InPedILD® study apply and are 
listed below. 
 
Please refer to Section 8.3.1 (Source Documents) for the documentation requirements 
pertaining to the in- and exclusion criteria. 
3.3.2 
Inclusion criteria 
For new patients:  
1. Children and adolescents 6 to 17 years old at Visit 2. In France, only adolescents 12 to 17 
years old at Visit 2. 
2. Signed and dated written informed consent and assent, where applicable, in accordance 
with ICH-GCP and local legislation prior to admission to the trial. 
3. Male or female patients. Female of childbearing potential (WOCBP1) must confirm that 
sexual abstinence is standard practice and will be continued until 3 months after last drug 
intake, or be ready and able to use a highly effective method of birth control per ICH M3 
(R2) that results in a low failure rate of less than 1% per year when used consistently and 
correctly, in combination with one barrier method, from 28 days prior to initiation of 
study treatment, during treatment and until 3 months after last drug intake. Sexual 
abstinence is defined as abstinence from any sexual act that may result in pregnancy. A 
list of contraception methods meeting these criteria is provided in the parental 
information and in CTP Section 4.2.2.3. 
 
1 A woman is considered of childbearing potential (WOCBP), i.e. fertile, following menarche and until becoming post-
menopausal unless permanently sterile.  
Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. 
Tubal ligation is NOT a method of permanent sterilisation. 

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4. Patients with evidence of fibrosing ILD on HRCT within 12 months of Visit 1 as assessed 
by the investigator and confirmed by central review.  
5. Patients with FVC % predicted ≥25% at Visit 2. 
[Note: Predicted normal values will be calculated according to GLI (Global Lung 
Initiative)] 
6. Patients with clinically significant disease at Visit 2, as assessed by the investigator based 
on any of the following: 
• Fan score ≥3, or 
• Documented evidence of clinical progression over time based on either 
o a 5-10% relative decline in FVC% predicted accompanied by worsening 
symptoms, or 
o a ≥10% relative decline in FVC % predicted, or 
o increased fibrosis on HRCT, or 
o other measures of clinical worsening attributed to progressive lung disease (e.g. 
increased oxygen requirement, decreased diffusion capacity). 
Instructions on Fan score will be given in Appendix 10.2. 
 
For roll-over patients from the InPedILD® study: 
Only criteria 2 and 3 listed for new patients are applicable with the following additional 
inclusion criterion: 
7. Patients who completed the InPedILD® trial as planned and who did not permanently 
prematurely discontinue study treatment.  
 
For patients who prematurely discontinued treatment permanently in 1199-0337 but are 
potentially eligible and for completed patients from parent trial not able to roll over into the 
extension trial within 12 weeks following their End of Treatment Visit in the parent trial: 
Inclusion criteria for new patients are applicable except criteria 4, and 6 (as eligibility for 
these criteria has been confirmed already in 1199-0337 and does not need to be repeated) and 
also except inclusion criterion 1 for completed patients from parent trial not able to roll over 
within 12 weeks following their End of Treatment Visit in the parent trial. 
 
3.3.2.1 
Evidence of fibrosing ILD for new patients: 
Determination of fibrosing ILD on HRCT by the investigator will be based on clinical 
evaluation. However, given the lack of published guidelines regarding imaging criteria for the 
diagnosis of fibrosing lung disease in children, central review confirmation to determine 
eligibility will be based on pre-defined imaging criteria to ensure consistency. The imaging 
criteria to be used will be determined by expert consensus and included in the imaging 
manual provided to study sites.  
 
For patients with previous pathological findings of fibrosis on lung biopsy, confirmation of 
fibrosis on HRCT will be required with at least one of the following imaging findings on one 
HRCT scan. 
 

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Any of the following biopsy findings or diagnoses will be accepted as documentation of 
fibrosis as confirmed by central review: 
• Nonspecific interstitial pneumonia (NSIP), fibrosing 
• Usual interstitial pneumonia (UIP) 
• Evidence of interstitial fibrosis on a significant* component of the lung biopsy 
• Evidence of lobular remodelling on a significant* component of the lung biopsy 
• Honeycomb lung 
*based on the opinion of the central reviewer. 
 
Confirmation of fibrosis on HRCT will be made if at least one of the following imaging 
criteria are met within 12 months of screening visit (Visit 1) as confirmed by central review: 
• Reticular abnormality or 
• Traction bronchiectasis or 
• Architectural distortion or 
• Honeycombing 
Co-existing features cystic abnormalities or ground glass opacity are acceptable but are not 
counted as features that confirm fibrosis. Co-existing multifocal non-fibrotic, non-dependent 
consolidations (e.g. organizing pneumonia, infection) will not be allowed. 
 
 
For patients without any documented lung biopsy or whose biopsy results do not meet the 
biopsy criteria for fibrosis listed above, confirmation of fibrosis on two HRCT scans will be 
required. 
 
At least two different findings of the following imaging findings are required on at least two 
HRCT scans (most recent one must be within 12 months of Visit 1):  
• Reticular abnormality,  
• Traction bronchiectasis,  
• Architectural distortion with/without ground glass opacification,  
• Honeycombing, 
• Cystic abnormality. 
Co-existing ground glass opacity is acceptable but is not counted as feature that confirms 
fibrosis. Co-existing multifocal non-fibrotic, non-dependent consolidations (e.g. organizing 
pneumonia, infection) will not be allowed. 
3.3.3 
Exclusion criteria 
For new patients: 
 
1. AST and/or ALT >1.5 x ULN at Visit 1. 
2. Bilirubin >1.5 x ULN at Visit 1. 
3. Estimated Glomerular Filtration Rate (eGFR) <30 mL/min/1.73m2  at Visit 1(please 
refer to Appendix 10.3). 
[Note: Laboratory parameters from Visit 1 have to satisfy the laboratory threshold 
values as shown above. Visit 2 laboratory results will be available only after the visit In 
case, at Visit 2, the results do no longer satisfy the entry criteria, the Investigator has to 

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decide whether it is justified that the patient remains on study drug. The justification for 
decision needs to be documented. Laboratory parameters that are found to be abnormal 
at Visit 1 are allowed to be re-tested (once) if it is thought to be a measurement error 
(i.e. there was no abnormal result of this test in the recent history of the patient and 
there is no related clinical sign) or the result of a temporary and reversible medical 
condition, once that condition is resolved.] 
4. Patients with underlying chronic liver disease (Child Pugh A, B or C hepatic 
impairment) at Visit 1. 
5. Other investigational therapy received within 1 month or 5 half-lives (whichever is 
shorter but ≥1 week) prior to Visit 2 except investigational therapy received in 
InPedILD® trial. 
6. Significant pulmonary arterial hypertension (PAH) defined by any of the following: 
a. Previous clinical or echocardiographic evidence of significant right heart failure 
b. History of right heart catheterization showing a cardiac index ≤2 l/min/m² 
c. PAH requiring parenteral therapy with epoprostenol/treprostinil 
7. In the opinion of the Investigator, other clinically significant pulmonary abnormalities. 
8. Cardiovascular diseases, any of the following: 
a. Severe hypertension, uncontrolled under treatment, within 6 months of Visit 1. 
Uncontrolled hypertension is defined as 
i. In children 6 to ≤12 years old: ≥95th percentile + 12 mm Hg or ≥140/90 mm Hg 
(whichever is lower) (systolic or diastolic blood pressure equal to or greater than 
the calculated target value) (please refer to Appendix 10.5). Not applicable in 
France. 
ii. In adolescents 13 to 17 years old: systolic blood pressure ≥140 mm Hg or 
diastolic blood pressure ≥90 mm Hg (please refer to Appendix 10.5). In France, 
applicable for adolescents 12 to 17 years old. 
b. Myocardial infarction within 6 months of Visit 1 
c. Unstable cardiac angina within 6 months of Visit 1 
9. Bleeding risk, any of the following: 
a. Known genetic predisposition to bleeding 
b. Patients who require  
i. Fibrinolysis, full-dose therapeutic anticoagulation (e.g. vitamin K antagonists, 
direct thrombin inhibitors, heparin, hirudin) 
ii. High dose antiplatelet therapy 
[Note: Prophylactic low dose heparin or heparin flush as needed for 
maintenance of an indwelling intravenous device, as well as prophylactic use of 
antiplatelet therapy are not prohibited.] 
c. History of haemorrhagic central nervous system (CNS) event within 12 months of 
Visit 1 
d. Any of the following within 3 months of Visit 1: 
i. Haemoptysis or haematuria 
ii. Active gastro-intestinal (GI) bleeding or GI – ulcers 
iii. Major injury or surgery (investigator’s judgment) 
e. Any of the following coagulation parameters at Visit 1:  
i. International normalized ratio (INR) >2 

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ii. Prolongation of prothrombin time (PT) by >1.5 x ULN 
iii. Prolongation of activated partial thromboplastin time (aPTT) by >1.5 x ULN  
10. History of thrombotic event (including stroke and transient ischemic attack) within 12 
months of Visit 1. 
11. Known hypersensitivity to the trial medication or its components (i.e. soya lecithin). 
12. Patients with documented allergy to peanut or soya. 
13. Other disease that may interfere with testing procedures or in the judgment of the 
investigator may interfere with trial participation or may put the patient at risk when 
participating in this trial. 
14. Life expectancy for any concomitant disease other than ILD <2.5 years (investigator 
assessment). 
15. Female patients who are pregnant, nursing, or who plan to become pregnant while in 
the trial. 
16. Patients not able or willing to adhere to trial procedures, including intake of study 
medication. 
17. Patients who must or wish to take any drug considered likely to interfere with the safe 
conduct of the trial according to investigator’s benefit-risk assessment for the individual 
patient 
18. Patients with any diagnosed growth disorder such as growth hormone deficiency or any 
genetic disorder that is associated with short stature (e.g. Turner Syndrome, Noonan 
Syndrome, Russell-Silver Syndrome) and/or treatment with growth hormone therapy 
within 6 months before Visit 2. Patients with short stature considered by the 
investigator to be due to glucocorticoid therapy may be included. 
19. Patients <13.5 kg of weight at Visit 1 (same threshold to be used for male and female 
patients). 
 
For roll-over patients from the InPedILD® study: 
Only criteria 11, 12, 13, 15, 16, 17 and 19, listed for new patients are applicable with the 
following additional exclusion criterion: 
20. Patient not compliant in parent trial (InPedILD®), with trial medication or trial visits, 
according to investigator’s judgement. 
 
Roll-over patients may qualify for participation even though other exclusion criteria may 
have been met during the participation in InPedILD®, if the investigator’s benefit-risk 
assessment for the individual patient remains favourable. This should be discussed with 
sponsor before the roll-over of patient. 
 
For patients who prematurely discontinued treatment permanently in 1199-0337 but are 
potentially eligible and for completed patients from parent trial not able to roll over into the 
extension trial within 12 weeks following their End of Treatment Visit in the parent trial: 
All exclusion criteria for new patients are applicable. In addition, the following additional 
exclusion criterion is applicable for patients who prematurely discontinued treatment 
permanently in 1199-0337: 
21. Patients who experienced drug-related adverse events during parent trial leading to 
permanent study treatment discontinuation. 

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3.3.4 
Discontinuation of patients from treatment or assessments 
Patients may discontinue trial treatment or patient/parent(s)/legal guardian may withdraw 
consent/assent to trial participation as a whole (“withdrawal of consent”) with very different 
implications; please see Sections 3.3.4.1 and Section 3.3.4.2 below.  
However, if the patients agree, they should stay in the trial even if continued trial treatment is 
not possible: roll-over patients should attend further trial visits until Visit 15 and new patients 
should attend until the overall end of trial to ensure their safety and to collect important trial 
data. 
Measures to control the withdrawal rate include careful patient selection, appropriate 
explanation of the trial requirements and procedures prior to trial enrolment, as well as the 
explanation of the consequences of withdrawal.  
The decision to discontinue trial treatment or withdraw consent to trial participation and the 
reason must be documented in the patient files and eCRF. If applicable, consider the 
requirements for Adverse Event collection reporting (please see Section 5.2.7.2). 
3.3.4.1 
Discontinuation of trial treatment 
An individual patient will discontinue trial treatment if:  
• The patient wants to discontinue trial treatment or if parent(s)/legal guardian want(s) the 
patient to discontinue trial treatment. They will be asked to explain the reasons but have 
the right to refuse to answer.  
• The patient has repeatedly shown to be non-compliant with important trial procedures 
and, in the opinion of both the investigator and sponsor representative, the safety of the 
patient cannot be guaranteed as he / she is not willing or able to adhere to the trial 
requirements in the future.  
 
In the following cases discontinuation of trial medication is highly recommended. Only in 
special circumstances the investigator, upon thorough assessment of all available clinical data 
and taking into consideration the potential risks associated with administration of nintedanib, 
may decide not to withdraw the trial medication, even though one or more of the below 
mentioned criteria are fulfilled. In such a case, continuation of treatment with trial medication 
should be discussed with the patient/parent(s)/legal guardian, and the decision and reasoning 
documented in the source data. 
• Major surgery, including any abdominal or intestinal surgery. 
• Anti-coagulation. Patients who require full-dose therapeutic anticoagulation (e.g. vitamin 
K antagonists, heparin, hirudin, direct thrombin inhibitors, etc.), or high-dose antiplatelet 
therapy. Prophylactic low dose heparin or heparin flush as needed for maintenance of an 
indwelling intravenous device, as well as prophylactic use of antiplatelet therapy is 
allowed. 
• Major thrombo-embolic events e.g. stroke, deep vein thrombosis, pulmonary embolism, 
myocardial infarction. 
• Increased risk of bleeding e.g. haemorrhagic CNS event, gross / frank haemoptysis or 
haematuria, active GI-bleeding or GI-ulcers.  
 
In case of a temporary reason, trial treatment should be restarted if medically justified, please 
see Section 4.1.4 

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In case, the laboratory results at Visit 2 do no longer satisfy the entry criteria, the Investigator 
has to decide whether it is justified that the patient remains on study drug. The justification 
for decision needs to be documented in the patient’s medical records. 
 
The trial medication has to be permanently discontinued in the following circumstances: 
• The patient experiences signs of hepatic injury attributable to trial drug, as defined in 
Section 5.2.7.1.4. 
• In the opinion of the Investigator, the patient experiences unacceptable adverse events 
despite dose adjustments and supportive care, as defined in Section 4.1.2. 
• The patient needs to take concomitant medication that interferes with the safety of the 
investigational medicinal product or other trial treatment. Please refer to Sections 4.2.1 
and 4.2.2. 
 
The patient can no longer receive trial treatment for medical reasons such, adverse events, 
other diseases, or pregnancy.  
If a patient becomes pregnant during the trial the investigational product must be interrupted 
immediately, and the patient will be followed up until birth of the child/children or otherwise 
termination of the pregnancy. The study medication may be only re-introduced once the child 
has been born and the mother is no longer nursing, if supported by individual benefit risk as 
judged by the investigator. The data of the patient will be collected and reported in the 
clinical trial report (CTR) until patient´s last visit, and any events thereafter will be reported 
in the Boehringer Ingelheim (BI) drug safety database. Refer to Section 5.2.7.2.3 for detailed 
information on event reporting in case of pregnancy. 
 
In case of permanent discontinuation of trial medication, it is of utmost importance for the 
robustness and integrity of the trial results that the patient remains in the study and returns to 
all regularly scheduled visits until the end of the planned observation period. For those 
patients who are unable to complete the remaining scheduled visits, every attempt will be 
made to get information on vital status as outlined in the Flow Chart and Section 6.2.3. 
If it is intended by a treatment discontinued patient to use available nintedanib outside the 
trial after trial treatment discontinuation, the patient should directly undergo to the EoS visit 
28 days after the EOT visit (no vital status will be required for this patient). 
If new efficacy / safety information becomes available, Boehringer Ingelheim will review the 
benefit-risk-assessment and, if needed, instruct to pause or discontinue the trial treatment for 
all patients or take any other appropriate action to guarantee the safety of the trial patients.  
3.3.4.2 
Withdrawal of consent to trial participation  
Patient/parent(s)/legal guardian may withdraw their consent/assent to trial participation, at 
any time without the need to justify the decision. 
If patient/parent(s)/legal guardian want(s) to withdraw consent/assent, the investigator should 
be involved in the discussion with the patient/parent(s)/legal guardian and explain the 
difference between trial treatment discontinuation and withdrawal of consent to trial 
participation, as well as explain the options for continued follow-up after trial treatment 
discontinuation, please see Section 3.3.4.1 above. 

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3.3.4.3 
Discontinuation of the trial by the sponsor 
Boehringer Ingelheim reserves the right to discontinue the trial overall or at a particular trial 
site at any time for the following reasons: 
1. Failure to meet expected enrolment goals overall or at a particular trial site. 
2. 
3. Deviations from GCP, the trial protocol, or the contract impairing the appropriate conduct 
of the trial. 
4. 
Further treatment and follow up of patients affected will occur as described in Section 
3.3.4.1. 
The investigator / the trial site will be reimbursed for reasonable expenses incurred in case of 
trial termination (except in case of the third reason). 

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4. 
TREATMENTS 
4.1 
INVESTIGATIONAL TREATMENTS 
The investigational medicinal products are nintedanib soft capsules 150 mg, 100 mg, and 25 
mg. All patients will be treated with nintedanib in this trial; there is no active comparator or 
placebo. 
 
Nintedanib soft capsules 100 mg (oblong shape, 6.2 mm diameter and 16.3 mm length) and 
150 mg (oblong shape, 7.1 mm diameter and 17.6 mm length) are commercially available for 
adults. Nintedanib soft capsules 25 mg of smaller size (oval shape, 5.1 mm diameter and 8.0 
mm length) have been developed for paediatric population. The 75 mg and 50 mg doses will 
be provided as multiples of the 25 mg dosage strength. 
 
The sizes of the commercially available 100 mg and 150 mg capsules are considered suitable 
for the targeted age-range. However, for patients who are unable to swallow the 
commercially available form, a multiple of the 25 mg capsule is proposed as an alternative 
administration strategy for the 100 mg or 150 mg: 
• 4 x 25 mg for the 100 mg 
• 6 x 25 mg for the 150 mg 
 
The investigational products will be provided by BI or a designated clinical research 
organisation (CRO). They will be packaged and labelled in accordance with the principles of 
Good Manufacturing Practice (GMP). 
4.1.1 
Identity of the Investigational Medicinal Products 
Table 4.1.1:1 Test product 1 
Substance: 
Nintedanib (Ofev®) 
Pharmaceutical formulation: 
Soft gelatin capsule 
Source: 
Boehringer Ingelheim Pharma GmbH & Co. KG 
Unit strength: 
150 mg, 100 mg, 25 mg 
Posology: 
150 mg, or 100 mg, or 3x25 mg, or 2x25 mg, or 25 
mg, each b.i.d. 
Method and route of administration: 
Oral (swallowed) 
 

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4.1.2 
Selection of doses in the trial and dose modifications 
In order to match the systemic exposure reached in adult IPF patients, the nintedanib doses in 
paediatric patients were predicted based on body weight dependent allometric scaling 
(scaling of adult clearance using an exponent of 0.75, consistent with the exponent estimated 
in population pharmacokinetics [PopPK] analyses in adults; refer to the current version of the 
Investigator's Brochure Nintedanib in Idiopathic Pulmonary Fibrosis, Systemic Sclerosis and 
Progressive Fibrosing Interstitial Lung Disease [c01783972] for details).  
 
This approach was considered acceptable, assuming a minor role of developmental changes 
referring to nintedanib PK for the selected target population. A population mean nintedanib 
exposure of 80% to 125% compared to adult IPF patients treated with 150 mg b.i.d. was 
targeted for the determination of the planned doses by body weight bin in the paediatric 
population. 
 
Confirmation or, if needed, adaptation of the dosing algorithm to achieve nintedanib exposure 
in pediatric patients comparable to the plasma exposure in adult IPF/SSc-ILD/ chronic 
fibrosing ILD of a progressive phenotype patients receiving the approved dose of nintedanib 
150mg b.i.d. was a part of benefit/risk assessment to be performed in the Phase III parent 
study InPedILD® following DBL1. 
Upon confirmation of the algorithm used in the 1199-0337 InPedILD® study, the doses of 
nintedanib will be assigned by body weight bin as shown in table below. 
 
Table 4.1.2:1 Dose assignment and dose reduction possibilities based on body weight bins 
according to ICH E11 
 
 
InPedILD®  
1199-0378 
Body weight bin – 
Provenance of patient 
Weight 
range** 
Last dose used 
(b.i.d.) and 
treatment groups 
Dose (b.i.d.) and 
treatment groups 
Dose reduction 
possibility 
(b.i.d.) 
1 - Patients from Part B  
of InPedILD® 
13.5* to <23.0 
kg 
50 mg or 25 mg*** 
(nintedanib) 
50 mg or 25 mg 
(nintedanib) 
25 mg 
(nintedanib) 
1 - Patients from Part A  
of InPedILD® 
13.5 to <23.0 kg 
50 mg or 25 mg*** 
(nintedanib/placebo) 
50 mg or 25 mg  
(nintedanib) 
25 mg 
(nintedanib) 
1 - New patients 
13.5 to <23.0 kg 
  
50 mg 
(nintedanib) 
25 mg 
(nintedanib) 
2 - Patients from Part B  
of InPedILD® 
23.0 to <33.5 kg 
75 mg or 50 mg*** 
(nintedanib) 
75 mg or 50 mg 
(nintedanib) 
50 mg 
(nintedanib) 
2 - Patients from Part A  
of InPedILD® 
23.0 to <33.5 kg 
75 mg or 50 mg*** 
(nintedanib/placebo) 
75 mg or 50 mg 
(nintedanib) 
50 mg 
(nintedanib) 
2 - New patients 
23.0 to <33.5 kg 
  
75 mg 
(nintedanib) 
50 mg 
(nintedanib) 
 

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InPedILD®  
1199-0378 
Body weight bin – 
Provenance of patient 
Weight 
range** 
Last dose used 
(b.i.d.) and 
treatment groups 
Dose (b.i.d.) and 
treatment groups 
Dose reduction 
possibility 
(b.i.d.) 
3 - Patients from Part B  
of InPedILD® 
33.5 to <57.5 kg 
100 mg or 75 mg** 
(nintedanib) 
100 mg or 75 mg 
(nintedanib) 
75 mg 
(nintedanib) 
3 – Patients from Part A  
of InPedILD® 
33.5 to <57.5 kg 
100 mg or 75 mg** 
(nintedanib/placebo) 
100 mg or 75 mg 
(nintedanib) 
75 mg 
(nintedanib) 
3 - New patients 
33.5 to <57.5 kg 
  
100 mg 
(nintedanib) 
75 mg 
(nintedanib) 
4 - Patients from Part B  
of InPedILD® 
≥57.5 kg 
150 mg or 100 mg** 
(nintedanib) 
150 mg or 100 mg 
(nintedanib) 
100 mg 
(nintedanib) 
4 - Patients from Part A  
of InPedILD® 
≥57.5 kg 
150 mg or 100 mg** 
(nintedanib/placebo) 
150 mg or 100 mg 
(nintedanib) 
100 mg 
(nintedanib) 
4 - New patients 
≥57.5 kg 
  
150 mg 
(nintedanib) 
100 mg 
(nintedanib) 
*patients < 13.5 kg of weight are excluded from the trial. 
**Confirmation or, if needed, adaptation of the weight range in the algorithm will be part of 
benefit/risk assessment in InPedILD®. 
***If dose already reduced in InPedILD® or if dose reduction is needed at visit 2. In these 
cases, no further reduction will be possible. However, for treatment interruption please refer 
to Section 4.2.1. 
 
New patients: 
The patient’s weight will be measured at screening and at each IMP dispensing visit (see 
Flow Chart for details). The dose assigned will be based on the patient’s weight at baseline 
(Visit 2). At subsequent visits the dose will be adjusted for any changes of the patient’s 
weight resulting in a change of the body weigh bin. IRT will assign the proper dose based on 
the patient’s weight recorded at the respective visit. 
 
Roll-over patients:  
Patient will receive nintedanib at corresponding dose assigned in the parent trial, whether the 
patient was previously assigned to the nintedanib or the placebo treatment group. If the 
patient’s weight has changed such that a different dose is required (please refer to Table 
4.1.2: 1, the appropriate dose of nintedanib will be assigned. 
For those patients who dose reduced in the parent trial, the dose can stay reduced or be 
increased based on the judgement of the investigator.  
 
Similar to the parent trial, treatment interruption and dose reduction to the next lower dose 
are allowed to manage adverse events.  
 

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4.1.3 
Method of assigning patients to treatment groups 
An Interactive Response Technology (IRT) system will be used to screen eligible patients, 
perform drug assignment, register EoT and manage initial/re-supply ordering of drug 
supplies. The investigator will receive all necessary instructions to access the IRT from the 
Sponsor.  
After the assessment of all in- and exclusion criteria, each eligible patient will receive 
treatment with nintedanib. The assigned dose of nintedanib will be based on the patient’s 
weight at Visit 2 as shown in Table 4.1.2: 1. 
IRT will be used to assign medication numbers to eligible patients until EoT or premature 
discontinuation. Details of IRT procedures can be found in the IRT manual located in the 
Investigator Site File (ISF). 
The appropriate medication numbers will be assigned and documented in the eCRF. Note that 
the medication number is different from the patient number (the latter is generated during 
screening via the IRT System). 
4.1.4 
Drug assignment and administration of doses for each patient 
For an individual patient, the start of treatment period will be planned at Visit 2, and the end 
of treatment period is planned at the EoT Visit. The first dose of trial medication should be 
taken during the Visit 2 in the morning at the clinic and the last dose of trial medication 
should be taken in the evening before the EoT Visit.  
During the treatment period, the treatment for an individual patient will be assigned via IRT 
contact during scheduled clinic visits detailed in the Flow Chart.  
 
Each patient will receive active drug at dosage of 150 mg bid, 100 mg bid, 75 mg bid, 50 mg 
bid or 25 mg bid. Nintedanib will be administered orally on a twice daily basis.  
 
Based on the assigned dose, including possible dose reduction, the daily dose of trial 
medication will consist of 1 capsule (150 mg, 100 mg, or 25 mg strength) or 2 capsules (25 
mg strength), or 3 capsules (25 mg strength) to be taken per os twice daily (b.i.d.) (see Table 
4.1.2: 1).  
 
Patients not able to swallow the 150 mg strength or the 100 mg strength capsule will have the 
possibility to take the 25 mg strength capsules (6 or 4 capsules per dose, respectively). To 
obtain kits with smaller capsules, an unscheduled visit should be registered in IRT.  
 
At each concerned visit, the number of dispensed wallets will be adapted to assure sufficient 
coverage until the next dispensing visit.  
 
The investigational product should only be dispensed to parents/caregiver(s) (or patients if 
applicable based on their maturity) by authorized personnel as documented in the “Trial Staff 
List”. 
 
In the event of force majeure or other disrupting circumstances (e.g. pandemic, war, please 
see Section 6.1), physical patient visits to the sites may not be feasible or may need to be 
restricted to ensure patient safety. Based on a thorough assessment of the benefits and risks, 

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the investigator may still decide to continue trial treatment. Where permitted by local law and 
regulations, trial medication may be shipped directly to the patients’ home. If the defined 
minimum frequency of trial procedures cannot be adhered to, discontinuation from trial 
medication should be considered. (see Appendix 10.9. for details). 
 
The patient should take the capsules twice daily, at about the same time every day (between 
06:00 and 11:00 in the morning, 18:00 and 23:00 in the evening), with a dose interval of 
approximately 12 hours from one dose to the next dose. 
 
The patient should swallow the whole capsules with water (a glass, approximately 250 mL) 
and should not chew or crush the capsules. If contact with the content of the capsule occurs, 
hands should be washed immediately and thoroughly. As nintedanib may cause stomach 
discomfort, the patient is recommended to take the capsules with food, i.e. during or 
immediately before or after a meal. 
 
In case a dose is forgotten, the dose should be skipped if the time window to the next dose is 
less than 8 hours. The next dose should be taken as scheduled. No catch up of missed doses is 
permitted. 
 
In case of adverse events requiring a dose reduction between planned visits (see Section 4.1.2 
for details), the patient will attend an unscheduled visit. The investigator will visit the patient, 
record the reason for dose change, assign the new dose via IRT and instruct the 
patient/parent(s)/legal guardian on the number of capsules to be taken in the morning and in 
the evening until the next visit. 
In case the start/end of an AE requires a dose reduction/increase without the need of a change 
in capsule size and without requiring a meeting with the investigator in person, the 
unscheduled visit for the patient can be replaced by a phone call. The investigator will 
register the phone call in IRT as an unscheduled visit and register the dose reduction/increase 
on the respective page in the eCRF. 
Drug accountability will be completed carefully. Please refer to Section 6.2.2 for instructions. 
If needed, an unscheduled visit can be registered in IRT at any time during the course of the 
trial to register a dose change, to obtain additional kit(s) or to obtain kits with smaller or 
larger capsules. 
 
In case of adverse events requiring a dose interruption please refer to Section 4.1.2 for 
instructions. 
4.1.5 
Blinding and procedures for unblinding 
4.1.5.1 
Blinding 
In this open-label trial, treatment allocation will not be concealed throughout the trial. The 
eCRF will contain information on actual treatment. 
 
For patients coming from InPedILD®, the previous treatment received in InPedILD® part A 
(active drug or placebo) will remain unknown to the investigator and patient until after the 

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final database lock of InPedILD®. No individual unblinding regarding treatment received in 
InPedILD® should occur prior to this time. 
4.1.5.2 
Unblinding and breaking the code 
Not applicable. 
4.1.6 
Packaging, labelling, and re-supply 
The investigational medicinal products will be provided by BI or a designated CRO. They 
will be packaged and labelled in accordance with the principles of Good Manufacturing 
Practice (GMP). Re-supply to the sites will be managed via an IRT system, which will also 
monitor expiry dates of supplies available at the sites. 
 
The investigational medicinal product, i.e. capsules containing nintedanib, will be packaged 
in blister cards. Blisters cards will be packaged into one child-resistant tamper-evident wallet. 
Each wallet will be labelled with a multi-language booklet according to the requirements of 
the participating countries.  
 
For details of packaging and the description of the label, refer to the ISF. 
4.1.7 
Storage conditions 
Drug supplies will be kept in their original packaging and in a secure limited access storage 
area according to the recommended storage conditions on the medication label. A 
temperature log must be maintained for documentation. 
If the storage conditions are found to be outside the specified range, the Clinical Research 
Associate (CRA) (as provided in the list of contacts) must be contacted immediately. 
4.1.8 
Drug accountability 
The investigator or designee will receive the investigational drugs delivered by the sponsor or 
delegate when the following requirements are fulfilled: 
• Approval of the clinical trial protocol by the IRB / ethics committee 
• Availability of a signed and dated clinical trial contract between the sponsor or delegate 
and the investigational site, 
• Approval / notification of the regulatory authority, e.g. competent authority, 
• Availability of the curriculum vitae of the Principal Investigator, 
• Availability of a signed and dated clinical trial protocol, 
• Availability of the proof of a medical license for the Principal Investigator,  
• Availability of FDA Form 1572. 
 
Investigational drugs are not allowed to be used outside the context of this protocol. They 
must not be forwarded to other investigators or clinics. Patients should be instructed to return 
unused investigational drug. 
The investigator or designee must maintain records of the product’s delivery to the trial site, 
the inventory at the site, the use by each patient, and the return to the sponsor or warehouse / 

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drug distribution centre or alternative disposal of unused products. If applicable, the sponsor 
or warehouse / drug distribution centre will maintain records of the disposal.  
 
These records will include dates, quantities, batch / serial numbers, expiry (‘use- by’) dates, 
and the unique code numbers assigned to the investigational medicinal product and trial 
patients. The investigator or designee will maintain records that document adequately that the 
patients were provided the doses specified by the Clinical Trial Protocol (CTP) and reconcile 
all investigational medicinal products received from the sponsor. At the time of return to the 
sponsor and / or appointed CRO, the investigator or designee must verify that all unused or 
partially used drug supplies have been returned by the clinical trial patient and that no 
remaining supplies are in the investigator’s possession. 
4.2 
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS 
4.2.1 
Other treatments and emergency procedures 
Rescue medications to reverse the action of nintedanib are not available.  
 
 during the trial will be recorded in the eCRF. 
 
Treatment should be interrupted in case the patient experiences a weight decrease below 13.5 
kg. Treatment can be resumed when patient’s weight reaches the threshold of 13.5 kg. 
 
If a patient experiences a drug related adverse event, the dose can be reduced to the next 
lower dose and the dose can be re-escalated after recovery.  
 
The dose can be reduced without prior interruption, i.e. immediately stepping down from one 
dose to the next dose. If the reduced dose is well tolerated, re-escalation is possible within 4 
weeks after dose reduction in case of AEs considered drug related, or within 8 weeks in case 
of AEs not considered drug related. If this occurs between scheduled visits, this will also 
require an unscheduled visit.  
 
Only one reduced dose is possible for each body weight bin meaning that if patient is 
receiving already a reduced dose, no further dose reduction will be possible without re-
increase before. Dose reduction and re-increase are allowed at multiple occasions.  
 
The reduced dose per body weight bin is mentioned in Table 4.2.1:1. This should be 
considered to manage adverse events. No further dose reduction outside of those listed will 
be allowed.  
 
Temporary treatment interruption is also allowed to manage adverse events. 
 
In case of pathological findings identified on follow-up bone imaging, or stunted growth 
identified on follow-up dental imaging, treatment should be interrupted, the patient case 
presented to the SMC by the sponsor and recommendations for next steps obtained. 
Treatment may be resumed upon recommendation of the SMC. 

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In case of persistent adverse events observed at the reduced dose, or severe effects at the 
starting dose for new patients, permanent treatment discontinuation should be considered. 
 
The criteria to be followed for treatment interruption, re-start and re-escalation are shown in 
Table 4.2.1:1. 
Table 4.2.1:1 Allowed treatment reduction / interruption periods 
 
AEs considered related to 
study drug  
AEs or other events not 
considered related to study drug 
Maximum interruption 
4 weeks 
8 weeks 
Recommended restart 
of treatment 
with reduced dose per Table 
4.1.2: 1 
with the same dose as before 
interruption 
Re-escalation 
re-escalation to the dose 
assigned per Table 4.1.2: 1 
may occur any time per 
investigator judgement 
n.a. 
 
In case of pathological findings identified on follow-up bone imaging, or stunted growth 
identified on follow-up dental imaging, treatment should be interrupted, the patient case 
presented to the SMC by the sponsor and recommendations for next steps obtained. 
Treatment may be resumed upon recommendation of the SMC. 
 
To manage diarrhoea and liver enzyme elevations guidelines similar to the parent trial and 
based on guidelines in adult programme are provided. 
4.2.1.1 
Management of diarrhoea 
Diarrhoea is a known and the most frequent side effect of nintedanib treatment. However, 
potential causes for diarrhoea other than trial medication should always be considered and 
treated accordingly (e.g. viral infections, bacterial overgrowth, and antibiotic treatment). 
Diarrhoea should be managed as early as possible after onset of first symptoms with standard 
anti-diarrhoeal symptomatic treatment, e.g. loperamide. 
If diarrhoea persists despite optimal symptomatic treatment, treatment interruption and/or 
dose reduction of nintedanib should be considered. Table 4.2.1.1: 1 shows the 
recommendations for children and adolescents with the appropriate age and weight-adjusted 
dosing. 
 
 
 
 

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Table 4.2.1.1: 1 Management of diarrhoea (considered related to trial medication) in children 
and adolescents 
Description 
Symptomatic Treatment* 
Action with trial medication 
Diarrhoea with 
increase of <4 stools 
per day over 
baseline1 
Initiate anti-diarrhoeal medicines 
at first signs of symptoms e.g. 
loperamide, as per the age-adjusted 
dosing regimen (Table 4.2.1.1: 2) 
until bowel movements cease for 
12 hours. 
Monitor for signs or symptoms of 
dehydration. Consider oral 
rehydration therapy. 
Continue same trial medication dose. 
Diarrhoea with 
increase of 4 to 6 
stools per day over 
baseline1 
Initiate/continue anti-diarrhoeal 
medicines; 
If diarrhoea of this severity persists 
for ≥48 to 72 hours assess for 
dehydration and electrolyte 
imbalance;  
In addition, consider i.v. fluids and 
electrolyte replacement as 
clinically indicated. 
If diarrhoea persists for ≥48 to 72 
hours despite optimal symptomatic 
care: 
1. Interrupt trial medication until 
recovery. 
2. Reduce dose to the next lower 
dose after recovery.  
3. Re-escalate to the weight-
adjusted dose within 4 weeks if 
deemed clinically appropriate. 
Diarrhoea with 
increase of ≥7 stools 
per day over 
baseline1; stool 
incontinence,  
or 
life threatening 
consequences 
Follow recommendations above. 
In addition, consider stool work-up 
to exclude infectious colitis; 
adequate i.v. fluid replacement ≥24 
hours, hospitalization as clinically 
indicated; consider referral to a GI 
specialist to rule out potential 
differential diagnoses. 
1. Interrupt trial medication until 
recovery. 
2. Reduce dose to the next lower 
dose after recovery. 
3. Consider re-escalation within 4 
weeks to the weight-adjusted 
dose if deemed clinically 
appropriate. 
In case of reoccurrence of diarrhoea 
of this severity despite optimal 
symptomatic treatment and dose 
reduction, treatment with trial 
medication should be permanently 
discontinued. 
Footnotes: 
* Other potential causes for diarrhoea should always be considered and treated accordingly (e.g. viral infections, bacterial 
overgrowth, antibiotic treatment) 
1 Baseline defined as usual stools/day prior Visit 2. 

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Table 4.2.1.1: 2 
Loperamide dose regimen based on group age 
Group age  
Posology 
Children 6-8 years 
One 5 ml (1 mg) dose three or four times daily with the duration 
limited to 3 days 
Children 9-11 years 
Two 5 ml (1 mg) doses four times daily with the duration limited 
to 5 days 
Children 12-17 years  
4 mg followed by 2 mg after each loose stool or every 2-4 hours 
to a maximum of 12 mg/day 
4.2.1.2 
Management of liver enzyme elevations 
Nintedanib can be associated with increased liver enzymes. Concomitant use of other drugs 
known to cause liver enzyme elevations should be evaluated. For a detailed guidance on how 
to manage liver enzyme elevations, please refer to Table 4.2.1.2: 1 for patients. 
Table 4.2.1.2: 1 
Recommendations for managing liver enzyme elevations  
 
AST or ALT increase to 
Signs of hepatic injury* 
 
>1.5x to <3x 
ULN 
≥3x to <5x 
ULN and no 
signs of hepatic 
injury 
≥5x to <8x 
ULN and no 
signs of hepatic 
injury 
At Visit 2 for 
new patients 
(start of 
treatment)  
Permanently 
discontinue trial 
medication or 
justify 
continuation1 
Permanently 
discontinue trial 
medication  
Permanently 
discontinue trial 
medication  
Permanently discontinue 
trial medication  
At any other 
Visit for new 
patients  
and  
At all visits 
for roll-over 
patients 
Continue as 
planned2 
Reduce dose or 
interrupt trial 
medication3 
Interrupt trial 
medication 
Interrupt trial medication 
(may subsequently need to 
be permanently 
discontinued5) 
 
Close 
observation4 
 
After 2 weeks or 
any time later 
Close 
observation4 
 
After 2 weeks or 
any time later 
CLINICAL 
EVALUATION OF 
HEPATIC INJURY 
 
 
 
<3x ULN 
≥3x ULN 
<3x ULN 
≥3x ULN 
 
Reduced: return 
to initial dose. 
 
Interrupted: 
restart at 
reduced dose. 
Monitor every 2 
weeks for at 
least 8 weeks 
Permanently 
discontinue trial 
medication 
 
Close 
observation4 
Restart at 
reduced dose 
 
Monitor weekly 
for 4 weeks, then 
every 2 weeks 
for at least 8 
weeks 
Permanently discontinue 
trial medication. 
 
 
Close observation4 
 

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Footnotes: 
*Signs of hepatic injury are defined as 
• 
ALT and/or AST ≥8 fold ULN 
• 
ALT and/or AST ≥3 fold ULN and total bilirubin ≥2 fold ULN  
• 
ALT and/or AST ≥3 fold ULN and unexplained INR >1.5 
• 
ALT and/or AST ≥3 fold ULN and unexplained eosinophilia (>5%) 
• 
ALT and/or AST ≥3 fold ULN and appearance of fatigue, nausea, vomiting, right upper abdominal quadrant pain 
or tenderness, fever and/or rash 
1Investigator to confirm in writing that continuation is justified (e.g. intermittent fluctuation of transaminases). 
2According to visit schedule. Consider additional control visits as adequate. 
3To be decided by Investigator, based on individual risk assessment. 
4Close observation: Re-test ALT and AST, alkaline phosphatase, total bilirubin, and eosinophils within 48 to 72 hours, then 
approximately 7 days, then approximately 2 weeks, preferably by using appropriate visit lab kit as instructed to site by the 
sponsor. 
5Permanently discontinue after discussion with the sponsor if hepatic injury is a confirmed diagnosis and judged related to 
trial medication 
 
Initial assessment of liver enzyme elevation should be performed at the investigational site. 
Blood samples for additional monitoring may be collected at the investigational site, primary 
care physician or external laboratory preferably with specific trial lab kits sent to the central 
laboratory for analysis or analysed locally. 
4.2.1.3 
Management of acute ILD exacerbations 
In case of acute ILD exacerbations or clinical deterioration, all treatment options considered 
adequate by the Investigator are allowed. The patient may interrupt study treatment for up to 
8 weeks, if necessary (e.g. if short-term full anticoagulation is performed). 
4.2.2 
Restrictions 
4.2.2.1 
Restrictions regarding concomitant treatment 
As detailed in the exclusion criteria, new patients receiving nintedanib, full dose therapeutic 
anticoagulation or high dose antiplatelet therapy (e.g. acetyl salicylic acid >325 mg/day, or 
clopidogrel >75 mg/day, or equivalent doses of other antiplatelet therapy) are not eligible for 
participation in the study. 
 
In case full-dose therapeutic anticoagulation or high-dose antiplatelet therapy is needed 
throughout the study, discontinuation of trial medication is highly recommended (see Section 
3.3.4.1). 
 
The use of nintedanib other than the investigational product is prohibited throughout the 
study, including the follow-up period (if any). If it is intended by a treatment discontinued 
patient to use available nintedanib outside the trial after trial treatment discontinuation, the 
patient should directly undergo the EoS visit 28 days after the EOT visit (no vital status will 
be required for this patient). 
 
There are no restrictions for trial participants to receive vaccination for COVID-19 during or 
after study treatment period. 
 
 

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Cautionary notes 
Nintedanib is a substrate of P-gp and, to a minor extent, CYP3A4. Co-administration with 
oral doses of a potent P-gp and CYP3A4 inhibitors, e.g. ketoconazole, erythromycin, may 
increase exposure to nintedanib. In such cases, patients should be monitored closely. 
Management of adverse reactions may require interruption, dose reduction, or discontinuation 
of therapy with nintedanib. 
 
Co-administration with oral doses of a potent P-gp and CYP3A4 inducers, e.g. rifampicin, 
carbamazepine, phenytoin, and St. John’s Wort may decrease exposure to nintedanib and 
should be avoided. 
 
For reasons given above, the use of potent P-gp and CYP3A4 inhibitors and inducers is 
restricted as shown in Table 4.2.2.1: 1. 
 
Table 4.2.2.1: 1 
Restrictions regarding use of potent P-gp and CYP3A4 inhibitors and 
inducers 
P-glycoprotein (P-gp) and Cytochrome P450 3A4 (CYP3A4) inhibitors 
Ketoconazole, cyclosporine A (or 
ciclosporin), boceprevir, clarithromycin, 
conivaptan, erythromycin, indinavir, 
itraconazole, lopinavir, mibefradil, 
nefazodone, nelfinavir, posaconazole, 
ritonavir, saquinavir, telaprevir, 
telithromycin, voriconazole. 
NOT permitted: 
P-gp and CYP3A4 strong inducers 
Avasimibe, carbamazepine, phenytoin, 
rifampin 
NOT permitted: 
Products including St. John’s wort 
NOT permitted: 
 
As the most common side effects known for nintedanib are GI effects i.e. diarrhoea, nausea 
and vomiting (see Section 1.4.2) the concomitant use of medication with an overlapping 
safety profile (e.g. mycophenolate mofetil) should be carefully considered. 
 
Nintedanib is also associated with increases in liver enzymes and bilirubin. If in addition to 
the trial medication, a treatment is introduced that is known to induce AST/ALT elevations 
(e.g. methotrexate, bosentan), additional measurements of liver enzymes (ALT and AST, 
alkaline phosphatase, total bilirubin, and eosinophils) every 2 weeks for approximately 6 
weeks, preferably by using intermediate (a-visit) trial lab kit are recommended. 
 

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Patients who are using a bronchodilator must have their spirometry performed according to 
the guidelines provided below: 
- Withhold short–acting bronchodilators for at least 8 hours before the assessments, 
- Withhold long–acting bronchodilators for at least 24 hours before the assessments. 
 
In case of a patient forgets to withhold bronchodilator(s) intake in the morning of clinic visits, 
the study visit has to be rescheduled the day after. 
4.2.2.2 
Restrictions on diet and life style 
There is no restriction on diet and life style. 
4.2.2.3 
Contraception requirements 
The anti-angiogenic properties of nintedanib indicate a high potential for teratogenicity and 
embryotoxicity, including fetotoxicity and lethality. 
 
WOCBP (for the definition please refer to Section 3.3.3) must use two medically approved 
methods of birth control throughout the trial, and until 3 months after last trial drug intake: 
one barrier method and one highly effective non-barrier method. The contraception of new 
female patients enrolled in the trial should have been started from 28 days prior to initiation 
of study treatment.  
WOCBP (trial participant) must use a highly effective method of birth control per ICH M3 
(R2) that results in a low failure rate of less than 1% per year when used consistently and 
correctly if their sexual partner is a man able to father a child. 
Contraception methods meeting these criteria are: 
• Combined (estrogen and progestogen containing) hormonal birth control that prevents 
ovulation (oral, intravaginal, transdermal). 
• Progestogen-only hormonal birth control that prevents ovulation (oral, injectable, 
implantable). 
• Intrauterine device (IUD) or intrauterine hormone-releasing system (IUS). 
• Bilateral tubal occlusion 
or 
Patients must abstain from male-female sex. This is defined as being in line with the 
preferred and usual lifestyle of the patient. Periodic abstinence e.g. calendar, ovulation, 
symptothermal, post-ovulation methods; declaration of abstinence for the duration of 
exposure to study drug; and withdrawal are not acceptable. 
4.3 
TREATMENT COMPLIANCE 
Patients are requested to bring all remaining trial medication including empty package 
material with them when attending visits. 
Based on capsules counts, treatment compliance will be calculated as shown in the formula 
below. Compliance will be verified by the CRA authorised by the sponsor or delegate. 

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Treatment compliance (%) = 
Number of capsules actually taken  100 
    Number of capsules which should have been taken as 
directed by the investigator 
 
If the number of doses taken is not between 80-120%, site staff will explain to the 
patient/parent(s)/legal guardian the importance of treatment compliance. 

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5. 
ASSESSMENTS 
For the assessment of primary endpoint see Section 5.2 (assessment of safety). 
5.1 
ASSESSMENT OF EFFICACY 
This Section describes the assessment of
5.1.1 
Assessment of FVC 
Spirometry measurements will be performed according to ATS/ERS 2005 guideline [P05-
12782]. Predicted normal values will be calculated according to GLI (Global Lung Initiative) 
[R15-0845] at each visit. 
 
FVC will be assessed using standardised spirometry equipment which will be supplied to all 
participating sites. Spirometry equipment provided centrally will include pre-calibrated 
disposable flow sensors. These sensors demonstrate variability within the required standards 
of +/-3% determined by ATS/ERS 2005 guideline [P05-12782]. As such there is no need to 
conduct daily calibration prior to use, or the weekly linearity check. Mouthpieces suitable for 
the paediatric population will also be provided centrally. 
 
Training will be given to ensure pulmonary function testing is properly conducted in the 
paediatric population when needed. 
 
Spirometry will be conducted while the patient is in a seated position. The test will be done in 
triplicate (three curves to be provided), and the best result selected according to the 
guidelines. The best of three efforts will be defined as the highest FVC, obtained on any of 
the three blows meeting the ATS/ERS criteria with preferably a maximum of five 
manoeuvres. 
 
Efforts should be made to schedule the spirometric measurements at approximately the same 
time of the day, with reference to baseline measurement (Visit 2), as specified in the Flow 
Chart. 
 
On days of clinic visits, patients must refrain from strenuous activity at least 12 hours prior to 
pulmonary function testing. Smoking (if applicable) should be discouraged throughout the 
visit days (clinic visit) and will not be permitted in the 30-minute period prior to spirometry. 
Patients should also avoid cold temperatures, environmental smoke, dust, or areas with strong 
odours (e.g. perfumes). If treated with bronchodilators, wash-out of 24 hours for long acting 
and 8 hours for short acting bronchodilators should be observed before spirometry. 
 
Spirometry results will be electronically transmitted. To ensure the quality of endpoint 
measurement a central spirometry review is put in place to provide feedback to the 
investigational site, the CRA and the Clinical Trial Manager on the quality of the data 
received from the site. 
 

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Further instructions regarding FVC measurements will be provided in the ISF. 
 evaluating the effect of nintedanib on these events, AEs reported by the 
Investigator will be used; the AEs will not be adjudicated. 

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5.2 
ASSESSMENT OF SAFETY 
This Section describes the assessment of primary 
 endpoints of safety. 
The primary 
 endpoints of safety will be based on data at time points defined in 
Section 2.1.2 and Section 2.2.2. 
5.2.1 
Physical examination 
A complete physical examination will be performed at the time points specified in the Flow 
Chart. It includes at a minimum general appearance, neck, lungs, cardiovascular system, 
abdomen, extremities, and skin. 

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Measurement of height and body weight will be performed at the time points specified in the 
Flow Chart. 
The results must be included in the source documents available at the site.  
 
For new patients, all abnormal findings at baseline (Visit 2) will be recorded on the Baseline 
Condition eCRF page. New abnormal findings or worsening of baseline conditions detected 
at the subsequent physical examinations, if judged clinically relevant, will be recorded as 
adverse events on the appropriate eCRF page. 
5.2.1.1 
Body weight 
Measurement of body weight will be performed at the time points specified in the Flow 
Chart.  
 
For new patients, if possible, the patient’s weight in the 2 years before screening (Visit 1) will 
be recorded, in order to detect any potential change in growth velocity over time. For roll-
over patients, data from the 2 previous years collected in parent trial will be used. 
 
Body weight measurements will be recorded in the source documents and transcribed into the 
eCRF. 
 
These measurements will be used to assess safety and to assign the proper dose of trial 
medication at Visit 2 and subsequent IMP dispensing visits. 
5.2.1.2 
Height, leg length 
Close monitoring of standing and sitting heights and leg length will be conducted at the time 
points specified in the Flow Chart and footnotes (see ISF for further instructions).  
 
For new patients, if possible, the patient’s height in the 2 years before screening (Visit 1) will 
be recorded, in order to detect any potential change in growth velocity over time. For roll-
over patients, data from the 2 previous years collected in parent trial will be used. 
 
At each time point, height, sitting height will be assessed three times, and the average of the 3 
measurements will be taken. Height and sitting height will be assessed using a stadiometer. 
The stadiometer should be calibrated at regular intervals (see ISF for further instructions). 
The sitting height should be standardized and calibrated. For roll-over patients, the procedure 
followed to make these measurements for a given patient must be consistent with procedure 
followed in the parent trial as communicated to site by the sponsor. 
Leg length will be assessed by measuring the distance between the anterior iliac spine and the 
medial malleolus. This will be measured three times on each leg, and the average of the 3 
measurements will be taken. 
 
These measurements will be recorded in the source documents available at the site and the 
average transcribed into the eCRF. 
 
These measurements will be used to assess safety and be periodically reviewed by the SMC. 

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5.2.2 
Vital signs 
Vital signs will be evaluated at the time points specified in the Flow Chart, prior to blood 
sampling. 
This includes systolic and diastolic blood pressure and pulse rate (electronically or by 
palpation count for 1 minute) in a seated position after 5 minutes of rest. The results must be 
included in the source documents available at the site. See also Appendix 10.5 for details. 
 
For new patient, all abnormal findings at baseline will be recorded on the Baseline Condition 
eCRF page. New abnormal findings or worsening of baseline conditions detected at the 
subsequent physical examinations, if judged clinically relevant, will be recorded as adverse 
events on the appropriate eCRF page. 
5.2.3 
Safety laboratory parameters 
Safety laboratory parameters to be assessed at scheduled visits are listed in Table 5.2.3:1. For 
the sampling time points please see the Flow Chart. 
 
All analyses will be performed by a central laboratory, the respective reference ranges will be 
provided in the ISF.  
 
The eGFR will be calculated based on serum creatinine according to Schwartz formula [R10-
0828, R11-4789] in adolescent and according to CKD/EPI formula in adults [R12-1392] (see 
Appendix 10.3)  
 
Patients do not have to be fasted for the blood sampling for the safety laboratory.  
 
Blood sampling will be conducted using materials and techniques suitable for the paediatric 
population. Venous whole blood will be collected in appropriate syringes provided by the 
sponsor through the assigned central laboratory. All efforts should be made to use the lowest 
amount of blood per sample as technically possible, e.g. by using special paediatric collection 
systems. 
 
Instructions regarding sample collection, sample handling / processing and sample shipping 
are provided in the Laboratory Manual in the ISF.  
The central laboratory will send reports to the investigator. It is the responsibility of the 
investigator to evaluate the laboratory reports. Clinically relevant abnormal findings as 
judged by the investigator will be reported as adverse events (please refer to Section 5.2.7). 
 
Overall, approximately 6.1 mL blood will be taken for standard safety laboratory tests at each 
scheduled visit during the trial. 
 
Pregnancy tests 
During the treatment period and the follow-up period a pregnancy test must be conducted in 
all female patients every 4 weeks, either at home or at site. ß-HCG test on blood will be 
conducted at all visits until end of treatment on blood collected for laboratory tests. A urine 
dipstick pregnancy test will be conducted at the EoS/Follow-up Visit (if acceptable). 

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Urine dipstick pregnancy test kits will be provided locally for use between regular visits 
every 4 weeks.  
A pregnancy test diary card will be dispensed at visits defined in the Flow Chart. 
The patient/parent(s)/legal guardian will be instructed on how it should be used to support the 
record of the date and result of urine pregnancy test(s) between consecutive visits. 
Test results must be documented in the patient’s pregnancy test diary card and will be 
transferred to the patient’s records by site staff at the next site visit. In case of positive results, 
procedures defined in Section 5.2.7.2.3 should be followed. 
 
At ‘a-Visits’, safety blood, and urine samples will be collected and submitted to the central 
laboratory if needed for additional safety monitoring at the discretion of the Investigator (see 
cautionary notes under Section 4.2.2.1 for additional safety monitoring). Safety laboratory 
parameters to be assessed at regular visits are listed in Table 5.2.3:1 Safety laboratory 
parameters to be assessed at these additional visits are listed in Table 5.2.3:2. 
The samples may be collected at the office of a local doctor using preferably trial specific lab 
kits that will be sent to a central laboratory for analyses or may be analysed locally. These 
kits will be provided to patients at study visits as applicable. Around 2.5 mL will be taken at 
each a-Visit. 
 
If laboratory values indicate abnormality, adequate and more frequent blood sampling may be 
performed at the discretion of the Investigator. 
In case of liver function value elevations, close monitoring must be ensured by the 
Investigator. Refer to Section 4.1.2 for monitoring elevations and Section 3.3.4 for 
withdrawal criteria. 
 
In case the criteria for hepatic injury are fulfilled, a number of additional measures will be 
performed (please see Section 5.2.7.1 and the DILI Checklist provided in the eDC system).  
The amount of blood taken from the patient concerned will be increased due to these 
additional samplings. 
 
The central laboratory will transfer the results of the analysis to the sponsor or delegate. 
 
Table 5.2.3:1  
Safety laboratory tests at scheduled site visits 
The laboratory tests at regular site visits will include:
Functional lab group 
Test name  
Haematology 
Haematocrit 
Haemoglobin 
Red blood cells (RBC) 
White blood cells (WBC) 
Platelet count 
Mean corpuscular volume (MCV) 
Automatic WBC differential  
(relative and absolute) 
 
Neutrophiles total 
Lymphocytes total 
Eosinophiles  
Basophiles  

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Functional lab group 
Test name  
Monocytes  
Lymphocytes  
Manual differential WBC (if automatic differential 
WBC is abnormal) 
Polymorphonuclear neutrophils (segs), band 
neutrophils (stabs), eosinophils, basophils, 
monocytes, lymphocytes  
Coagulation 
Activated partial thromboplastin time (aPTT) 
Prothrombin Time (PT) 
INR 
Enzymes 
Aspartate aminotransferase (AST)  
Alanine aminotransferase (ALT)  
Alkaline phosphatase (AP) 
Gamma glutamyl transferase (GGT)  
Creatine kinase (CK) 
Lactate dehydrogenase (LDH) 
Substrates 
Glucose (non fasting, V1 and V2 only) 
Creatinine 
eGFR (V1 and V2 only) 
Uric Acid 
Total bilirubin  
Direct bilirubin 
Total protein 
Thyroid stimulating hormone 
Electrolytes 
Calcium 
Sodium 
Potassium 
Chloride 
Phosphate 
Serum Pregnancy test (in all female subjects) at all 
scheduled visits requiring blood sampling for 
laboratory tests and if urine pregnancy test is 
positive 
Human Serum Chorionic Gonadotropin 
Urine Pregnancy test (dipstick) (Locally provided 
for use between scheduled clinic visits to assure 
pregnancy test every 4 weeks) 
Human Chorionic Gonadotropin in the urine 
Urinalysis macro panel  
 
Semi-quantitative: 
Urine nitrite 
Urine protein 
Urine glucose 
Urine Blood 
Urine leukocyte esterase 
Urine pH 
Table 5.2.3:2  
Safety laboratory tests at intermediate ‘a’-visits 
The laboratory tests at intermediate ‘a’-visits will include: 
 
Functional lab group 
Test name  
Enzymes 
Aspartate aminotransferase (AST)  
Alanine aminotransferase (ALT)  

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Functional lab group 
Test name  
Alkaline phosphatase (AP) 
Gamma glutamyl transferase (GGT)  
 
Substrates 
Creatinine 
Total bilirubin  
Total protein 
Electrolytes 
Calcium 
Sodium 
Potassium 
Chloride 
Phosphate 
Urinalysis 
 
Semi quantitative: 
Urine nitrite 
Urine protein 
Urine glucose 
Urine Blood 
Urine leukocyte esterase 
Urine pH 
 
5.2.4 
Electrocardiogram 
Resting 12-lead ECGs will be conducted at sites using their own equipment.  
The 12-lead ECGs must be administered by a qualified technologist and results will be 
recorded as scheduled in the Flow Chart. The investigator or a designee will evaluate whether 
the ECG is normal or abnormal and assess clinical relevance. ECGs may be repeated for 
quality reasons and a repeated recording used for analysis.  
Additional ECGs may be recorded for safety reasons. Dated and signed printouts of ECG 
with findings should be documented in patient’s medical record. 
Clinically relevant abnormal findings will be reported either as baseline condition (if 
identified at the screening visit) or otherwise as AEs and will be followed up and / or treated 
as medically appropriate. 
For new patients, if the ECG was abnormal at Visit 1, the 12-lead ECG at rest will be 
repeated (if possible prior to blood draw) and evaluated by qualified personnel at site. 
5.2.5 
Assessment of pathological findings of epiphyseal growth plate 
MRI assessments of the distal femur and proximal tibia will be conducted as primary bone 
imaging methodology to assess the potential risk of skeletal toxicity of nintedanib in the 
growing population. In each patient the same side should be imaged at each assessment. In 
situations in which MRI cannot be performed, especially if sedation is required, x-rays of the 
distal femur and proximal tibia (AP knee radiograph) will be conducted as secondary 
methodology. For roll-over patients, the procedure followed to make these measurements for 
a given patient must be consistent with the procedure followed in the parent trial. 
 
MRIs/x-rays of growth plates will be conducted in all patients who qualified for assignment 
of nintedanib treatment at Visit 2 (baseline) except in roll-over patients with closed physes at 

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the end of parent trial and patients that had previous MRIs or x-rays in the time window 
described below.  
Imaging follow-ups will be conducted only in patients with open physes, at pre-defined time 
points until end of the study or closure of physes.  
The follow-up will be planned, irrespective of scheduled visits, in order to respect the 
frequency of around every 12 weeks for first year and around every 24 weeks thereafter, 
taking in account, for roll-over patients, the participation in the parent trial with always 
minimum 10 weeks (first year)/22 weeks (thereafter) and always maximum 16 weeks (first 
year)/28 weeks (thereafter) from previous procedure. For patients aged 19 and older, bone 
imaging follow-up procedures will be performed around every 48 weeks (instead of around 
every 24 weeks) until the end of the study or closure of the physes. 
Please refer to Flow Chart footnotes for more details. Timepoints may be adapted on a case-
by-case basis after discussion with the sponsor if appropriate for patient’s safety. Previous 
MRIs or x-rays of epiphyseal growth plates within respectively 12 weeks (for the first year) 
or 24 weeks (after the first year) prior baseline should be used at baseline for patients 
previously involved in InPedILD® with respectively less or more than 52 weeks in 
InPedILD®.  
The same acquisition protocol specifications should be used for all MRIs/x-rays of growth 
plates. Details will be provided in the image acquisition guideline for bone safety monitoring 
available in the ISF. Whenever possible, scans should be completed on the same scanner and 
by the same radiologist at each site. Scans will be transferred for central review and stored at 
the sponsor facilities or by an external vendor. 
 
MRI/x-ray assessments will be evaluated in a centralised manner by an external expert in 
radiology.  
Results of central review will be reported to the investigator. In case of pathological 
findings/potentially pathological findings on Epiphyseal Growth Plate Results Report 
identified by central reviewer, the investigator should assess if these findings should be 
reported (as AE/AESI) or not (see Section 5.2.7.1.4.). 
In addition, all MRI/x-ray assessments and height measurements (see Section 5.2.1.2) will be 
periodically reported to the SMC. 
5.2.6 
Assessment of pathological findings on dental examination or imaging 
Dental examination (clinical examination) and imaging (panoramic x-ray) will be conducted 
in all patients to assess the potential severe/irreversible effects of nintedanib on teeth in the 
study population: 
 
Dental examination will be conducted in all patients who qualified for assignment of 
nintedanib treatment at Visit 2 (baseline). Follow-up will be conducted at predefined time 
points. Dental examination follow-ups will be planned, irrespective of scheduled visits, in 
order to respect the frequency of around every 12 weeks for first year and around every 24 
weeks thereafter, taking in account, for roll-over patients, the participation in the parent trial 
with always maximum 16 weeks (first year)/28 weeks (thereafter) from previous procedure. 
Please refer to Flow Chart footnotes for more details. Timepoints may be adapted on a case-

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by-case basis after discussion with the sponsor if appropriate for patient’s safety. Previous 
dental examination within 12 weeks prior baseline may be used at baseline for patients 
previously involved in InPedILD®.  
 
Dental imaging will be conducted in all patients who qualified for assignment of nintedanib 
treatment at Visit 2 (baseline) and do not have previous panoramic x-ray in the time window 
described below available. Follow-up will be conducted at predefined time points until the 
end of the study. Dental imaging follow-ups will be planned, irrespective of scheduled visits, 
in order to respect the frequency of around every 24 weeks for first year and around every 48 
weeks thereafter, taking in account, for roll-over patients, the participation in the parent trial 
with always minimum 22 weeks (first year)/46 weeks (thereafter) and always maximum 28 
weeks (first year)/52 weeks (thereafter) from previous procedure. Please refer to Flow Chart 
footnotes for more details. Timepoints may be adapted on a case-by-case basis after 
discussion with the sponsor if appropriate for patient’s safety. Previous panoramic x-ray 
within 24 weeks prior baseline may be used at baseline for patients previously involved in 
InPedILD®.  
 
Dental examination will be conducted at the investigational site or external facility by a 
dentist. 
Panoramic x-rays will be conducted at the investigational site or external facility.  
The same specifications will be used for all panoramic x-rays. Details will be provided in the 
image acquisition guideline for teeth safety monitoring available in the ISF. Whenever 
possible, panoramic x-rays should be completed on the same device. Dental cone beam 
computed tomography can be conducted only in case panoramic x-rays cannot be performed, 
as far as it allows the same assessments, it is conducted according to the image acquisition 
guideline, and the same device is used consistently in the same patient. 
 
X-rays will be transferred for central review and stored at the sponsor facilities or by an 
external vendor. Panoramic x-rays will be evaluated in a centralised manner by a blinded 
external expert in paediatric dentistry.  
Results of central review will be reported to the investigator. In case of pathological 
findings/potentially pathological findings identified by central reviewer, the investigator 
should consult immediately the local dentist, to confirm if these findings should be reported 
(as AE/AESI) or not (see Section 5.2.7.1.4.). 
 
Dental examination and imaging will be periodically reported to the SMC. 
5.2.7 
Assessment of adverse events 
5.2.7.1 
Definitions of AEs  
5.2.7.1.1 
Adverse event 
An AE is defined as any untoward medical occurrence in a patient or clinical investigation 
subject administered a medicinal product and which does not necessarily have to have a 
causal relationship with this treatment. 
 
 

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An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether considered related or not. 
 
The following should also be recorded as an AE in the eCRF and BI SAE form (if 
applicable): 
• Worsening of the underlying disease (including acute ILD exacerbations) or of other pre-
existing conditions Pathological findings of epiphyseal growth plate on imaging; 
• Pathological findings on dental examination or imaging;Changes in vital signs, ECG, 
physical examination and laboratory test results, if they are judged clinically relevant by 
the investigator. 
 
If such abnormalities already exist prior to trial inclusion, they will be considered as baseline 
conditions and should be collected in the eCRF only. However, if these abnormalities are 
Adverse events from the parent trial in patients that have been rolled over and are still 
ongoing at Visit 1, then they should not be recorded as baseline conditions but as ongoing 
Adverse Events.  
5.2.7.1.2 
Serious adverse event 
A serious adverse event (SAE) is defined as any AE, which fulfils at least one of the 
following criteria: 
- 
results in death, 
- 
is life-threatening, which refers to an event in which the patient was at risk of death at 
the time of the event; it does not refer to an event that hypothetically might have 
caused death if more severe, 
- 
requires inpatient hospitalisation or prolongation of existing hospitalisation 
- 
results in persistent or significant disability or incapacity,  
- 
is a congenital anomaly / birth defect, 
- 
is deemed serious for any other reason if it is an important medical event when based 
on appropriate medical judgement which may jeopardise the patient and may require 
medical or surgical intervention to prevent one of the other outcomes listed in the 
above definitions. Examples of such events are intensive treatment in an emergency 
room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do 
not result in hospitalisation or development of dependency or abuse.  
5.2.7.1.3 
AEs considered “Always Serious” 
In accordance with the European Medicines Agency initiative on Important Medical Events, 
Boehringer Ingelheim has set up a list of AEs, which by their nature, can always be 
considered to be “serious” even though they may not have met the criteria of an SAE as 
defined above. 
The latest list of “Always Serious AEs” can be found in the eDC system. A copy of the latest 
list of “Always Serious AEs” will be provided upon request. These events should always be 
reported as SAEs as described in Section 5.2.7.2. 
Cancers of new histology and exacerbations of existing cancer must be classified as a serious 
event regardless of the time since discontinuation of the drug and must be reported as 

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described in 5.2.7.2, subsections “AE Collection” and “AE reporting to sponsor and 
timelines”. 
5.2.7.1.4 
Adverse events of special interest 
The term adverse events of special interest (AESI) relates to any specific AE that has been 
identified at the project level as being of particular concern for prospective safety monitoring 
and safety assessment within this trial, e.g. the potential for AEs based on knowledge from 
other compounds in the same class. AESIs need to be reported to the sponsor’s 
Pharmacovigilance Department within the same timeframe that applies to SAEs, please see 
Section 5.2.7.2.2. 
 
The following are considered as AESIs: 
• adverse events relating to gastrointestinal perforation 
• bleeding 
• hepatic injury. 
• pathological findings identified on bone imaging 
• stunted growth identified on dental imaging. 
 
Hepatic injury 
In this trial protocol, signs of hepatic injury are defined as: 
• ALT and/or AST ≥8 fold ULN 
• ALT and/or AST ≥3 fold ULN and total bilirubin ≥ 2 fold ULN*  
• ALT and/or AST ≥3 fold ULN and unexplained INR > 1.5* 
• ALT and/or AST ≥3 fold ULN and unexplained eosinophilia (>5%)* 
• ALT and/or AST ≥3 fold ULN and appearance of fatigue, nausea, vomiting, right 
upper abdominal quadrant pain or tenderness, fever and/or rash 
*in the same blood draw sample. 
 
These lab findings constitute a hepatic injury alert and the patients showing these lab 
abnormalities need to be followed up according to the “DILI checklist” provided in the eDC 
system.  
 
In case of clinical symptoms of hepatic injury (icterus, unexplained encephalopathy, 
unexplained coagulopathy, right upper quadrant abdominal pain, etc.) without lab results 
(ALT, AST, total bilirubin) available, the investigator should make sure these parameters are 
analysed, if necessary, in an unscheduled blood test. Should the results meet the criteria of 
hepatic injury alert, the procedures described in the DILI checklist should be followed. 
5.2.7.1.5 
Intensity (severity) of AEs 
The intensity (severity) of the AE should be judged based on the following: 
 
Mild:  
Awareness of sign(s) or symptom(s) that is / are easily tolerated. 
Moderate: 
Sufficient discomfort to cause interference with usual activity. 
Severe: 
Incapacitating or causing inability to work or to perform usual activities. 
 

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In addition, the intensity (severity) of diarrhoea adverse events should be classified and 
recorded in the eCRF according to the Common Terminology Criteria for Adverse Events 
(CTCAE) version 5 on an additional diarrhoea adverse events eCRF [R18-1357]. See Table 
5.2.7.1.5: 1. below. 
Table 5.2.7.1.5: 1 
CTCAE Categorization for diarrhoea 
CTCAE Grade 
Diarrhoea 
1 
Increase of <4 stools per day over baseline 
2 
Increase of 4 to 6 stools per day over baseline 
3 
Increase of ≥7 stools per day over baseline; incontinence 
4  
Life threatening consequences 
5 
Death 
 
5.2.7.1.6 
Causal relationship of AEs 
Medical judgement should be used to determine the relationship between the adverse event 
and the BI investigational compound, considering all relevant factors, including pattern of 
reaction, temporal relationship, de-challenge or re-challenge, confounding factors such as 
concomitant medication, concomitant diseases and relevant history.  
 
Arguments that may suggest that there is a reasonable possibility of a causal relationship 
could be: 
• The event is consistent with the known pharmacology of the trial drug.  
• The event is known to be caused by or attributed to the drug class. 
• A plausible time to onset of the event relative to the time of drug exposure. 
• Evidence that the event is reproducible when the drug is re-introduced. 
• No medically sound alternative aetiologies that could explain the event (e.g. pre-existing 
or concomitant diseases, or co-medications). 
• The event is typically drug-related and infrequent in the general population not exposed 
to drugs (e.g. Stevens-Johnson syndrome). 
• An indication of dose-response (i.e. greater effect size if the dose is increased, smaller 
effect size if dose is reduced). 
 
Arguments that may suggest that there is no reasonable possibility of a causal relationship 
could be: 
• No plausible time to onset of the event relative to the time of drug exposure is evident 
(e.g. pre-treatment cases, diagnosis of cancer or chronic disease within days / weeks of 
drug administration; an allergic reaction weeks after discontinuation of the trial drug 
concerned). 
• Continuation of the event despite the withdrawal of the medication, taking into account 
the pharmacological properties of the compound (e.g. after 5 half-lives). 

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• Of note, this criterion may not be applicable to events whose time course is prolonged 
despite removing the original trigger. 
• There is an alternative explanation, e.g. situations where other drugs or underlying 
diseases appear to provide a more likely explanation for the observed event than the drug 
concerned. 
• Disappearance of the event even though the trial drug treatment continues or remains 
unchanged. 
5.2.7.2 
Adverse event collection and reporting 
5.2.7.2.1 
AE Collection 
The investigator shall maintain and keep detailed records of all AEs in the patient files. 
 
The following must be collected and documented on the appropriate eCRF(s) by the 
investigator: 
 
From signing the informed consent onwards until the individual patient’s end of trial (= the 
End of Study (EoS) visit): all AEs (serious and non-serious) and all AESIs.  
For roll-over patients, any (S)AE that occurred after start of treatment in the parent trial and 
is continuing up to Visit 1 of this extension trial, will be recorded as (S)AEs at Visit 1 of this 
trial with the same information as it was recorded in the parent trial. If this ongoing AE is an 
SAE, then the follow-up report will still be sent on the parent trial SAE form, no new SAE 
form is to be completed for the extension trial.  
 
After the individual patient’s end of trial:  
The investigator does not need to actively monitor the patient for new AEs but should only 
report any occurrence of cancer and trial drug related SAEs and trial drug related AESIs of 
which the investigator may become aware of by any means of communication, e.g. phone call. 
Those AEs should be reported on the BI SAE form (Section 5.2.7.2.2.), but not on the eCRF. 
Vital Status Data Collection 
Patients who discontinue trial treatment prematurely, who agree to be contacted further but 
do not agree to physical visits, should be followed up as described in Section 3.3.4.1, 
withdrawal from trial treatment. From then on until the individual patient’s end of the trial the 
investigator must report any occurrence of cancer, report all deaths / fatal AEs regardless of 
relationship, and trial drug related SAEs and trial drug related AESIs the investigator 
becomes aware of.  
5.2.7.2.2 
AE reporting to the sponsor and timelines 
The investigator must report SAEs, AESIs, and non-serious AEs which are relevant for the 
reported SAE or AESI, on the BI SAE form to the sponsor’s unique entry point within 24 
hours of becoming aware of the event, the country specific process will be specified in the 
ISF. The same timeline applies if follow-up information becomes available. In specific 
occasions, the investigator could inform the sponsor upfront via telephone. This does not 
replace the requirement to complete the BI SAE form. 

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With receipt of any further information to these events, a follow-up SAE form has to be 
provided. For follow-up information the same rules and timeline apply as for initial 
information. All (S)AEs, including those persisting after individual patient’s end of trial must 
be followed up until they have resolved, have been assessed as “chronic” or “stable”, or no 
further information can be obtained. 
5.2.7.2.3 
Pregnancy 
In rare cases, pregnancy might occur in a clinical trial. Once a patient has been enrolled in the 
clinical trial and has taken trial medication, the investigator must report any drug exposure 
during pregnancy in a trial participant immediately (within 24 hours) by means of Part A of 
the Pregnancy Monitoring Form to the sponsor’s unique entry point. 
The outcome of the pregnancy associated with the drug exposure during pregnancy must be 
followed up and reported to the sponsor’s unique entry point on the Pregnancy Monitoring 
Form for Clinical Studies (Part B). 
The ISF will contain the Pregnancy Monitoring Form for Clinical Studies (Part A and B). 
 
As pregnancy itself is not to be reported as an AE, in the absence of an accompanying SAE 
and / or AESI, only the Pregnancy Monitoring Form for Clinical Studies and not the SAE 
form is to be completed. If there is an SAE and / or AESI associated with the pregnancy an 
SAE form must be completed in addition. 
5.2.7.2.4 
Safety monitoring and adverse events with additional information collection 
• An external expert in radiology will review all MRI/radiological assessments (bone 
imaging). Additionally, images of a particular patient may be reviewed by other radiology 
or clinical experts selected by the sponsor for consultancy, if judged needed by the 
sponsor to assess safety of this particular patient or to support overall safety assessment. 
• A blinded external expert in paediatric dentistry will review all panoramic x-rays (dental 
imaging). Additionally, images of a particular patient may be reviewed by other external 
dentist/expert in paediatric dentistry selected by the sponsor for consultancy, if judged 
needed by sponsor to assess safety of this particular patient or to support overall safety 
assessment. 
• An independent SMC will conduct regular reviews of the trial safety data, with access to 
any data including MRI/radiological assessments, height measurements, and panoramic 
x-rays, as detailed in Section 3.1, in Section 5.2.5 and in the SMC charter. 
• An independent Adjudication Committee (AC) will review all fatal cases and adjudicate 
all deaths to either cardiac, respiratory or other causes and will review all adverse events 
categorized as major adverse cardiovascular events (MACE). MACE is defined as non-
fatal myocardial infarction, non-fatal stroke and cardiac death. In parallel, the 
Adjudication Committee/a member of the Adjudication Committee will review all dental 
findings of stunted growth of the dental root identified by central review to assess them to 
either pathological finding /stunted growth or not. Certain further dental findings on 
dental imaging may potentially be assessed if defined in the Adjudication Charter (dental 
imaging from 1199-0337 study may be included in this assessment process). 

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• Additional details (on top of standard AE and SAE reporting) will be collected in the 
eCRF for the adverse event ‘diarrhoea’ and the adverse events in the subordinate 
Standard MedDRA Query (SMQ) ‘Haemorrhage terms, excluding laboratory terms’. 

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5.5 
BIOBANKING 
n.a. 
5.6 
OTHER ASSESSMENTS 

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5.6.4 
Assessment of DLCO 
The diffusing capacity of the lung for carbon monoxide (DLCO) will be assessed at Visit 2 to 
characterize the new patients. 
 
Single-breath DLCO measurement will be carried out according to the ATS/ERS guideline on 
DLCO measurements [R06-2002] using the site own equipment. Before beginning the test, the 
manoeuvres should be demonstrated and the subject carefully instructed. 
 
For new patients, DLCO will be measured at Visit 2 and corrected for haemoglobin (Hb) 
measured at Visit 1 (see Appendix 10.4 for details).  
 
DLCO values will also be adjusted for altitude and carboxyhaemoglobin (COHb). For 
predicted normal values, different sites may use different prediction formulas, based on the 
method used to measure DLCO. In any case, the calculation method used must be in 
compliance with the ATS/ERS guideline on DLCO measurements [R06-2002] and the 
prediction formula appropriate for that method. Raw data (gas mixture, equation used for 
prediction of normal, further adjustments made if so) must be traced. 

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The DLCO assessment should be performed after the FVC measurement. 
Physician reported Fan severity score [R09-5337] at Visit 2 will be used to determine 
eligibility of new patient. 
 
. For instructions on how to assign the severity-of-
illness score see Appendix 10.2 
 
The score used to determine eligibility of the patient can be based on historical data. 
Documentation of measurements used to determine the score at Visit 2 (e.g. ambulatory 
oxygen saturation or night time oximetry reports) will need to be documented and made 
available for central review. Data from study visit procedures (e.g. ambulatory oxygen 
saturation) can also be used. 
5.6.6 
Assessment of HRCT 
HRCT assessment of presence of fibrosis has become an essential part of the evaluation and 
diagnosis of patients with paediatric fibrosing ILDs.  
 
Screening HRCT will be used in all new patients to determine study eligibility. Central 
review of the screening HRCT images will ensure that relevant lung fibrosis is present. 
 
In addition to confirmation of the presence of relevant fibrosis, visual and potentially 
quantitative analyses of the screening HRCTs might be performed to explore potential 
predictors of clinical outcomes e.g. FVC decline, progression, exacerbation. 
 
The same acquisition protocol specifications will be used for all screening HRCT scans and 
should be followed when possible. Details will be provided in the image acquisition guideline 
available in the ISF. Scans will be transferred for central review. HRCT scans might be 
stored for up to 30 years at the sponsor facilities or by an external vendor for future scientific 
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5.7 
APPROPRIATENESS OF MEASUREMENTS 
All measurements conducted for the assessment of endpoints in this study are using standard 
methods. Some measurements might be new methodologies already used in clinical trials but 
not yet validated for this rare disease. 
 
Refer to Section 1.4.2 for the discussion of the benefit-risk of monitoring the potential impact 
of the investigational treatment in bone development and growth, as well as in dentition. 
 
The pharmacokinetic measurements and measurements outlined in Section 5.3 are generally 
used as measurements to assess drug exposure. 

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6. 
INVESTIGATIONAL PLAN 
6.1 
VISIT SCHEDULE 
All study visits should be scheduled as defined in the Flow Chart. Some flexibility is allowed 
by time windows specified in order to accommodate scheduling problems.  
All efforts should be made to perform all visits as requested. If a delay is observed for a 
particular visit, subsequent visits should follow the original planned visit schedule (calculated 
from Visit 2). 
In case of a missed visit, the investigator should contact the sponsor; these situations will be 
addressed on a case-by-case basis. Should a visit be postponed until the time window of the 
next visit, the visit will be skipped, and the next visit will be scheduled as defined by Flow 
Chart, based on the actual date of Visit 2. 
All deviations from the planned visit schedule will be documented. 
 
Timing of visits should also be properly planned, taking into account that: 
• The patient should take the trial medication twice daily, at about the same time every day 
(between 06:00 and 11:00 in the morning, 18:00 and 23:00 in the evening), with a dose 
interval of approximately 12 hours from one dose to the next dose.  
• 
• Spirometric measurements should always be conducted at the same time (+/- 90 min) 
with reference to baseline measurement (Visit 2). 
 
The trial will run until all patients have stopped treatment, which is when, nintedanib is 
available outside the clinical trial or alternative treatment options become available or a 
stopping criterion is met according to Section 3.3.4 
 
In the event of force majeure or other disruptive circumstances (e.g. pandemic, war) the 
investigational plan as per this clinical trial protocol may not be feasible at a site. With the 
consent/assent of the patient/parent(s)/legal guardian, sponsor and investigator may agree on 
alternative, back-up or rescue methodology which may include but will not be limited to 
direct-to-patient shipment of trial medication from the site, laboratory tests done by local 
physician/local lab (if possible samples collected and processed by local physician/local lab 
using kits provided by central laboratory and sent to central laboratory for analyses), bone 
and dental assessments (bone imaging, dental imaging, oral examination) done at local 
facilities, home visits by site staff or trained healthcare provider (e.g. nurse) that could be 
combined with remote patient visits (via telephone and/or internet based means of 
communication). Risk mitigation measures and modifications to CTP standard procedures 
that can be implemented at a site are described in Appendix 10.9. Measures implemented at a 
site should be mentioned in the information leaflet for patient/parent(s)/legal guardian. The 
implementation of these measures will depend on consent from the patient/parent(s)/legal 
guardian, operational feasibility, local law and regulations. If alternative procedures are 

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implemented, the deviations from the standard trial procedures will be precisely documented 
and the implications considered for the analysis of the trial data. If the defined minimum 
frequency of trial procedures cannot be adhered to, discontinuation from trial medication 
should be considered. See Appendix 10.9 for details. 
6.2 
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS 
The investigator and site personnel involved in the conduct of the study should carefully 
prepare what is needed for the conduct of the visit, taking into account the specific structure 
of the site and the mandatory needs outlined in the clinical trial protocol. Efforts should be 
made to ensure the well-being of the pediatric patient during the visit taking in account its 
age-appropriate needs. 
 
Study procedures and assessments to be performed at each visit are listed in the Flow Chart. 
Explanations of procedures and assessments are given in Section 5.  
Additional details regarding visit procedures and assessments are provided below. 
6.2.1 
Screening and run-in period(s) 
For new patients,  
 
Before or at the latest at Visit 1 
• Informed consent (and assent where applicable) will be obtained before any procedure 
related to the study, including HRCT transfer to central review.  
• Upon obtaining informed consent, the investigator will register the patient’s Screening 
transaction in the IRT system, and the patient will receive a patient number and trial 
identification card. 
• A preliminary check of in-/exclusion criteria is recommended at time of informed consent 
to avoid unnecessary wash-out procedures in non-eligible patients.  
• An HRCT not older than 12 months will be evaluated by the investigator and sent for 
central review if meeting criteria defined in Section 3.3.2.1. If the patient does not have 
an HRCT within 12 months from the time of the scheduled Visit 1, or the available 
HRCT does not meet the image acquisition specifications of the study (see image 
acquisition guideline available in the ISF), an HRCT can be performed for the purposes 
of participation in the trial provided the patient meets eligibility criteria that can be 
assessed at that time point. 
• If available, a lung biopsy will be evaluated by the investigator and sent for central review 
if meeting criteria defined in Section 3.3.2.1 
• In patients without any documented lung biopsy, or whose biopsy results do not meet the 
criteria listed in Section 3.3.2.1, a second HRCT will be evaluated by the investigator and 
sent for central review if meeting criteria defined in Section 3.3.2.1 
• After giving informed consent, the patient will enter in the screening period. 
Patient/parent(s)/legal guardian will be instructed on procedures to be followed until the 
next study visit. The Visit 1 should take place within 28 days prior to Visit 2. Results of 
all study procedures and assessments in determining patient’s eligibility must be available 
prior to Visit 2. 
 

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Visit 1 (Screening)  
 
Information to be collected during screening period: 
• Demographic will be recorded. This includes age on the day of informed consent (in 
years and month)  
• Sex (male, female in order to describe the subject’s sex at birth),  
• 
Ethnicity and race in order to sufficiently characterize the patient population, to support 
possible subgroup analyses if needed  unless not acceptable according to local 
regulations. 
• Baseline Conditions/Medical History: 
• Medical history including pre-existing conditions (including 
 
 if applicable) will be recorded. 
• Concomitant therapy including previous medications 
 will 
be recorded. 
• Any adverse events (since consent, if applicable) will be recorded. 
• Prior to blood draw, physical examination including vital signs, weight, height (standing 
and sitting) will be performed; data will be recorded in source documents and timely 
transferred per instructions provided (see ISF), to ensure central review as needed. 
• If possible, prior to blood draw, a 12-lead ECG at rest will be conducted with the site’s 
own equipment and evaluated by qualified personnel at site. 
• 
. 
• FVC measurement will be conducted with the spirometer provided by the sponsor, 
according to procedures defined (see ISF for details). 
• Prior to blood draw a pre-assessment of all in-/exclusion criteria is highly recommended 
to avoid unnecessary blood draws. 
• Blood and urine samples (safety laboratory tests, and pregnancy test on serum in female 
patients only) will be collected and submitted to the central laboratory (for details refer to 
Section 5.2.3 and instructions given in the ISF).  
 
• If the patient does not have an HRCT within 12 months from the time of the scheduled 
Visit 1, or the available HRCT does not meet the image acquisition specifications of the 
study, an HRCT will be done and sent to central review by site personnel (if not done 
before). 
 
• If the patient qualifies to enter the screening period, Visit 2 will be scheduled; 
patient/parent(s)/legal guardian will be instructed on procedures to be followed until the 
next visit. 
 
• If a patient results in a screen failure the patient must be registered as a screen failure in 
IRT system. Patient rescreening is possible later. At due time a new informed 
consent/assent will be collected. Rescreening transaction must be registered in the IRT 
system. A new patient number will be provided which will be linked to the previous 
patient number in the IRT system and patient will complete all study procedures 
according to Flow Chart. Re-screening of a previously screen failed patient will be 
permitted once. 
 

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For roll-over patients,  
 
• Informed consent (and assent where applicable) must be obtained before any procedure 
related to the 1199-0378 trial. After giving informed consent, the patient is considered to 
have started the screening process and is assigned a unique patient number in the IRT 
system. A trial identification card is provided.  
 
• Visit 1 and Visit 2 should be conducted the same day and should, if possible, occur the 
same day as the EoT Visit of the parent trial to avoid any treatment interruption. In this 
case, informed consent/assent must be obtained at the latest, at the beginning of 1199-
0337 EoT visit before any procedure (in particular, before any blood sample collection). 
Assessments conducted as part of EoT of the InPedILD® trial do not need to be repeated if 
they are performed the same day. In case it is not possible to perform Visit 1 on the same 
day as the EoT Visit of InPedILD®, the maximum time allowed between EoT of parent 
trial and Visit 1 of this trial will be 8 weeks. (for details of combined Visit 1/Visit 2, 
please refer to Section 6.2.2) 
 
• 
6.2.2 
Treatment period(s) 
Visit 2: 
If for any reason the screening phase for an individual patient lasts for more than 6 weeks, 
then the laboratory examination for Visit 1 has to be repeated before assignment of study 
treatment. The screening phase (from informed consent until Visit 2) must be no longer than 
12 weeks. 
 
Detailed procedures and assessment to be performed at Visit 2 are described in Flow Chart 
and Section 5.  
 
Visit 2 for new patients  
 
The following prerequisites must be met: 
• Confirmation of fibrosing ILD based on HRCT central review (and biopsy central review 
if needed). 
• Safety laboratory results from blood sampling conducted at Visit 1, including 
haemoglobin and eGFR measurement have been provided and are available at the site. 
 
Observations and procedures 
• 
• 

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• Adverse events, 
 
, concomitant therapy 
 
since last visit will be reviewed and recorded. 
• Prior to blood draw, physical examination including vital signs, weight, height (standing 
and sitting), and leg length will be performed; data will be recorded in source documents 
and entered timely into the eCRF. 
• If the ECG was abnormal at Visit 1, the 12-lead ECG at rest will be repeated (if possible, 
prior to blood draw) and evaluated by qualified personnel at site. 
• 
 
• FVC measurement will be conducted according to procedures defined (see ISF for 
details). 
• DLCO measurement will be conducted after FVC measurement and patient’s rest. DLCO 
will be corrected for haemoglobin (Hb) measured at Visit 1 (see Section 5.6.4 for details). 
• All in/exclusion criteria will be checked, and if all in-/exclusion criteria are fulfilled the 
patient will qualify for the treatment period of the study. 
• 
. 
• Blood and urine samples (safety laboratory tests, and pregnancy test on serum in female 
patients only) will be collected and submitted to the central laboratory. 
• 
• If a patient is eligible for the trial, treatment assignments will be performed by using the 
IRT system. 
• The assigned trial medication will be administered at the site.  
• Medication wallets will be dispensed, patient/parent(s)/legal guardian will be properly 
instructed about how and when the study medication should be taken until the next visit. 
The patient/parent(s)/legal guardian will be properly instructed to contact the site in case 
of adverse events (details given in the informed consent and assent where applicable). 
• 
• The next visit will be scheduled; patient/ parent(s)/legal guardian will be instructed on 
procedures to be followed until the next visit. 
 
Procedures to be conducted in all eligible patients, if possible, on the day of the visit, or if 
not, to be done in the 2 weeks immediately after the visit (please refer to the image 
acquisition guideline available in the ISF for details). 
• An MRI of epiphyseal growth plates will be conducted according to protocol 
requirements (see Section 5.2.5). If MRI cannot be performed, an x-ray will be 
conducted. The MRI (or x-ray) will be sent to central evaluation by radiology expert on a 
timely manner. 
• Dental examination will be conducted according to protocol requirements (see Section 
5.2.6) and evaluated at site. 
• Dental imaging will be conducted according to protocol requirements (see Section 5.2.6). 
The panoramic x-ray will be sent to central evaluation by a paediatric dentistry expert in a 
timely manner. 
 

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If, by the end of Visit 2, the patient does not qualify for assignment of study treatment, 
screening failure will be notified via IRT.  
 
Visit 1/Visit 2 for roll-over patients  
 
Assessments conducted as part of EoT of the InPedILD® trial do not need to be repeated if 
they are performed the same day in particular: 
• Physical examination including vital signs, weight, height (standing and sitting), and leg 
length 
• 12-lead ECG 
• 
  
• FVC measurement 
• Blood and urine samples for safety laboratory tests, 
 
(and pregnancy test on serum in female patients only)  
• All in/exclusion criteria will be checked, and if all in-/exclusion criteria are fulfilled the 
patient will qualify for the treatment period of the study. 
 
Prior to additional blood draw, the assessment of all in-/exclusion criteria is highly 
recommended to avoid unnecessary blood draw. 
• An additional blood sample to check safety parameter(s) 
 
 for the 1199-0378 study may be collected at the same time as blood and urine 
samples for EoT of 1199-0337. 
 
Information to be collected at this visit: 
• Demographic will be recorded. This includes age on the day of informed consent (in 
years and month), sex (male, female in order to describe the subject’s sex at birth),  
• 
Ethnicity and race in order to sufficiently characterize the patient population, to support 
possible subgroup analyses if needed, y unless not acceptable according to local 
regulations. 
• 
Baseline Conditions/Medical History:  
Medical history including pre-existing conditions (
 
) will be recorded. 
• Concomitant therapy including previous medications 
 will be 
recorded. 
• Any adverse events (since consent, if applicable) will be recorded. If this AE is an 
ongoing AE from parent trial, then it will be recorded as AE with same information 
than in the parent trial 
 
Other observations and procedures 
• 
• 
• 
• If a patient is eligible for the trial, treatment assignments will be performed by using the 
IRT system. 

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• The first dose of assigned trial medication will be administered at the site.  
• Medication wallets will be dispensed, patient/ parent(s)/legal guardian will be properly 
instructed about how and when the study medication should be taken until the next visit. 
The patient/parent(s)/legal guardian will be properly instructed to contact the site in case 
of adverse events (details given in the informed consent and assent where applicable). 
• 
 will be dispensed; the patient/parent(s)/legal guardian will be instructed 
on how it should be completed in the 3 days before the next visit. 
• The next visit will be scheduled; patient/parent(s)/legal guardian will be instructed on 
procedures to be followed until the next visit. 
 
Procedures to be conducted if possible, in all eligible patients, on the day of the visit, or if 
not, to be done in the 2 weeks immediately after the visit (please refer to the image 
acquisition guideline available in the ISF for details). 
• Bone imaging: Previous MRIs or x-rays of epiphyseal growth plates within 12 weeks 
prior baseline should be used as baseline for roll-over patients with less than 52 weeks in 
InPedILD®. Previous MRIs or x-rays of epiphyseal growth plates within 24 weeks prior 
Visit 2 should be used as baseline for roll-over patients with more than 52 weeks in 
InPedILD®. If a previous MRI or x-ray as outlined above, is not available, imaging of 
epiphyseal growth plates should be conducted according to protocol requirements (see 
Section 5.2.5). If MRI cannot be performed, an x-ray will be conducted. Not applicable 
for patients with closed physes at the end of InPedILD®. 
• Dental examination: Previous panoramic x-ray within 12 weeks prior Visit 2 should be 
used as baseline. If a previous dental examination as outlined above is not available, a 
dental examination will be conducted according to protocol requirements (see Section 
5.2.6) and evaluated at site.  
• Dental imaging: Previous panoramic x-ray within 24 weeks prior Visit 2 should be used 
as baseline. If a dental imaging is not available as outlined above, a dental imaging will 
be conducted according to protocol requirements (see Section 5.2.6). The panoramic x-
ray will be sent to central evaluation by a paediatric dentistry expert in a timely manner.  
 
Visits 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, X (treatment period) 
 
Additional clinic visits will be scheduled on regular basis from Visit 2 until End of Treatment 
(EOT) visit. Detailed procedures and assessment to be performed at each Visit are described 
in Flow Chart and Section 5. 
As the treatment duration for each patient will be variable, some visits may not apply (to 
some new patients and to some patients aged 21) 
 
For roll-over patients with 26 weeks or more in InPedILD®, Visit 3 is not needed. This 
additional visit is scheduled after 2 weeks of treatment to assure close monitoring of new 
patients and roll-over patients with less than 26 weeks in InPedILD®, during the first month 
of study. 
 
The following must be ensured during trial visits according to the study Flow Chart: 
• 
  

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• FVC measurements at all visits should be performed approximately at the same time of 
the day to reference time point at Visit 2. 
 
Observations and procedures:  
Observations and procedures 
:  
 
Other observations and procedures:  
• Compliance will be checked, and drug accountability will be completed. 
• Criteria for dose reduction / interruption will be checked, if any. 
• The site personnel will check the pregnancy test diary card and confirm that since the last 
scheduled visit at the site the pregnancy test has been repeated every 4 weeks until the 
current visit. If not confirmed, the investigator will re-instruct the patient/parent(s)/legal 
guardian. Test results will be documented in the patient’s records. In case a positive test is 
reported the sponsor should be contacted immediately. Refer to Section 3.3.4.1 for further 
instructions. Refer to Section 5.2.7.2.3 for detailed information on event reporting in case 
of pregnancy (applicable for female patients only, all scheduled visits after Visit 3). 
• Adverse events, 
 
, concomitant therapy 
 
since last visit will be reviewed and recorded. 
• Prior to blood draw, physical examination including vital signs, weight, height, and leg 
length will be performed (height and leg length not planned at Visit 3; leg length planned 
at Visit4, Visit 5, Visit 6, Visit 7, Visit 9, Visit 11, Visit 13, Visit 15 and every 24 weeks 
thereafter, until the end of the study); data will be recorded in source documents and 
timely transferred per instructions provided (see ISF), to ensure central review as needed. 
• The 12-lead ECG at rest will be conducted (if possible, prior to blood draw) and 
evaluated by qualified personnel at site (Visit 5, Visit 7, Visit 9, Visit 11, Visit 13, Visit 
15 and every 24 weeks thereafter, until the end of the study). 

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• 
 
• FVC measurement will be conducted according to procedures defined (see ISF for 
details). 
• 
• 
• Blood and urine samples (safety laboratory tests, and pregnancy test on serum in female 
patients only) will be collected and submitted to the central laboratory. 
• 
• New medication wallets will be assigned by using the IRT system and dispensed, returned 
wallets will be collected as instructed (see ISF for details). 
• 
; the patient/parent(s)/legal guardian will be instructed 
on how it should be completed in the 3 days before the next visit (Visit 4 only). 
• A pregnancy test diary card will be dispensed; the patient/parent(s)/legal guardian will be 
instructed on how it should be used to support the record of the date and result of urine 
pregnancy test(s) between consecutive visits (applicable for female patients only, all 
scheduled visits after Visit 3). 
• The next visit will be scheduled; patient/parent(s)/legal guardian will be instructed on 
procedures to be followed until the next visit. 
 
Procedures to be conducted at predefined time points, irrespective of scheduled visits, 
according to time window defined in the Flow Chart. If it is not possible to conduct the 
follow-up at the predefined time points, please refer also to footnotes 21, 22, and 23 in the 
Flow Chart. 
 
• 
Follow-up bone imaging (MRIs or x-rays if baseline MRI was not possible) will be 
planned, in order to follow the frequency of around every 12 weeks for first year and 
around every 24 weeks thereafter, taking in account, for roll-over patients, the 
participation in the parent trial: 
•For new patients, imaging follow-up will be conducted, if applicable, at 12 weeks, 24 
weeks, 36 weeks, 52 weeks, 76 weeks, 104 weeks, 128 weeks, 156 weeks, and every 24 
weeks thereafter until the end of the study or closure of the physes.  
•For roll-over patients, imaging follow-up will be conducted around every 12 weeks in 
the following year after the MRI/x-ray considered as baseline for parent trial (when 
applicable) and around every 24 weeks thereafter until the end of the study or closure of 
the physes. 
MRIs (or x-rays) will be sent to central evaluation by radiology expert on a timely 
manner. 
• For patients aged 19 and older, bone imaging follow-up procedures will be performed 
around every 48 weeks (instead of around every 24 weeks) until the end of the study or 
closure of the physes. 
 

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• 
Follow-up dental examination will be planned in order to follow the frequency of around 
every 12 weeks for first year and around every 24 weeks thereafter, taking in account, 
for roll-over patients, the participation in the parent trial: 
•For new patients, follow-up will be conducted, if applicable, at 12 weeks, 24 weeks, 
36 weeks, 52 weeks, 76 weeks, 104 weeks, 128 weeks, 156 weeks, and every 24 weeks 
thereafter until the end of the study. 
•For roll-over patients, follow-up will be conducted around every 12 weeks in the 
following year after the dental examination considered as baseline in parent trial (when 
applicable) and around every 24 weeks thereafter until the end of the study. 
• 
Follow-up dental imaging will be planned in order to follow the frequency of around 
every 24 weeks for first year and around every 48 weeks thereafter, taking in account, 
for roll-over patients, the participation in the parent trial: 
•For new patients, follow-up will be conducted, if applicable, at 24 weeks, 52 
weeks,104 weeks, 156 weeks, and every 48 weeks thereafter until the end of the study. 
•For roll-over patients, follow-up will be conducted, irrespective of scheduled visits, 
around every 24 weeks in the following year after the dental imaging considered as 
baseline for parent trial (when applicable) and around every 48 weeks thereafter until the 
end of the study.  
Dental imaging will be sent to central evaluation by paediatric dentistry expert on a 
timely manner. 
 
Dose reduction visit / dose increase visit/ Change of capsule size visit 
If a patient experiences a drug related AE, the dose can be reduced via IRT and the dose can 
be increased to the original dose via IRT after recovery as described in Section 4.1.2. 
If a patient, assigned to 150 mg or 100 mg bid, is not able to swallow the 150 mg strength or 
the 100 mg strength capsule, the patient will have the possibility to take the 25 mg strength 
capsules (6 or 4 capsules per dose, respectively).  
 
If the dose change or change of capsule size does not occur in concomitance to a scheduled 
visit, the patient will attend an unscheduled visit at the site for this dose reduction or dose 
increase or capsule change.  
The following procedures will be completed: 
• Compliance will be checked, and drug accountability will be completed. 
• Criteria for dose reduction will be checked, if any, and recorded. 
• Adverse events, 
 
, concomitant therapy 
 
since last visit will be reviewed and recorded. 
• Prior to blood draw, physical examination including vital signs and weight will be 
performed. 
• Blood and urine samples (safety laboratory tests, and pregnancy test on serum in female 
patients only) will be collected and submitted to the central laboratory. 

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• New medication wallets will be assigned by using the IRT system and dispensed, returned 
wallets will be collected as instructed (see ISF for details). 
 
In case the start/end of an AE requires a dose reduction/increase without the need of a change 
in capsule size and without requiring a meeting with the investigator in person, the 
unscheduled visit for the patient can be replaced by a phone call. The investigator will 
register the phone call in IRT as an unscheduled visit and register the dose reduction/increase 
on the respective page in the eCRF. 
 
Intermediate ‘a-Visits’ 
Intermediate lab tests (“a”-Visits) for safety monitoring may be conducted between scheduled 
visits, as needed at the discretion of the investigator or as recommended by the SMC. 
 
• Blood and urine samples will be collected and submitted to the central laboratory for 
analysis.  
Samples may be collected locally (e.g. by the general practitioner or a nurse). The 
Investigator or site personnel may give the patient/parent(s)/legal guardian written 
instructions and procedures to be followed, together with the trial lab kits for the respective 
‘a-Visit’ to be used for collecting and shipping samples to the central laboratory (preferable 
option) or samples may be analysed locally. 
 
Intermediate pregnancy tests 
During the treatment period and the follow-up period a pregnancy test must be conducted in 
all female patients every 4 weeks. 
Urine dipstick pregnancy test kits will be provided locally for use between visits when visit 
intervals are > 4 weeks. Test results must be documented in the patient’s pregnancy test diary 
card and transferred to the patient’s records at the next site visit. 
 
Treatment period duration 
Treatment duration for each patient will be variable. 
Roll-over patients will be requested to stay in the trial for at least 156 weeks (until Visit 15). 
At week 156, roll-over patients who can be treated with nintedanib or alternative treatment 
options outside the clinical trial will have their EoT Visit. The remaining roll-over patients 
will continue in the trial until nintedanib or alternative treatment options become available to 
them outside the clinical trial. 
 
Trial treatment will be stopped prematurely if a reason for withdrawal is met (refer to Section 
3.3.4).  
 
After week 156, if reason for study treatment discontinuation is that nintedanib or alternative 
treatment options become available for patient outside the clinical trial, then the patient will 
not be considered as early discontinued for treatment. 
 
New patients will stay in the trial until the overall end of the trial (with expected minimum 
treatment duration of 76 weeks), then patients will perform the EoT Visit. 
 
 

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End of Treatment Visit 
If a patient discontinues the study during a scheduled treatment visit, then the scheduled visit 
will be replaced by the EoT visit. As consequence, roll-over patients that discontinue trial 
treatment at week 156 should perform EoT visit instead of Visit 15. 
 
Observations and procedures:  
• 
 
• Compliance will be checked, and drug accountability will be completed. 
• The site personnel will check the pregnancy test diary card and confirm that since the last 
scheduled visit at the site the pregnancy test has been repeated every 4 weeks until the 
current visit. Refer to Section 5.2.7.2.3 for detailed information on event reporting in case 
of pregnancy (applicable for female patients only). 
• Adverse events, 
 
, concomitant therapy 
 
since last visit will be reviewed and recorded. 
• Prior to blood draw, physical examination including vital signs, weight, height, and leg 
length will be performed (height and leg length; leg length planned every 24 weeks after 
the first year); data will be recorded in source documents and timely transferred per 
instructions provided (see ISF), to ensure central review as needed. 
• The 12-lead ECG at rest will be conducted (if possible, prior to blood draw) and 
evaluated by qualified personnel at site. 
• 
 
• FVC measurement will be conducted according to procedures defined (see ISF for 
details). 
• 
• 
• Blood and urine samples (safety laboratory tests, and pregnancy test on serum in female 
patients only) will be collected and submitted to the central laboratory. 
• 
 if applicable and if not 
collected before. 
• A pregnancy test diary card will be dispensed; the patient/parent(s)/legal guardian will be 
instructed on how it should be used to support the record of the date and result of urine 
pregnancy test(s) between consecutive visits (applicable for female patients only). 
• The EoT visit will be registered in the IRT system and dispensed, returned wallets will be 
collected as instructed (see ISF for details). 
• The next visit will be scheduled; patient/parent(s)/legal guardian will be instructed on 
procedures to be followed until the next visit. 
 
Procedures to be conducted if possible, on the day of the visit, or if not, to be done in the 
week immediately before or after the visit. 
• Follow-up MRIs (or x-rays if baseline MRI was not possible) of epiphyseal growth plates 
will be conducted - in patients with open physes only. The MRI/x-ray should not be 
repeated if the last MRI/x-ray was conducted within 24 weeks. 

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• Follow-up dental examination will be conducted in all patients at EoT. The dental 
examination will not be repeated if the last examination was conducted within 12 weeks. 
• Follow-up dental imaging will be conducted in all patients at EoT. The dental imaging 
will not be repeated if the last examination was conducted within 24 weeks. 
 
Exception: patients aged 21 years must complete the trial before their 22nd birthday. 
The EoT visit followed by EoS visit must be performed before the 22nd birthday.  
 
Patients who prematurely discontinued trial medication 
Patients who discontinued trial treatment prematurely will undergo the EoT visit as soon as 
possible. 
 
Roll-over patients who discontinued trial treatment prematurely before week156, patient will 
be asked to remain in the study and to return to remaining scheduled visits until the initial 
planned week 156 (Visit 15) 
New patients who discontinued treatment prematurely will be asked to remain in the study 
and to return to remaining scheduled visits until the overall end of trial. 
 
At remaining scheduled visits, all procedures and assessments planned to be done under 
treatment need to be followed by the patient 
 and IRT 
call/notification. 
The first visit after the EoT will be skipped if the EoT Visit occurs within 4 weeks prior to 
the scheduled visit but if MRI and/or dental examinations were planned at this visit, then they 
should be performed as planned. Only one additional regular follow-up for bone imaging and 
for dental imaging procedures will be needed after the EOT visit if there is no pathological 
finding. If there is a pathological finding, follow-up procedures will be conducted on 
individual basis upon discussion with the sponsor and with the investigator. Follow –up 
procedures for clinical dental examination will be conducted as initially planned by the 
protocol. Urine pregnancy tests at home (for female patients) are only required to be 
continued every 4 weeks for the 3 months after last trial drug intake. 
The last visit to be performed by prematurely discontinued roll-over patients will be the Visit 
15 including trial completion and the last visit to be performed by new patients prematurely 
discontinued will be EoS including trial completion. 
 
If patients are not able to complete the remaining scheduled visits, a follow-up (FU) visit 
should be planned for 28 days after EoT. In addition, every attempt will be made to get 
information on vital status, when applicable, at 24 weeks, 52 weeks, 76 weeks and 104 
weeks, 128 weeks, 156 weeks, and for new patients at EoS.  
 
Exception: patients aged 21 years must complete the trial before their 22nd birthday. 
Remaining scheduled visits or vital status will be replaced by the EoS visit which must be 
performed the 22nd birthday.  
 
Additionally, for treatment discontinued patients, if it is intended by the patient to use 
commercial nintedanib after trial treatment discontinuation, the patient should directly 
undergo the EoS visit 28 days after the EOT visit. 
 

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Follow-up visit: 
F-up visit should be conducted 28 days (+7 days) after the EoT visit for all discontinued 
patients who are not able to complete the remaining visits off-treatment or who accepted the 
vital status collection 
If the EoT visit has been delayed and has been done 28 days or more after the treatment 
discontinuation, the follow-up visit can be skipped 
 
Observations and procedures to be performed are listed in the Flow Chart. 
 
6.2.3 
Follow-up period and trial completion 
End of Study visit 
EoS visit should be conducted 28 days (+7 days) after the EoT visit for patients who have 
completed the trial on treatment as planned. 
In exceptional cases, when the patient is not able to come at site for medical reason, the EoS 
visit can be replaced by a phone call. 
If the EoT visit has been delayed and has been done 28 days or more after the treatment 
discontinuation, the EoS visit can be skipped. 
 
The EoS should be conducted at week 156 for prematurely discontinued roll-over patients 
who were able to complete the remaining visits off-treatment until week 156 and at the 
overall end of the trial for new patients who prematurely discontinued trial treatment and 
were able to stay in the trial until the overall end of trial. 
 
Observations and procedures:  
• Adverse events, 
, 
concomitant therapy 
 since last visit will be reviewed and 
recorded. 
• Physical examination including vital signs will be performed; weight and height will 
be repeated at follow-up in case of clinically relevant changes at EoT; data will be 
recorded in source documents and timely transferred per instructions provided (see 
ISF), to ensure central review as needed. 
• Blood and urine samples will be repeated at EoS in case of clinically relevant changes 
at EoT. 
• 
 
 
• Pregnancy test on urines will be conducted in female patients only. Test results will 
be documented in the patient’s records. 
 
If needed in the opinion of the investigator, after the EoS visit, additional visits may be 
scheduled for continued safety monitoring.  
Abnormal assessments or lab values judged clinically relevant by the investigator will be 
monitored until they returned to a medically acceptable level.  
 
Trial completion  

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The trial completion CRF page must be filled-in when the patient has terminated the trial. 
The trial completion (individual patient’s end of trial) is: 
• At the end of the EoS Visit for patients who have completed the trial on treatment as 
planned (including patients aged 21). 
• At week 156, for roll-over patients who prematurely discontinued trial treatment before 
Visit 15 and were able to stay in the trial until week 156. 
• At the overall end of the trial for new patients who prematurely discontinued trial 
treatment and were able to stay in the trial until the overall end of trial. 
• At F-up/EoS visit, for roll-over patients who prematurely discontinued trial treatment 
before Visit 15 and were not able to stay in the trial until week 156 and for new patients 
who prematurely discontinued trial treatment and were not able to stay in the trial until 
the overall end of trial. 
• At last contact, for other cases. 

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7. 
STATISTICAL METHODS AND DETERMINATION OF 
SAMPLE SIZE 
As the main objective of this extension trial is to study long-term tolerability and safety, only 
descriptive statistics will be used. Some limitations due to the nature of the extension trial 
should be considered when interpreting the data (bias in the selection of the population, no 
comparative arm). All endpoints are considered exploratory only. 
 
This statistical paragraph deals with the analyses to be performed on the extension trial only. 
7.1 
NULL AND ALTERNATIVE HYPOTHESES 
No confirmatory testing is performed and hence no null and alternative hypotheses are 
defined. 
7.2 
PLANNED ANALYSES 
7.2.1 
General considerations 
The following analysis sets will be defined for this trial: 
 
• Treated Set (TS): 
The Treated Set (TS) consists of patients who have received and taken at least one dose of 
open-label trial medication. 
 

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Adherence to the protocol will be assessed by the trial team. Important protocol deviation 
(iPD) categories will be documented in the DV domain template including protocol 
deviations relevant to the 
. IPDs will be 
identified no later than in the final Report Planning Meeting, and the iPD categories will be 
updated as needed. 
 
Patients will be analysed depending if and when they rolled-over from the parent trial 
(Group 1: New Patients [including patients who prematurely discontinued treatment 
permanently in 1199-0337, and completed patients from the parent trial not able to roll over 
into the extension trial within 12 weeks following their End of Treatment visit in the parent 
trial] and patients from 1199-0337 placebo arm Part A –, Group 2: patients from 1199-0337 
Part B and from 1199-0337 nintedanib arm Part A) and overall. 
 
Patients without any post-baseline data will be handled as missing for the respective 
endpoints and assessments (see Section 7.3). 
 
Endpoints will be analysed for those patients where respective data is collected. 
 
Further details will be specified in the TSAP. 
7.2.2 
Handling of Intercurrent Events 
The expected intercurrent events of interest in this trial are: 
 
• Treatment discontinuation 
 
The strategies for handling intercurrent events in this trial are as follows: 

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While-on-Treatment: This is the effect of treatment while patients take it. Intercurrent events 
will be handled by default using the while-on-treatment approach as defined in ICH E9(R1), 
with the treatment period defined as the period from first trial drug administration to the end 
of the residual effect period following last administration. Any changes to background 
therapy or temporary discontinuations of trial drug will be considered part of the treatment 
regimen being assessed. 
 
Each analysis will reference the strategy for handling intercurrent events that it will be 
estimating. The estimand for each main analysis in this protocol is the combination of the 
relevant detailed clinical objective from Section 2.1 and this strategy. 
7.2.3 
Primary objective analyses 
The primary endpoint listed in Section 2.1.2 will be derived according to BI standards. The 
primary analysis refers to the number of patients with any treatment-emergent adverse event 
reported during the trial, i.e. all adverse events occurring between start of treatment and end 
of the REP. The analysis will be based on the TS and will be descriptive in nature. 
 
As the primary objective of the study is to assess the tolerability and safety of nintedanib, 
please refer to Section 7.2.6. 
7.2.3.1 
Sensitivity Analyses 
No sensitivity analysis planned. 
7.2.3.2 
Subgroup Analyses 
Subgroup analyses will be specified in the TSAP. 
7.2.3.3 
Supplementary Analyses 
No supplementary analysis planned. 
7.2.4 
Secondary objective analyses 
Not applicable. 
7.2.6 
Safety analyses 
Adverse events will be coded using the Medical Dictionary for Drug Regulatory Activities 
(MedDRA). Standard BI summary tables and listings will be produced. All adverse events 

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with an onset between start of treatment and end of the REP, a period of 28 days after the last 
dose of trial medication, will be assigned to the on-treatment period for evaluation. 
 
All treated patients will be included in the safety analysis. In general, safety analyses will be 
descriptive in nature and will be based on BI standards. No hypothesis testing is planned. 
 
Statistical analysis and reporting of adverse events will concentrate on treatment-emergent 
adverse events, i.e. all adverse events occurring between start of treatment and end of the 
REP. Adverse events that start before first drug intake and deteriorate under treatment will 
also be considered as ‘treatment-emergent’. The frequency of patients with AEs as well as 
incidence rates per 100 patient years will be presented. 
 
Frequency, severity, and causal relationship of adverse events will be tabulated by system 
organ class and preferred term after coding according to the current version of the Medical 
Dictionary for Drug Regulatory Activities (MedDRA) at database lock. 
 
Laboratory data will be analysed both quantitatively as well as qualitatively. The latter will 
be done via comparison of laboratory data to their reference ranges. Values outside the 
reference range as well as values defined as clinically relevant will be summarised. Patient 
groups will be compared descriptively with regard to distribution parameters as well as with 
regard to frequency and percentage of patients with abnormal values or clinically relevant 
abnormal values. 
 
Vital signs, physical examinations, or other safety-relevant data observed at screening, 
baseline, during the course of the trial and at the end-of-trial evaluation will be assessed with 
regard to possible changes compared to findings before start of treatment. 
 
Further details will be provided in the TSAP. 
7.2.8 
Interim Analyses 
One interim analysis is planned after 1 year, i.e. after all roll-over patients completed the 52 
weeks visit or prematurely discontinued from the trial. Additional interim analyses could be 
performed upon request from Health Authorities or for publication purposes. All the 
previously mentioned analyses may be presented at each interim analysis. Further details will 
be provided in the TSAP. 
 

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A Safety Monitoring Committee (SMC) will be in place with tasks as described in Section 
8.7.  
 
7.3 
HANDLING OF MISSING DATA 
Missing or incomplete AE dates will be imputed according to BI rules. No imputation is 
planned for other safety criteria. 
 
Missing or incomplete data for 
 will be handled using standard 
survival analysis techniques (i.e. censoring). 
 
In the analysis of continuous endpoints, missing data will not be imputed. 
 
 
Further details will be provided in the TSAP. 
7.4 
RANDOMISATION 
Not applicable in this open label study. 
7.5 
DETERMINATION OF SAMPLE SIZE 
Not applicable as this is an open label trial to collect information on long-term tolerability 
and safety from patients rolling over from InPedILD® and newly identified patients with high 
unmet medical need. There will be two cohort of patients included in this trial:  
 
1. Patients who have completed and did not prematurely discontinue trial medication in the 
InPedILD® study, who fulfil the eligibility in this trial and are willing to participate.  
2. Newly identified children and adolescents with clinically significant fibrosing ILDs who 
meet eligibility criteria of this trial.  
It is expected that at least 30 patients will roll-over from trial InPedILD® and that 
approximately 20 to 30 newly identified patients with clinically significant fibrosing ILDs 
will enter treatment. 

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8. 
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY, AND 
ADMINISTRATIVE STRUCTURE 
The trial will be carried out in accordance with the Medical Device Regulation (EU) 2017 / 
745 and the harmonised standards for Medical Devices (ISO 14155, current version). 
 
The trial will be carried out in compliance with the protocol, the ethical principles laid down 
in the Declaration of Helsinki, in accordance with the ICH Harmonized Guideline for Good 
Clinical Practice (GCP), relevant BI Standard Operating Procedures (SOPs), the EU directive 
2001/20/EC / EU regulation 536/2014 and other relevant regulations. Investigators and site 
staff must adhere to these principles. Deviation from the protocol, the principles of ICH GCP 
or applicable regulations as will be treated as “protocol deviation”. 
Standard medical care (prophylactic, diagnostic and therapeutic procedures) remains the 
responsibility of the treating physician of the patient. 
 
The investigator will inform the sponsor or delegate immediately of any urgent safety 
measures taken to protect the trial patients against any immediate hazard, as well as of any 
serious breaches of the protocol or of ICH GCP. 
 
The Boehringer Ingelheim transparency and publication policy can be found on the following 
web page: trials.boehringer-ingelheim.com. The rights of the investigator and of the sponsor 
with regard to publication of the results of this trial are described in the investigator contract. 
As a rule, no trial results should be published prior to finalisation of the Clinical Trial Report. 
 
The certificate of insurance cover is made available to the investigator and the patients, and is 
stored in the ISF. 
8.1 
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED CONSENT 
This trial will be initiated only after all required legal documentation has been reviewed and 
approved by the respective Institutional Review Board (IRB) / Independent Ethics Committee 
(IEC) and competent authority (CA) according to national and international regulations. The 
same applies for the implementation of changes introduced by amendments. 
 
Prior to patient participation in the trial, written informed consent must be obtained from the 
parent(s)/legal guardian (and written informed assent must be obtained from the patient, 
where applicable) or when applicable by patient (or the patient’s legally accepted 
representative) according to ICH-GCP and to the regulatory and legal requirements of the 
participating country.  
For adolescents, where applicable, the patient will be provided with an age-adapted 
information sheet where his/her assent will be collected according to the regulatory and legal 
requirements of the participating country.  
 
Each signature must be personally dated by each signatory and the informed consent/assent 
and any additional patient/parent(s)/legal guardian-information form retained by the 

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investigator as part of the trial records. A signed copy of the informed consent and any 
additional patient information must be given to each patient or the patient’s legally accepted 
representative. 
The patient /patient’s parent(s)/legal guardian must be given sufficient time to consider 
participation in the trial. The investigator or delegate obtains written consent/assent of the 
patient/patient’s parent(s)/legal guardian own free will with the informed consent form 
/assent form after confirming that the patient /patient’s parent(s)/legal guardian understands 
the contents. The investigator or
delegate must sign (or place a seal on) and date the 
informed consent form/assent form when applicable. If a trial collaborator has given a 
supplementary explanation, the trial collaborator also signs (or places a seal on) and dates the 
informed consent form / assent form. 
The refusal of an adolescent to participate must be accepted independently of the consent of 
his/her parent(s)/legal guardian. 
For patients who may legally consent during the trial participation (turning to the age of legal 
consent in the participating country), written informed consent must be obtained to confirm 
the patient’s willingness to pursue trial participation. 
 
Re-consenting may become necessary when new relevant information becomes available and 
should be conducted according to the sponsor’s instructions. 
The consent and re-consenting process should be properly documented in the source 
documentation. The consent and re-consenting process (together with the assent and re-
assenting process where applicable) should be properly documented in the source 
documentation. 
In order to ensure continued consent and assent, the investigator or 
 delegate will seek 
affirmation from the patient and patient’s legally accepted representative as applicable about 
the continuation of the patient’s participation in the trial during each visit. The fact that the 
patient appears for the regular visit as per protocol is enough affirmation in this aspect mean. 
The regular visit must be documented in the patient’s medical records. 
8.2 
DATA QUALITY ASSURANCE 
A risk-based approach is used for trial quality management. It is initiated by the assessment 
of critical data and processes for trial subject protection and reliability of the results as well as 
identification and assessment of associated risks. An Integrated Quality and Risk 
Management Plan or alternative plan, in line with the guidance provided by ICH Q9 and 
ICH-GCP E6, documents the rationale and strategies for risk management during trial 
conduct including monitoring approaches, vendor management and other processes focusing 
on areas of greatest risk.  
Continuous risk review and assessment may lead to adjustments in trial conduct, trial design 
or monitoring approaches. 
A quality assurance audit /inspection of this trial may be conducted by the sponsor, sponsor’s 
designees, or by IRB / IEC or by regulatory authorities. The quality assurance auditor will 
have access to all medical records, the investigator’s trial-related files and correspondence, 
and the informed consent documentation of this clinical trial. 

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8.3 
RECORDS 
CRFs for individual patients will be provided by the sponsor. For drug accountability, refer to 
Section 4.1.8. 
8.3.1 
Source documents 
In accordance with regulatory requirements, the investigator should prepare and maintain 
adequate and accurate source documents and trial records that include all observations and 
other data pertinent to the investigation on each trial patient. Source data as well as reported 
data should follow the “ALCOA principles” and be attributable, legible, contemporaneous, 
original and accurate. Changes to the data should be traceable (audit trial). 
Data reported on the eCRF must be consistent with the source data or the discrepancies must 
be explained. 
The current medical history of the patient may not be sufficient to confirm eligibility for the 
trial and the investigator may need to request previous medical histories and evidence of any 
diagnostic tests. In this case, the investigator must make at least one documented attempt to 
retrieve previous medical records. If this fails, a verbal history from the patient, documented 
in their medical records, would be acceptable. 
Data will be collected as follows: 
• data recorded in patient’s files and transcribed into the eCRF 
• data collected at site using materials/instruments provided by vendors, 
analysed/checked at vendors and transferred from vendors to the sponsor (e.g. safety 
analyses and pregnancy tests, 
, spirometry) 
• data captured electronically at site, transferred to vendors and from vendors to the 
sponsor (e.g. HRCT, bone MRI/x-ray assessments, panoramic x-rays) 
 
Copies of source documents necessary for the purposes of the trial will be provided to the 
relevant committee/vendor, as listed below: to the Disease Review Committee for 
retrospective evaluation of patients’ characteristics compared to protocol inclusion criteria, to 
the Adjudication Committee for the adjudication of defined events, to the Safety Monitoring 
Committee for the evaluation of possible efficacy signals and for monitoring of safety 
throughout the conduct of the study, to the external radiology expert for central reading of 
HRCTs, to the external pathology expert for central reading of biopsies, to the external 
radiology expert for central reading of bone MRIs/x-rays, to the external paediatric dentistry 
expert for central reading of panoramic x-rays and to any other radiology/clinical experts or 
to any other external dentist/experts in pediatric dentistry selected by the sponsor for 
consultancy. Before sending or uploading those copies, the investigator must ensure that all 
patient identifiers (e.g. patient’s name, initials, address, phone number, social security 
number) have properly been removed or redacted from any copy of the patients’ source 
documents. 
If the patient is not compliant with the protocol, any corrective action e.g. re-training must be 
documented in the patient file. 
For the eCRF, data must be derived from source documents, for example: 
• Patient identification: gender, year of birth (in accordance with local laws and 
regulations) 

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• Patient participation in the trial (substance, trial number, patient number, date 
patient/parent(s)/legal guardian were informed) 
• Dates of patient’s visits, including dispensing of trial medication and any dose change 
• Dates of patient’s contacts for the purpose of vital status (if applicable) 
• Medical history (including trial indication and concomitant diseases, if applicable) 
• Medication history 
• Adverse events and outcome events (onset date (mandatory), and end date (if available)) 
• Serious adverse events (onset date (mandatory), and end date (if available)) 
• Concomitant therapy (start date, changes) 
• Originals or copies of laboratory results and other imaging or testing results, with proper 
documented medical evaluation (in validated electronic format, if available) 
• Completion of patient’s participation in the trial” (end date; in case of premature 
discontinuation document the reason for it). 
• Prior to allocation of a patient to a treatment into a clinical trial, there must be 
documented evidence in the source data (e.g. medical records) that the trial participant 
meets all inclusion criteria and does not meet any exclusion criteria. The absence of 
records (either medical records, verbal documented feedback of the patient or testing 
conducted specific for a protocol) to support inclusion / exclusion criteria does not make 
the patient eligible for the clinical trial. 
 
Source documents will include the following: 
• physician’s notes in patient files 
• patient’s / parent’s / legal guardian’s / site staff / physician’s answers in worksheets 
 
• laboratory print-outs 
• biopsy slides including any reading by the pathology expert (if applicable) 
• originals or copies of HRCT scans including any reading by the thoracic radiology 
expert (if applicable) 
• originals or copies of bone MRI (or x-ray) scans including any reading by the 
radiology expert 
• originals or copies of dental panoramic x-ray scans including any reading by the 
paediatric dentistry expert 
• dentist’s notes in patient files / dentist’s answers in worksheets 
• originals or copies of lung function test results 
• originals or copies of DLCO results (if applicable) 
• original or copies of resting ECG 
8.3.2 
Direct access to source data and documents 
The investigator / institution will allow site trial-related monitoring, audits, IRB / IEC review 
and regulatory inspections. Direct access must be provided to the eCRF and all source 
documents / data, including progress notes, copies of laboratory and medical test results, 
which must be available at all times for review by the CRA, auditor and regulatory inspector 
(e.g. FDA). They may review all eCRFs and informed consents. The accuracy of the data will 
be verified by direct comparison with the source documents described in Section 8.3.1. The 
sponsor or delegate will also monitor compliance with the protocol and GCP. 

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In the event of force majeure or other disrupting circumstances (e.g. pandemic, war, please 
see Section 6.1, site access may be restricted thus limiting the ability to perform standard site 
monitoring activities on site such as on-site source data review and source data verification. 
Therefore, some of these activities may be performed remotely or replaced by centralized 
monitoring to the extent possible, based on a documented risk assessment and in alignment 
with local regulations. 
8.3.3 
Storage period of records 
Trial site(s): 
The trial site(s) must retain the source and essential documents (including ISF) according to 
contract or the local requirements valid at the time of the end of the trial (whatever is longer). 
Sponsor: 
The sponsor must retain the essential documents according to the sponsor’s SOPs. 
8.4 
EXPEDITED REPORTING OF ADVERSE EVENTS 
BI is responsible to fulfil their legal and regulatory reporting obligation in accordance with 
regulatory requirements.  
8.5 
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY 
Data protection and data security measures are implemented for the collection, storage and 
processing of patient data in accordance with the principles 7 and 12 of the WHO GCP 
handbook.  
Individual patient data obtained as a result of this trial is considered confidential and 
disclosure to third parties is prohibited with the following exceptions: 
Personalised treatment data may be given to the patient’s personal physician or to other 
appropriate medical personnel responsible for the patient’s welfare. Data generated at the site 
as a result of the trial need to be available for inspection on request by the participating 
physicians, the sponsor’s representatives, by the IRB / IEC and the regulatory authorities. 
8.5.1 
Collection, storage and future use of biological samples and corresponding 
data  
Measures are in place to comply with the applicable rules for the collection, biobanking and 
future use of biological samples and clinical data, in particular 
• Sample and data usage have to be in accordance with the informed consent 
• 
• An appropriate sample and data management system, incl. audit trail for clinical data and 
samples to identify and destroy such samples according to ICF is in place 
• 
• 

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• Samples and / or data may be transferred to third parties and other countries as specified 
in ICF 
8.6 
TRIAL MILESTONES 
The start of the trial is defined as the date when the first patient in the whole trial signs 
informed consent. 
The end of the trial is defined as the date of the last visit of the last patient in the whole trial 
(“Last Patient Completed”). The “Last Patient Last Treatment” (LPLT) date is defined as 
the date on which the last patient in the whole trial is administered the last dose of trial 
treatment (as scheduled per protocol or prematurely). Individual investigators will be notified 
of SUSARs occurring with the trial medication until 30 days after LPLT at their site. Early 
termination of the trial is defined as the premature termination of the trial due to any reason 
before the end of the trial as specified in this protocol. 
Temporary halt of the trial is defined as any unplanned interruption of the trial by the 
sponsor with the intention to resume it. 
Suspension of the trial is defined as an interruption of the trial based on a Health Authority 
request. 
The IEC / competent authority in each participating EU member state will be notified about 
the trial milestones according to the respective laws. 
A final report of the clinical trial data will be written only after all patients have completed 
the trial in all countries (EU or non-EU) to incorporate and consider all data in the report. 
The sponsor will submit to the EU database a summary of the final trial results within one 
year from the end of a clinical trial as a whole, regardless of the country of the last patient 
(EU or non-EU). 
8.7 
ADMINISTRATIVE STRUCTURE OF THE TRIAL 
The trial is sponsored by Boehringer Ingelheim (BI).  
A Coordinating Investigator chosen among experts in the field of paediatric ILD is 
responsible to provide expert medical support and to coordinate investigators at the different 
sites participating in this trial. Tasks and responsibilities are defined in a contract.  
 
The targeted (Principal) Investigators will be paediatricians, pulmonologists, rheumatologists, 
and other physicians responsible for the investigational sites. Study sites will consist of 
specialized referral centres experienced in the management of ILDs in children and 
adolescents. Relevant documentation on all participating (Principal) Investigators and other 
important study personnel, including their curricula vitae, will be filed in Investigator Site 
File (ISF). The investigators will have access to the BI web portal Clinergize to access 
documents provided by the sponsor. 
 
A blinded external expert in thoracic radiology will review HRCT scans from new patients 
and confirm evidence of fibrosing ILD to the Investigator. Tasks and responsibilities are 
defined in a contract. 
 

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A blinded external pathology expert will review biopsies from new patients as needed and 
confirm evidence of fibrosing ILD to the Investigator. Tasks and responsibilities are defined 
in a contract. 
 
A blinded external expert in radiology will review MRI/x-ray assessments of epiphyseal 
growth plates. Review by external expert and images will be provided to the SMC for the 
evaluation of potential effects on bone development. Additionally, images of a particular 
patient may be reviewed by other radiology or clinical experts selected by the sponsor for 
consultancy, if judged needed by sponsor to assess safety of this particular patient or to 
support overall safety assessment. Tasks and responsibilities are defined in a contract for each 
expert.  
 
A blinded external expert in paediatric dentistry will review all panoramic x-rays. Review by 
external expert and panoramic x-rays will be provided to the SMC for the evaluation of 
potential effects on teeth. Additionally, images of a particular patient may be reviewed by a 
second paediatric dentistry for consultancy, if judged needed by the sponsor to assess safety 
of this particular patient or to support overall safety assessment. Tasks and responsibilities 
are defined in a contract for each expert.  
 
 
A SMC composed of external experts independent from the trial and selected BI non-trial 
team members will be established to review 
 and safety data at 
regular intervals to determine the safety profile and risk/benefit ratio and recommend dose 
modification, additional assessments (e.g. laboratory tests), appropriateness of further 
enrolment and continuation/modification/premature interruption of the study. The SMC will 
also conduct regular reviews of the trial safety data, including MRI/x-rays assessments, 
height measurements, and dental panoramic x-rays, as detailed in Section 3.1, in Section 
5.2.5. Details of the SMC responsibilities and procedures are described in the SMC charter. 
 
To determine how well the protocol inclusion criteria were able to identify the intended 
population, an independent Disease Review Committee (DRC) will be established to 
retrospectively review patient’s clinical data and results of HRCT and biopsy central reading 
for all new patients evaluated for study participation at Visit 1. Members of the committee 
will be blinded to patient screening outcome. The composition of the DRC will be 
documented in the Trial Master File (TMF). The tasks and responsibilities will be agreed in 
contracts between the DRC members and the sponsor and also summarised in a DRC charter. 
Charter and meeting minutes will be filed in the TMF. The data will be collected at set 
interval and analysed after DBL 1.  
 
An independent Adjudication Committee (AC) will review all fatal cases and adjudicate all 
deaths to either cardiac, respiratory or other causes, and review all adverse events categorized 
as MACE (see Section 5.2.7.2.4 for details). In parallel, the Adjudication Committee/a 
member of the Adjudication Committee will review all dental findings of stunted growth of 
the dental root identified by central review to assess them to either pathological finding 
/stunted growth or not. Certain further dental findings may potentially be assessed if defined 
in the Adjudication Charter (dental imaging from 1199-0337 study may be included in this 
assessment process). 

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A steering committee will provide scientific advice on the clinical development program of 
nintedanib in the pediatric population. Tasks and responsibilities are defined in a contract. 
 
BI has appointed a Clinical Trial Leader responsible for coordinating all required activities, in 
order to  
- 
manage the trial in accordance with applicable regulations and internal SOPs, 
- 
direct the clinical trial team in the preparation, conduct, and reporting of the trial, 
- 
ensure appropriate training and information of Clinical Trial Managers (CT 
Managers), Clinical Research Associates (CRAs), and investigators of participating 
countries. 
In the participating countries the trial will be performed by the respective local or regional 
BI-organisation (Operating Unit, OPU) in accordance with applicable regulations and BI 
SOPs, or by a Contract Research Organisation (CRO) based on a contract. The CRO will 
perform project management, clinical field monitoring, medical monitoring, and reporting. 
 
Data Management and Statistical Evaluation will be done by BI according to BI SOPs. 
 
Tasks and functions assigned in order to organise, manage, and evaluate the trial are defined 
according to BI SOPs. A list of responsible persons and relevant local information can be 
found in the ISF. 
A central laboratory service, a central spirometry service, central imaging services, and an 
IRT vendor will be used in this trial. Details will be provided in the IRT Manual, central 
Spirometry Manual, Central Imaging Manual and Central Laboratory Manual, available in 
the ISF. 

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9. 
REFERENCES 
9.1 
PUBLISHED REFERENCES 
P04-08733 
The fourth report on the diagnosis, evaluation, and treatment of high blood 
pressure in children and adolescents. Pediatrics. 2004. 114 (2, Part 3) 
(Suppl): 555-576. 
P05-12782 
Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, et 
al. Standardisation of spirometry. Eur Respir J. 2005. 26 (2): 319-338. 
P08-08684 
Hilberg F, Roth GJ, Krssak M, Kautschitsch S, Sommergruber W, 
Tontsch-Grunt U, et al. BIBF 1120: triple angiokinase inhibitor with 
sustained receptor blockade and good antitumor efficacy. Cancer Res. 
2008. 68 (12): 4774-4782. 
P14-02860 
Wollin L, Maillet I, Quesniaux V, Holweg A, Ryffel B, Anti-fibrotic and 
anti-inflammatory activity of the tyrosine kinase inhibitor, nintedanib, in 
experimental models of lung fibrosis. J Pharmacol Exp Ther. 2014. 349: 
209-220. 
P14-07999 
Wollin L, Ostermann A, Wex E, Herrmann FE, Doods H. Nintedanib 
attenuates motility of lung fibroblasts from patients with idiopathic 
pulmonary fibrosis. Am J Respir Crit Care Med. 2014. 189, A2008, Abstr. 
P14-17410 
Hostettler KE, Zhong J, Papakonstantinou E, Karakiulakis G, Tamm M, 
Seidel P, Sun Q, Mandal J, Lardinois D, Lambers C, Roth M Anti-fibrotic 
effects of nintedanib in lung fibroblasts derived from patients with 
idiopathic pulmonary fibrosis. Respir Res (Lond). 2014. 15, 157. 
P15-06100 
Huang J, Beyer C, Palumbo-Zerr K, Zhang Y, Ramming A, Distler A, 
Gelse K, Distler O, Schett G, Wollin L, Distler JHW. Nintedanib inhibits 
fibroblast activation and ameliorates fibrosis in preclinical models of 
systemic sclerosis. Ann Rheum Dis. 2016. 75 (5): 883-890. 
P16-05905 
Wollin L, Schuett J, Ostermann A, Herrmann F. The effect of nintedanib 
on platelet derived growth factor-stimulated contraction of human primary 
lung fibroblasts. Am J Respir Crit Care Med. 2016. 193, A2384, Abstr. 
P17-03310 
Ackermann M, Kim YO, Wagner WL, Schuppan D, Valenzuela CD, 
Mentzer SJ, et al. Effects of nintedanib on the microvascular architecture 
in a lung fibrosis model. Angiogenesis. 2017. 20 (3): 359-372. 
P17-06049 
Tandon K, Herrmann F, Ayaub E, Parthasarathy P, Ackermann M, Inman 
MD, et al. Nintedanib attenuates the polarization of profibrotic 
macrophages through the inhibition of tyrosine phosphorylation on CSF1 
receptor. Am J Respir Crit Care Med. 2017. 195, A2397, Abstr. 
P17-06052 
Wollin L, Ostermann A, Brauchle V, Williams C. Nintedanib inhibits 
profibroticmediators with relevance in connective tissue disease-

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associatedinterstitial lung diseases. ATS 2017, 113th Int Conf of the 
AmericanThoracic Society (ATS), Washington, 19 - 24 May 2017. Am J 
Respir CritCare Med. 2017. 195, A2450, Abstr. 
P17-10564 
Huang J, Maier C, Zhang Y, Soare A, Dees C, Beyer C, et al. Nintedanib 
inhibits macrophage activation and ameliorates vascular and fibrotic 
manifestations in the Fra2 mouse model of systemic sclerosis. Ann Rheum 
Dis. 2017. 76 (11): 1941-1948. 
P17-10582 
Flaherty KR, Brown KR, Wells AU, Clerisme-Beaty E, Collard HR, 
Cottin V, et al. Design of the PF-ILD trial: a doubleblind, randomised, 
placebo-controlled phase III trial of nintedanib in patients with progressive 
fibrosing interstitial lung disease. BMJ Open Resp Res. 2017. 4: e000212. 
P18-00197 
Hilberg F, Tontsch-Grunt U, Baum A, Le AT, Doebele RC, Lieb S, et al. 
The triple angiokinase inhibitor nintedanib directly inhibits tumor cell 
growth and induces tumor shrinkage via blocking oncogenic receptor 
tyrosine kinases. J Pharmacol Exp Ther. 2018- 364(3): 494-503. 
P18-02512 
Redente EF, Aguilar MA, Black BP, Edelman BL, Bahadur AN, 
Humphries SM, et al. Nintedanib reduces pulmonary fibrosis in a model of 
rheumatoid arthritis-associated interstitial lung disease. Am J Physiol. 
2018. 314 (6), L998 - L1009. 
P18-05607 
Akter T, Atanelishvili I, Noguchi A, Wollin L, Silver RM, Bogatkevich 
GS. Molecular evidences for antifibrotic potential of nintedanib in 
interstitial lung disease associated with systemic sclerosis. Am J Respir 
Crit Care Med. 2018. 197, A4638, Abstr. 
P18-05618 
Prasse A, Plappert L, Jaeger B, Wollin L. Nintedanib treatment attenuates 
pulmonary fibrosis in a new humanized mouse model for IPF. ATS 2018, 
114th Int Conf of the American Thoracic Society (ATS), San Diego, 18 - 
23 May 2018. Am J Respir Crit Care Med. 2018. 197, A5754, Abstr. 
P18-08230 
Kidokoro K, Sogawa Y, Cherney D, Kulasingam V, Nagasu H, Satoh M, 
et al. Evaluation of glomerular hemodynamic function by empagliflozin in 
diabetic mice using in vivo imaging. 78th Sci Sess of the American 
Diabetes Association (ADA), Orlando, 22 - 26 Jun 2018. Diabetes. 2018. 
67 (Suppl 1), A23, Abstr 89-OR. 
P19-08802 
Flaherty KR, Wells AU, Cottin V, Devaraj A, Walsh SLF, Inoue Y, et al, 
INBUILD Trial Investigators. Nintedanib in Progressive Fibrosing 
Interstitial Lung Diseases. NEJM. Published Online September 29, 2019, 
doi: 10.1056/NEJMoa1908681; 2019. 
P20-02333 
Wells AU, Flaherty KR, Brown KK, Inoue Y, Devaraj A, Richeldi L, et al, 
INBUILD Trial Investigators. Nintedanib in patients with progressive 
fibrosing interstitial lung diseases - subgroup analyses by interstitial lung 
disease diagnosis in the INBUILD trial: a randomised, double-blind, 
placebo-controlled, parallel-group trial. Lancet Respiratory Medicine, 
Published Online March 5, 2020, doi: 10.1016/S2213-2600(20)30036-9; 

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2020. 
R06-2002 
Macintyre N, Crapo RO, Viegi G, Johnson DC, Grinten CPM van der, 
Brusasco V, et al. Standardisation of the single-breath determination of 
carbon monoxide uptake in the lung. Eur Respir J. 2005. 26(4): 720-735. 
R09-5337 
Fan LL, Kozinetz CA. Factors influencing survival in children with 
chronic interstitial lung disease. Am J Respir Crit Care Med. 1997. 156: 
939–942. 
R10-0828 
Schwartz GJ, Brion LP, Spitzer A The use of plasma creatinine 
concentration for estimating glomerular filtration rate in infants, children, 
and adolescents. Pediatr Clin North Am. 1987. 34(3): 571-590. 
R11-4789 
Schwartz GJ, Munoz A, Schneider MF, Mak RH, Kaskel F, Warady BA, 
Furth SL. New equations to estimate GFR in children with CKD. J Am 
Soc Nephrol. 2009. 20: 629-637. 
R12-1392 
Levey AS, Stevens LA, Schmid CH, Zhang Y, Castro AF, Feldman HI, 
Kusek JW, Eggers P, Lente F van, Greene T, Coresh J, Chronic Kidney 
Disease Epidemiology Collaboration (CKD-EPI)cr 
A new equation to estimate glomerular filtration rate. 
Ann Intern Med 150 (9), 604 - 612 (2009) 
R15-0845 
Quanjer PH, Stanojevic S, Cole TJ, Baur X, Hall GL, Culver BH, et al. on 
behalf of the ERS Global Lung Function Initiative. Multi-ethnic reference 
values for spirometry for the 3 - 95 year age range: the global lung 
function 2012 equations: report of the Global Lung Function Initiative 
(GLI), ERS task force to establish improved lung function reference 
values. Eur Respir J. 2012. 40(6): 1324-1343. 
R17-3628 
Holland AE, Spruit MA, Troosters T, Puhan MA, Pepin V, Saey D, et al 
An official European Respiratory Society/American Thoracic Society 
technical standard: field walking tests in chronic respiratory disease. Eur 
Respir J. 2014. 44: 1428-1446. 
R18-1357 
U.S. Department of Health and Human Services Common terminology 
criteria for adverse events (CTCAE) version 5.0 (published: November 27, 
2017). U.S. Department of Health and Human Services, National Institutes 
of Health, National Cancer Institute. 2017. 
R19-0760 
Niemitz M, Schwerk N, Goldbeck L, Griese M. Development and 
validation of a health-related quality of life questionnaire for pediatric 
patients with interstitial lung disease. Pediatr Pulmonol. 2018. 53: 954-
963. 
R19-0805 
Griese M. Chronic interstitial lung disease in children. EurRespirRev. 
2018. 27 (147), 170100. 
9.2 
UNPUBLISHED REFERENCES 
U07-1710 
: Internal report. 07B002. 28 

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August 2007. 
U07-1814 
: Internal report. 07B030. 21 
January 2008. 
U10-1991 
 Multicentre, randomised, double-blind, 
Phase III trial to investigate the efficacy and safety of oral BIBF 1120 plus 
standard docetaxel therapy compared to placebo plus standard docetaxel 
therapy in patients with stage IIIB/IV or recurrent non small cell lung 
cancer after failure of first line chemotherapy (LUME Lung 1). Trial 
1199.13. 19 Sep 2012. 
U13-1478 
 Relative 
bioavailability of a single oral dose of nintedanib given alone and in 
combination with multiple oral doses of rifampicin in healthy male 
volunteers (an open-label, two-period, fixed-sequence clinical Phase I 
trial). Study 1199.162. 8 August 2013. 
U13-1504 
 Multicentre, randomised, double-
blind, Phase III trial to investigatze the efficay and safety of oral BIBF 
1120 plus standard docetaxel therapy compared to placebo plus standard 
docetaxel therapy in patients with stage IIIB/IV or recurrent non small cell 
lung cancer after failure of first line chemotherapy (LUME Lung 1). 
Clinical Reports 1199.13. 26 August 2013. 
U13-1506 
Clinical Overview: Nintedanib (BIBF 1120) soft capsules, 150 mg, 100 
mg. 02 Sep 2013. 
U13-1925 
 Relative bioavailability of 
nintedanib given alone and in combination with ketoconazole at steady 
state in healthy male volunteers (an open-label, randomised, two-way 
cross-over clinical Phase I study). Study 1199.161. 4 July 2013. 
c02153150 
Clinical Overview: Nintedanib (BIBF 1120) soft capsules, 150 mg 100 
mg. 07 April 2014. 
c01783972 
Investigator's Brochure Nintedanib (BIBF 1120), Indications: Idiopathic 
Pulmonary Fibrosis, Systemic Sclerosis, Progressive Fibrosing Interstitial 
Lung Disease. 
c26450188 
Clinical Trial Protocol 1199-0337 
 

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10. 
APPENDICES 
10.1 
 
 
 

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10.2 
FAN SEVERITY SCORE 
The severity-of-illness score assigned by the investigator will be based on information in the 
patient records at the time of evaluation [R09-5337]. Refer to Table 10.2:1 for details. 
 
Table 10.2:1 
Severity-of-illness score 
 
 
 
 
 

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10.3 
ESTIMATED GLOMERULAR FILTRATION RATE 
• Calculation of eGFR according to Schwartz Formula in adolescents 13-17 years old [R10-
0828]  
Conventional: 
• in adolescent males k=0.70: 
eGFR (mL/min./1.73m2) = height (cm) x 0.70 / serum creatinine (mg/dL) 
• in adolescent females k=0.55: 
eGFR (mL/min./1.73m2) = height (cm) x 0.55 / serum creatinine (mg/dL) 
 
SI: 
• in adolescent males k=0.70: 
eGFR (mL/min./1.73m2) = height (cm) x 0.70 / (serum creatinine (µmol/L) x 0.01131) 
• in adolescent females k=0.55: 
eGFR (mL/min./1.73m2) = height (cm) x 0.55 / (serum creatinine (µmol/L) x 0.01131) 
 
 
Calculation of eGFR according to Schwartz Formula in children 2-12 years of age [R11-
4789]: 
 
Conventional: 
• in children 2-12 years of age k=0.41: 
eGFR (mL/min/1.73m2) = height (cm) x 0.41 / serum creatinine (mg/dL) 
 
SI: 
• in children 2-12 years of age k=0.41: 
eGFR (mL/min/1.73m2) = height (cm) x 0.41 / (serum creatinine (µmol/L) x 0.01131) 
 
Calculation of eGFR according to CKD/EPI formula in adults [R12-1392]: 
Conventional: 
eGFR (mL/min/1.73m2) = 141 x min(SCr /κ, 1)α x max(SCr /κ, 1)-1.209 x 0.993Age x1.018 [if 
female] x 1.159 [if Black] 
 
SCr = standardized serum creatinine (mg/dL) 
κ = 0.7 (females) or 0.9 (males) 
α = -0.329 (females) or -0.411 (males) 
min = indicates the minimum of SCr/κ or 1 
max = indicates the maximum of SCr/κ or 1 
age = years 
 
SI: 
eGFR (mL/min/1.73m2) = 141 x min(SCr /κ, 1)α x max(SCr /κ, 1)-1.209 x 0.993Age x1.018 [if 
female] x 1.159 [if Black] 
 
SCr = standardized serum creatinine (µmol/L) 

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κ = 61.9 (females) or 79.6 (males) 
α = -0.329 (females) or -0.411 (males) 
min = indicates the minimum of SCr/κ or 1 
max = indicates the maximum of SCr/κ or 1 
age = years 
 
 
 

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10.4 
EQUATIONS FOR DLCO ADJUSTMENT FOR HAEMOGLOBIN 
• For new patients, Percent predicted DLCO results from Visit 2 will be corrected for 
haemoglobin (value obtained at Visit 1) by the site. 
 
Percent predicted DLCO corrected for haemoglobin (Hb) expressed in g·dL-1 [R06-2002] can 
be calculated as follows: 
 
• In adolescents (and adult males) 
DLCO predicted corrected for Hb = DLCO predicted x (1.7Hb)/(10.22+Hb) 
 
Percent predicted DLCO corrected for Hb = [actual DLCO/ DLCO predicted corrected 
for Hb] x 100% 
 
• In children <15 years of age and females 
DLCO predicted corrected for Hb = DLCO predicted x (1.7Hb)/(9.38+Hb) 
 
Percent predicted DLCO corrected for Hb = [actual DLCO/ DLCO predicted corrected 
for Hb] x 100% 
 
 
 

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10.5 
RECOMMENDATIONS FOR AMBULATORY (OFFICE) BLOOD 
PRESSURE MEASUREMENTS IN CHILDREN AND ADOLESCENTS 
Recommendations for ambulatory (office) blood pressure measurements in children and 
adolescents [P04-08733]: 
 
• 
The recommended method is auscultation 
• 
Use K1 for systolic BP and K5 for diastolic BP 
• 
If the oscillometric method is used, the monitor needs to be validated 
• 
All abnormal values by oscillometric method need confirmation by auscultation 
• 
Use the appropriate cuff size according to arm width 
 
Table 10.5: 1 
Recommended Dimensions for BP Cuff Bladders 
 
 
 
Predicted Equations for Blood Pressure Levels 
NOTE: The predicted equations are being provided as an appendix for documentation 
purposes; they are not intended for use by individual sites. 
 
 

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Table 10.5: 2 
Predicted equations for Blood Pressure: white boys aged 1-10 years 
(from [P04-08733]) 
 
 
 

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Table 10.5: 3 
Predicted equations for Blood Pressure: white boys aged 11-17 years 
(from [P04-08733]) 
 
 
 
 

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Table 10.5: 4 
Predicted equations for Blood Pressure: white girls aged 1- 10 years 
(from [P04-08733]) 
 
 
 

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Table 10.5: 5 
Predicted equations for Blood Pressure: white girls aged 11- 17 years 
(from [P04-08733]) 
 
 
 

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10.9 
VISIT MODIFICATION IN EXCEPTIONAL CIRCUMSTANCES 
In the event of force majeure or other disruptive circumstances (e.g. pandemic), in case site 
visits are temporarily not possible for individual patients, to ensure trial continuity the 
following measures may be implemented at a site if possible per local requirements in the 
participating country. Implemented measures should be documented and needed approvals 
should be obtained upon (see Section 6.1 and ISF for details). 
 
Table 10.9: 1 Modifications to visit standard procedures in exceptional circumstances 
INITIAL / STANDARD 
MODIFIED or ADDED  
Face-to-face patient visit 
performed by an adequate site 
staff under the responsibility of a 
physician on site. 
• for Visit 3 (when applicable) and Visit 4: no 
possibility to postpone the visits more than initial 
time window defined by CTP except in case of 
agreement with sponsor and after discussion and 
evaluation of individual patient benefit risk. 
• for following visits, visits may be converted to home 
visits/combined home and remote visits. 
if physical exam, vital signs, height, weight cannot 
be performed at least every 16 weeks, it needs to be 
considered that individual patient treatment needs 
to be interrupted upon discussion with sponsor. 
Medical decision has to be documented in patient’s 
source notes. 
 
Home visit performed (with portable stadiometer, tape, scale, 
ECG machine, 
 by the 
(sub)investigator or delegated to trained personnel to complete 
at least:  
• 
Physical examination and vital signs  
• 
Height sitting and standing 
• 
Leg length 
• 
Weight 
• 
ECG 
• 
 
• 
Safety Lab using central lab kits if possible (otherwise use 
local lab facility, see below for instructions) 
• 
Questionnaires administered as an interview using printed 
questionnaires (if not done by separate call, see below for 
instructions) 
• 
Transfer imaging CDs of panoramic x-ray and bone 
MRI/x-ray to site (when needed) 
• 
Collect medication for IMP compliance 
• 
Assessments listed under “Investigator Call” if not done by 
separate call 
 

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INITIAL / STANDARD 
MODIFIED or ADDED  
Investigator Call: The following assessments could be 
completed by (sub)investigator via phone or telemedicine, if 
not done during the home visit: 
• 
AEs, SAEs, AESI 
• 
Trial medication and concomitant medications 
• 
Questionnaires administered as an interview using printed 
questionnaires 
• 
Pregnancy status and pregnancy diary completion check 
 
The following assessments cannot be made outside 
investigational site: 
• 
FVC,  
FVC, 
 and 
 will be missed if the 
scheduled visit is converted to home visit, or combined home 
and remote visit. 
Safety lab testing conducted at 
site using central lab kits 
• Haematology 
• Biochemistry 
• Electrolytes 
• Coagulation 
• Urinalysis 
 
 
Under treatment with nintedanib, regular safety lab including 
liver enzyme monitoring is required and needs to be ensured 
by the investigational site. If blood and urine sampling for 
safety lab testing at the trial site is not possible 
• 
samples could be collected at a local lab. / local doctor 
using central lab kits and sent to central lab for 
analyses. If this is not possible, 
• 
safety lab analyses can be performed at a local lab. The 
results of the lab tests must be transferred to the 
investigator who ensures medical review and 
documents any clinically relevant safety issue as an 
adverse event.  
Safety lab tests including liver function tests should be 
conducted at the planned timepoint defined by CTP. If safety 
lab tests cannot be conducted at least every 16 weeks the 
individual patient treatment needs to be interrupted upon 
discussion with sponsor. Medical decision has to be 
documented in patient’s source notes. 
Pregnancy test on blood 
conducted at site using central lab 
kits – female subjects only 
If blood sampling for pregnancy test at the trial site is not 
possible 
• 
Urine dipstick pregnancy tests will be used 

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INITIAL / STANDARD 
MODIFIED or ADDED  
• 
Testing must occur every 4 weeks and results documented 
in the pregnancy test diary card. 
• 
The results of the pregnancy tests must be transferred to 
the investigator who ensures medical review, documents 
any test results as needed, and reports any positive results 
as defined by CTP. 
If pregnancy tests cannot be conducted every 4 weeks, the 
individual patient treatment needs to be interrupted upon 
discussion with the sponsor. Medical decision has to be 
documented in patient’s source notes. 
Follow-up monitoring of bone 
and teeth conducted at 
site/external facilities 
• 
Bone MRI/x-ray,  
• 
Dental examination, 
• 
Dental panoramic x-ray 
If regular follow-up monitoring of bone and teeth at site is not 
possible 
• 
Bone MRI/x-ray, dental examination and dental panoramic 
x-ray can be performed at a local radiologist/ local dentist 
• 
The results (images and dental examination report) must be 
transferred to the investigator, who will send images to 
central reading, ensure medical review, and document any 
clinically relevant safety issue as an adverse event.  
Follow-up monitoring of bone and teeth should be conducted 
at the planned timepoint defined by CTP. If bone MRI/x-ray 
and/or dental examination cannot be conducted at least 
every 16 weeks (first year)/28 weeks (second year), and/or 
if dental panoramic x-ray cannot be conducted at least 
every 28 weeks (first year)/1 year (thereafter), the 
individual patient treatment needs to be interrupted upon 
discussion with the sponsor (except at the one time 
alignment with clinic visits). Medical decision has to be 
documented in patient’s source notes. 
Dispensation of trial treatment on 
site 
If study medication cannot be dispensed during a regular visit 
at the site 
• 
Direct to patient IMP shipment from Site can be requested 
• 
The patient/parent(s)/legal guardian must consent to 
provide contact details for shipping purposes  
• 
The patient/parent(s)/legal should retain all unused IMP 
and packaging, and return it to the site as soon as possible 
(e.g. via Investigator in case of home visit, or when they 
are able to attend a visit at the site, or by other means 
defined with the site staff and approved by the sponsor). 
 
The investigator will take the totality of information related to each single patient and the 
local COVID-19 situation into consideration when performing the individual benefit-risk 
assessment on a case-by-case basis. Considering all aspects, the investigator will decide upon 
each patient’s (continued) participation in the trial. The sponsor, where required, will support 
the investigator in their decision making. It is acknowledged that the investigator may decide 
to implement protocol deviations where this protects the safety, wellbeing and/or is in the 
best interest of the patient. 
 

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11. 
DESCRIPTION OF GLOBAL AMENDMENT(S) 
 
11.1 
GLOBAL AMENDMENT 1 
Date of amendment 
 
05 Aug 2022 
EudraCT number 
EU number 
 
2020-005554-23 
BI Trial number 
 
1199-0378 
BI Investigational Medicinal 
Product(s) 
 
Ofev®, nintedanib 
Title of protocol 
 
An open-label trial of the long-term safety and 
tolerability of nintedanib per os, on top of standard 
of care, over at least 2 years, in children and 
adolescents with clinically significant fibrosing 
Interstitial Lung Disease (InPedILD®-ON) 
Global Amendment due to urgent safety reasons 
 
Global Amendment 
x 
 
Section to be changed 
 
All sections in the protocol (when applicable) 
Description of change 
 
InPedILDTM and InPedILDTM-ON replaced by 
InPedILD® and InPedILD®-ON 
Rationale for change 
 
Administrative change 
Section to be changed 
 
Synopsis-Trial rationale and Section 1.3 Rationale 
for performing the trial  
Description of change 
 
Sentence below updated: 
The rationale of this open label trial is to collect 
additional safety and efficacy data of nintedanib in 
children and adolescents with clinically significant 
fibrosing ILD for at least 2 years (applies to 
patients rolling-over from the parent trial) or 
until alternative treatment options become or are 
made available (e.g., via marketing 
authorization, via compassionate use or via 
similar process) (applies to new patients and to 
roll-over patients after 2 years). 
Rationale for change 
 
To specify the trial rationale by patient’s category 
Section to be changed 
 
Synopsis – main inclusion and exclusion criteria 
and Section 3.3.3 - Exclusion criteria 3 
Description of change 
 
Exclusion criteria 3 updated: 
(eGFR) <30 mL/min/1.73m2  calculated by 
Schwartz formula at Visit 1(please refer to 
Appendix 10.3) 
Rationale for change 
 
Correction of eGFR unit and reference to Schwartz 
formula removed to be consistent with Appendix . 

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Section to be changed 
 
Synopsis –Duration of treatment, Section 3.1 
overall trial design, Figure 3.1:1 and Section 6.2.2 
Treatment period(s) - treatment period duration 
Description of change 
 
Treatment duration for each patient will be 
variable. 
New patients will stay in the trial until the overall 
end of the trial (with expected minimum treatment 
duration of 24 weeks) or, if earlier, until alternative 
treatment options become or are made available 
(e.g. via marketing authorization, via 
compassionate use, or via similar process) to the 
patient outside of the clinical trial. 
Rationale for change 
 
Change of study treatment duration for new 
patients by removal of minimum treatment 
duration of 2 years. 
Section to be changed 
 
Synopsis –Duration of treatment and Section 3.1 
overall trial design 
Description of change 
 
Sentence added to specify when the end of trial is 
expected: 
The overall end of trial will take place 
approximately when last roll-over patient 
reaches 2 years of treatment ensuring that 
nintedanib or alternative treatment options (e.g. 
via marketing authorization, via compassionate 
use or via similar process) will be available for 
all remaining patients (roll-over or new 
patients) outside the trial at this time 
 
 
Rationale for change 
 
Clarification on the overall end of trial as it will be 
earlier than initially planned 
Section to be changed 
 
Flow Chart – time window F-up/EoS 
Description of change 
 
Time window added: +7 days 
Rationale for change 
 
To allow flexibility 
Section to be changed 
 
Flow Chart – criteria for dose 
reduction/interruption check + footnote 29 
Description of change 
 
“dose reduction/interruption check” added only for 
roll-over patients at V2, and removed at EOT for 
all patients 
Rationale for change 
 
reduction/interruption may be needed at V2 for 
roll-over patients and is not applicable at EOT for 
all patients 
Section to be changed 
 
Flow Chart – Vital status data + footnote 25 
Description of change 
 
Vital status added at EoS for new patients 
Rationale for change 
 
Vital status may be needed for new patients 
prematurely discontinued  
Section to be changed 
 
Flow Chart –footnote 1 

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Description of change 
 
Footnote 1 updated for roll-over patients  
Rationale for change 
 
To allow the possibility of roll-over patients to 
roll-over later than initially planned in case site is 
not ready to be initiated at the period of switch and 
to allow flexibility 
Section to be changed 
 
Flow Chart –footnote 6 
Description of change 
 
Footnote 6 updated for new patients  
Rationale for change 
 
To clarify that one screening HRCT only should 
not be older than 12 months and to be consistent 
with other sections of CTP 
Section to be changed 
 
Flow Chart – footnote 21 Bone imaging 
Description of change 
 
Sentences below updated: 
For new patients: 
Imaging follow-up will be conducted at 12 weeks, 
24 weeks, 36 weeks, 52 weeks, 76 weeks, 104 
weeks and every 24 weeks thereafter until the end 
of study or closure of the physes.  
For roll-over patients: 
Not applicable for patients with closed physes at 
the end of InPedILD®. Previous MRIs/x-rays 
within 12 weeks prior EoT/Visit 1/Visit 2 should 
be used as baseline for roll-over patients with 
less than 52 weeks in InPedILD®. Previous 
MRIs or x-rays of epiphyseal growth plates 
within 24 weeks prior Visit 2 should be used as 
baseline for roll-over patients with more than 
52 weeks in InPedILD®. 
 
Imaging follow-up will be conducted, irrespective 
of scheduled visits, every 12 weeks in the 
following year after the start of the trial 
medication in the parent trial (when applicable) 
and every 24 weeks thereafter until the end of the 
study or closure of the physes.  
Rationale for change 
 
To be consistent with other sections of the CTP 
Section to be changed 
 
Flow Chart –– footnote 21 Bone imaging and 
Section 5.2.5 Assessment of pathological findings 
of epiphyseal growth plate 
Description of change 
 
Time window for timepoints of follow-up bone 
imaging updated as follow: 
If it is not possible to conduct the follow-up at the 
predefined time points, the procedure can be done 
within 2 weeks before or 4 weeks after this time 
point with always minimum 10 weeks (first 
year)/22 weeks (thereafter) and always 
maximum 16 weeks (first year)/28 weeks 

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(thereafter) from previous procedure. Within 
this timeframe, timepoints may be adapted on a 
case-by-case basis by sponsor if appropriate for 
patient’s safety. 
Rationale for change 
 
Revision of time window to allow flexibility while 
assuring patient safety 
Section to be changed 
 
Flow Chart – footnote 22 clinical dental 
examination 
Description of change 
 
Sentence below updated as follow: 
Imaging follow-up will be conducted, irrespective 
of scheduled visits, every 12 weeks in the 
following year after the start of the trial 
medication in the parent trial (when applicable) 
and every 24 weeks thereafter until the end of the 
study or closure of the physes. 
Rationale for change 
 
To be consistent with other sections of the CTP 
Section to be changed 
 
Flow Chart – footnote 22 clinical dental 
examination and Section 5.2.6 Assessment of 
pathological findings on dental examination or 
imaging 
Description of change 
 
Time window for timepoints of follow-up dental 
examination updated as follow: 
If it is not possible to conduct the follow-up at the 
predefined time points, the procedure can be done 
within 2 weeks before or 4 weeks after this time 
point with always maximum 16 weeks (first 
year)/28 weeks (thereafter) from previous 
procedure. Within this timeframe, timepoints 
may be adapted on a case-by-case basis by 
sponsor if appropriate for patient’s safety. 
Rationale for change 
 
Revision of time window to allow flexibility while 
assuring patient safety 
Section to be changed 
 
Flow Chart – footnote 23 Dental imaging  
Description of change 
 
Sentence below updated as follow: 
Imaging follow-up will be conducted, irrespective 
of scheduled visits, every 24 weeks in the 
following year after the start of the trial 
medication in the parent trial (when applicable) 
and every 48 weeks thereafter until the end of the 
study or closure of the physes. 
Rationale for change 
 
To be consistent with other sections of the CTP 
Section to be changed 
 
Flow Chart – footnote 23 Dental imaging and 
Section 5.2.6 Assessment of pathological findings 
on dental examination or imaging 
Description of change 
 
Time window for timepoints of follow-up dental 
imaging updated as follow: 

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If it is not possible to conduct the follow-up at the 
predefined time points, the procedure can be done 
within 2 weeks before or 4 weeks after this time 
point with always minimum 22 weeks (first 
year)/46 weeks (thereafter) and always 
maximum 28 weeks (first year)/52 weeks 
(thereafter) from previous procedure. Within 
this timeframe, timepoints may be adapted on a 
case-by-case basis after discussion with the 
sponsor if appropriate for patient’s safety. 
Rationale for change 
 
Revision of time window to allow flexibility while 
assuring patient safety 
Sections to be changed 
 
Flow Chart – footnote 24, Section 3.3.4 
Discontinuation of patients from treatment or 
assessments and Section 6.2.2 Treatment period(s) 
– Patients who prematurely discontinued trial 
medication  
Description of change 
 
In case of premature treatment discontinuation, 
new patients should attend remaining visits until 
the overall end of trial or, if earlier, until 
alternative treatment options become or are made 
available (e.g., via marketing authorization, via 
compassionate use or via similar process) to the 
patient outside the trial. 
Rationale for change 
 
Change of study treatment duration for new 
patients 
Section to be changed 
 
Flow Chart – footnote 26 
Description of change 
 
Footnote updated as below: 
End of Study (EoS), synonym for individual 
patient’s end of trial. 
Rationale for change 
 
Clarification to differentiate patient’s end of trial 
from “overall end of trial”. 
Section to be changed 
 
Flow Chart – footnote 28 and Section 6.2.2 
Treatment period(s) – Patients who prematurely 
discontinued trial medication  
Description of change 
 
The last visit to be performed by new patients 
prematurely discontinued will be EoS including 
trial completion. This visit will be done at the 
overall end of trial or, if earlier, when treatment 
options become or are made available for new 
patients. 
Rationale for change 
 
Treatment duration of roll-over patients and new 
patients will be different 
Section to be changed 
 
Flow Chart – after footnote 29, Section 4.1.4 Drug 
assignment and administration of doses for each 
patient, Section 6.1 Visit schedule and Section 

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8.3.2 Direct access to source data and documents 
Description of change 
 
War has been added as example of exceptional 
situation  
Rationale for change 
 
To ensure possible adaptations of protocol 
procedures in case of war in one country involved 
in the study. 
Section to be changed 
 
Flow Chart for 
  
Description of change 
 
Table and footnote 2 updated to clarify that 
timepoints are calculated from start of medication 
in the parent trial: 
Rationale for change 
 
Clarification 
Section to be changed 
 
Section 1.1 Medical background 
Description of change 
 
Sentence added: 
As the underlying diseases associated with the 
clinically significant fibrosing Interstitial Lung 
Disease may be multiple, different regimes of 
immunosuppressives/ supportive symptomatic 
therapy are considered as standard of care for 
the treatment of ILD in children. 
Rationale for change 
 
Definition of "standard treatment" added 
Section to be changed 
 
Section 1.1 Medical background 
Description of change 
 
Section updated with the current status of 
InPedILD® trial 
Rationale for change 
 
First results from InPedILD® DBL1 are now 
available 
Section to be changed 
 
Section 1.3 Rational for performing the trial 
Description of change 
 
Sentence below added: 
Alternative therapies outside of the trial would 
be alternative drugs shown to have a positive 
benefit- risk assessment, any new therapy which 
would be available on the market for this 
indication or most probably the availability of 
nintedanib via marketing authorization, or via 
compassionate use or via similar process, as 
offered/provided by the sponsor (depending on 
local laws). 
Rationale for change 
 
Definition of alternative treatments added  
 
 
Section 1.3 rationale for performing the trial 
 
 
Sentence below added: 
It is expected that availability of nintedanib via 
marketing authorization, or via compassionate 
use or via similar process, as offered/provided 

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by the sponsor (depending on local laws) occurs 
approximately when last roll-over patient 
reaches 2 years of treatment 
 
 
 
 
To clarify that availability of nintedanib outside 
the trial is expected at the time of the overall end 
of trial 
Section to be changed 
 
Section 1.4.2 Risk - Table 1.4.2:1 Overview of trial 
related risks  
Description of change 
 
Sentences below have been replaced for “Impact 
on bone development and growth”: 
Impact on Previous MRIs or x-rays of epiphyseal 
growth plates within respectively 12 weeks or 24 
weeks prior baseline may be used at baseline for 
patients coming from InPedILDTM with 
respectively less or more than 52 weeks in 
InPedILDTM. Please refer to Flow Chart 
footnotes and to CTP Section 5.2.5 for more 
details. 
Rationale for change 
 
To be consistent with other sections of the clinical 
trial protocol related to Bone imaging  
Section to be changed 
 
Section 1.4.2 Risk - Table 1.4.2:1 Overview of trial 
related risks  
Description of change 
 
Sentences below have been replaced for “Impact 
on dentition”:  
Previous dental examination within 12 weeks prior 
baseline may be used at baseline. Please refer to 
Flow Chart footnotes and to CTP Section 5.2.6 
for more details. 
Previous panoramic x-ray within 24 weeks prior 
baseline may be used at baseline. Please refer to 
Flow Chart footnotes and to CTP Section 5.2.6 
for more details. 
Rationale for change 
 
To be consistent with other sections of the clinical 
trial protocol related to Dental imaging and dental 
examination  
Section to be changed 
 
Section 1.4.2 Risk - Table 1.4.2:1 Overview of trial 
related risks 
Description of change 
 
Sentences below have been added for “radiation 
exposure”:  
MRI/x-ray required with minimum 10 weeks 
(first year)/22 weeks (thereafter) and maximum 
16 weeks (first year)/28 weeks (thereafter) from 
the previous procedure, taking into account, for 
roll-over patients, the participation in the 
parent trial. Similarly, MRI/x-ray at EoT 

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required only if previous MRI/x-ray not available 
within 12 weeks in the first year, 24 weeks 
thereafter. Within this timeframe, timepoints 
may be adapted on a case-by-case basis after 
discussion with the sponsor if appropriate for 
patient’s safety 
Rationale for change 
 
To be consistent with other sections of the clinical 
trial protocol related to Bone imaging and Dental 
imaging 
Section to be changed 
 
Section 1.4.3 Discussion 
Description of change 
 
Status of this trial has been updated 
Rationale for change 
 
To clarify that now this extension trial is started 
Section to be changed 
 
Description of change 
 
Rationale for change 
 
Section to be changed 
 
Description of change 
 
Rationale for change 
 
Section to be changed 
 
Description of change 
 
Rationale for change 
 
Section to be changed 
 
Section 3.1 Trial design 
Description of change 
 
Figure 3.1:1 of Trial design has been updated for 
group of new patients 
Rationale for change 
 
Recruitment period for new patients will be 
reduced and treatment duration for new patients 
will be variable  
Section to be changed 
 
Section 3.1 Trial design  
Description of change 
 
Complete section revised to include change of 
treatment duration between roll-over patients (at 
least 2 years) and new patients (variable duration 

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of treatment)  
Rationale for change 
 
Change of study treatment duration for new 
patients and consequences of this change  
Section to be changed 
 
Section 3.1 Trial design  
Description of change 
 
Introduction of new category of patients: 
completed patients not able to roll over into the 
extension trial within 12 weeks following their End 
of Treatment in the parent trial (i.e. time period 
between last dose of study drug in parent trial and 
first dose in extension trial is greater than 12 
weeks).  
These patients will be handled as new patients in 
1199-0378, i.e. they have to follow the visit 
schedule for new patients but will have adapted 
inclusion/exclusion criteria. 
Rationale for change 
 
New group of patients has been identified for the 
trial and for the trial analysis 
Section to be changed 
 
Section 3.1 Trial design  
Description of change 
 
Description of the overall end of trial has been 
updated  
Rationale for change 
 
To clarify when will be EoT visit for remaining 
patients at the overall end of trial 
Section to be changed 
 
Section 3.1 Trial design and Section 6.2.2 
Treatment period(s) – Patients who prematurely 
discontinued trial medication 
Description of change 
 
Sentences below adapted/added: 
If patients are not able to complete the remaining 
scheduled visits, a follow-up (FU) visit should be 
planned for 28 days after EoT. In addition, every 
attempt will be made to get information on vital 
status, when applicable, at 24 weeks, 52 weeks, 76 
weeks and 104 weeks and for new patients at 
EoS.  
(…) 
For new patients who prematurely discontinued 
trial drug, if nintedanib or alternative 
treatment options become or are made available 
outside the clinical trial before the overall end 
of trial, then vital status will be collected for the 
last time at that time and this will define the end 
of patient’s participation in the trial (trial 
completion). 
Rationale for change 
 
Update related to collection of vital status for new 
patients as change in study treatment duration for 
new patients 
Section to be changed 
 
Section 3.3 Selection of trial population 

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Description of change 
 
Reduction of recruitment period from 2 year to 18 
moths, increase of number of sites from 30 to 
around 40, and reduction of number of countries 
from 23 to 21. 
Rationale for change 
 
Reduction of trial duration and to reflect actual 
number of sites/countries. 
Section to be changed 
 
Section 3.3 Selection of trial population 
Description of change 
 
Sentence below updated as follow: 
Re-enrolment of screen failed patients will be 
permitted once. Patients who did not qualify for 
entering treatment during the early months of the 
recruitment period might qualify for entering 
treatment during the late months of the 
recruitment period of the study. 
Rationale for change 
 
Correction of wording as there is no randomisation 
but only treatment entry in this trial 
Section to be changed 
 
Section 3.3.2 Inclusion criteria and Section 3.3.3 
Exclusion criteria 
Description of change 
 
Sentence below updated as follow: 
For patients who prematurely discontinued 
treatment permanently in 1199-0337 but are 
potentially eligible  
Rationale for change 
 
Clarification 
Section to be changed 
 
Section 3.3.2 Inclusion criteria 
Description of change 
 
Sentences below updated as follow: 
For patients who prematurely discontinued 
treatment permanently in 1199-0337 but are 
potentially eligible and for completed patients 
from the parent trial, not able to roll over into 
the extension trial within 12 weeks following 
their End of Treatment Visit in the parent trial: 
Inclusion criteria for new patients are applicable 
except criteria 4, and 6 (as eligibility for these 
criteria has been confirmed already in 1199-0337 
and does not need to be repeated) and also except 
inclusion criterion 1 for completed patients 
from the parent trial not able to roll over within 
12 weeks following their End of Treatment Visit 
in the parent trial. 
Rationale for change 
 
To mention inclusion criteria of new category of 
patients: completed patients not able to roll over 
within 12 weeks following their EoT in the parent 
trial. 
Section to be changed 
 
Section 3.3.3 Exclusion criteria 
Description of change 
 
Sentences below updated as follow: 
For patients who prematurely discontinued 

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treatment permanently in 1199-0337 but are 
potentially eligible and for completed patients 
from parent trial not able to roll-over into the 
extension trial within 12 weeks following their 
End of Treatment Visit in the parent trial: 
All exclusion criteria for new patients are 
applicable. In addition, the following additional 
exclusion criterion is applicable for patients who 
prematurely discontinued treatment 
permanently in 1199-0337:  
21. Patients who experienced drug-related adverse 
events during parent trial leading to permanent 
study treatment discontinuation. 
Rationale for change 
 
To mention exclusion criteria of new category of 
patients: completed patients not able to roll over 
within 12 weeks following their EoT in the parent 
trial. 
Section to be changed 
 
Section 3.3.4.1 Discontinuation of trial treatment 
Description of change 
 
Sentence below added: 
In case, the laboratory results at Visit 2 do no 
longer satisfy the entry criteria, the Investigator 
has to decide whether it is justified that the 
patient remains on study drug. The justification 
for decision needs to be documented. In the 
patient’s medical records. 
Rationale for change 
 
Clarification added to be consistent with note 
mentioned in CTP section 3.3.3 related to 
exclusion criteria 3 
Section to be changed 
 
Section 3.3.4.3 Discontinuation of trial by sponsor  
Description of change 
 
One reason for trial discontinuation added:  
Alternative drugs shown to have a positive 
benefit- risk assessment/ any new therapy 
available on the market for this indication or 
the availability of nintedanib via marketing 
authorization, or via compassionate use or via 
similar process, as offered/provided by the 
sponsor (depending on local laws). 
Rationale for change 
 
Clarification that trial may be discontinued by 
sponsor when any new therapy available on the 
market for this indication or when availability of 
nintedanib outside the trial 
Section to be changed 
 
Section 4.1.4 Drug assignment and administration 
of doses for each patient 
Description of change 
 
Following sentence removed: 
Once smaller capsules have been assigned, IRT 
will not allow to switch back to bigger capsules 

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Rationale for change 
 
To give possibility for patient to switch back to 
larger capsules if appropriate  
Section to be changed 
 
Section 4.1.4 Drug assignment and administration 
of doses for each patient 
Description of change 
 
One sentence adapted: 
If needed, an unscheduled visit can be registered 
in IRT at any time during the course of the trial to 
register a dose change, to obtain additional 
kit(s) or to obtain kits with smaller or larger 
capsules. 
Rationale for change 
 
To clarify when unscheduled visit is needed  
Section to be changed 
 
Section 4.2.1.2 Management of liver enzyme 
elevation -Table 4.2.1.2:1 Clinical evaluation of 
hepatic injury 
Description of change 
 
one recommendation updated and new footnote 
added in the table (footnote 5). 
Rationale for change 
 
Recommendations for managing liver enzyme 
elevation updated 
Section to be changed 
 
Section 4.2.1.2 Management of liver enzyme 
elevation -Table 4.2.1.2:1 Clinical evaluation of 
hepatic injury 
Description of change 
 
Footnote 4 updated 
Rationale for change 
 
Clarification 
Section to be changed 
 
Section 4.2.2.1 Restrictions regarding concomitant 
treatment 
Description of change 
 
Duration of bronchodilators updated to: 
Withhold short–acting bronchodilators for at least 
more than 8 hours before the assessments, 
- Withhold long–acting bronchodilators for at least 
more than 24 hours before the assessments. 
Rationale for change 
 
Clarification to be consistent with other sections of 
CTP 
Section to be changed 
 
Section 4.2.2.3 Contraception requirements 
Description of change 
 
Sentence updated: 
WOCBP (trial participant or partner of a trial 
participant) must use a highly effective method of 
birth control per ICH M3 (R2) that results in a low 
failure rate of less than 1% per year when used 
consistently and correctly if their sexual partner is 
a man able to father a child. 
Rationale for change 
 
Correction to clarify that female partners of male 
patients receiving nintedanib are not required to 
follow contraceptive guidelines as mentioned 
already in the Investigator Brochure 
Section to be changed 
 
 
Description of change 
 
Sentence below removed: 

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This assessment will not be performed for new 
patients 
Rationale for change 
 
Clarification to be consistent with Flow Chart and 
other CTP section 
Section to be changed 
 
Section 5.2.1.2 Height, leg length 
Description of change 
 
Sentences below added:  
For roll-over patients, the procedure followed to 
make these measurements for a given patient 
must be consistent with procedure followed in 
the parent trial as communicated to the site by 
the sponsor. 
Rationale for change 
 
To assure consistency of measurements between 
parent trial and extension trial  
Section to be changed 
 
Section 5.2.3 Safety laboratory parameters - 
pregnancy test 
Description of change 
 
Sentence below updated: 
A pregnancy test diary card will be dispensed (at 
allvisits defined in the Flow Chartfor roll-over 
female patients, from Visit 3 for new female 
patients) 
Rationale for change 
 
Correction to be consistent with Flow Chart and 
other sections of protocol 
Section to be changed 
 
Section 5.2.3 Safety laboratory parameters – Table 
5.2.3:1 
Description of change 
 
Table revised to remove parameter mentioned 
twice  
Rationale for change 
 
Correction  
Section to be changed 
 
Section 5.2.3 Safety laboratory parameters – Table 
5.2.3:1 and Table 5.2.3:3 
Description of change 
 
Tables revised to specify that eGFR will be done 
only at V1 and V2 
Rationale for change 
 
eGFR to be done only at V1 and V2  
Section to be changed 
 
Section 5.2.5 Assessment of pathological findings 
of epiphyseal growth plate 
Description of change 
 
Senence below added: 
For roll-over patients, the procedure followed to 
make these measurements for a given patient 
must be consistent with procedure followed in 
the parent trial. 
Rationale for change 
 
Clarification 
Section to be changed 
 
Section 5.2.5 Assessment of pathological findings 
of epiphyseal growth plate 
Description of change 
 
Sentence below added: 
Results of central review will be reported to the 
investigator. In case of pathological 
findings/potentially pathological findings on 

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Epiphyseal Growth Plate Results Report 
identified by central reviewer, the investigator 
should assess if these findings should be 
reported (AE/AESI) or not (see Section 
5.2.7.1.4.). 
Rationale for change 
 
Clarification on assessment of imaging findings by 
investigator 
Section to be changed 
 
Section 5.2.6 Assessment of pathological on dental 
examination or imaging 
Description of change 
 
Sentence below added: 
Results of central review will be reported to the 
investigator. In case of pathological findings 
/potentially pathological findings identified by 
central reviewer, the investigator should consult 
immediately the local dentist, to confirm, if 
these findings should be reported (AE/AESI) or 
not (see Section 5.2.7.1.4.). 
Rationale for change 
 
Clarification on assessment of imaging findings by 
investigator 
Section to be changed 
 
Section 5.2.7.2.4 Safety monitoring and Adverse 
event with additional information collection and 
Section 8.7 administrative structure of trial  
Description of change 
 
Sentences below added: 
Additionally, images of a particular patient may 
be reviewed by other radiology or clinical 
experts selected by sponsor for consultancy, if 
judged needed by the sponsor, to assess safety of 
this particular patient or to support overall 
safety assessment 
Rationale for change 
 
To allow any additional external expert’s review of 
bone imaging if judged needed for patient’s safety. 
Section to be changed 
 
Section 5.2.7.2.4 Safety monitoring and Adverse 
event with additional information collection and 
Section 8.7 Administrative structure of trial  
Description of change 
 
Sentences below added: 
Additionally, images of a particular patient may 
be reviewed by other external dentists/experts 
in pediatric dentistry selected by sponsor for 
consultancy, if judged needed by the sponsor, to 
assess safety of this particular patient or to 
support overall safety assessment 
Rationale for change 
 
To allow any additional external expert’s review of 
dental imaging if judged needed for patient’s 
safety or to support overall safety assessment. 
Section to be changed 
 
Section 5.2.7.2.4 Safety monitoring and Adverse 
event with additional information collection and 

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Section 8.7 Administrative structure of trial 
Description of change 
 
Sentence below added: 
In parallel, the Adjudication Committee/a 
member of the Adjudication committee will 
review all dental findings of stunted growth of 
the dental root identified by central review to 
assess them to either pathological finding 
/stunted growth or not. Certain further dental 
findings may potentially be assessed if defined 
in the Adjudication Charter (dental imaging 
from 1199-0337 study may be included in this 
assessment process). 
Rationale for change 
 
To add new assessment process for dental findings 
Section to be changed 
 
Section 6.2.2 Treatment period(s) – Visit 1/Visit2 
for roll-over patients 
Description of change 
 
Section revised by updating following sentences: 
Blood and urine samples for (safety laboratory 
tests, and 
 (and 
pregnancy test on serum in female patients only)  
(…) 
An additional blood sample to check safety 
parameter(s) 
 
or the 1199-0378 study 
maywill be collected at the same time as blood and 
urine samples for EoT of 1199-0337. 
(…) 
Rationale for change 
 
To reflect the different situations that could 
happened for blood samples collection  
Section to be changed 
 
Section 6.2.2 Treatment period(s) – Visit 1/Visit2 
for roll-over patients 
Description of change 
 
Sentence below adapted: 
If a previous MRI or x-ray as outlined above, is 
not available, imaging an MRI of epiphyseal 
growth plates should be conducted according to 
protocol requirements  
Rationale for change 
 
To be consistent with other sections of protocol 
Section to be changed 
 
Section 6.2.2 Treatment period(s) – Visits 3, 4, 5, 
6, 7, 8, 9, 10, 11, X (treatment period) 
Description of change 
 
Sentence below updated: 
Additional clinic visits will be scheduled after 12, 
24, 36, 52, 64, 76, 88 and 104 weeks of treatment 
(Visits 4 to 11) and, when applicable, every 12 

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weeks (Visit X) thereafter. 
Rationale for change 
 
To be consistent with Flow chart 
Section to be changed 
 
Section 6.2.2 Treatment period(s) – Visits 3, 4, 5, 
6, 7, 8, 9, 10, 11, X (treatment period) 
Description of change 
 
Sentence below updated: 
Procedures to be conducted at predefined time 
points, irrespective of scheduled visits, according 
to time window defined in the Flow Chart.or if 
not, to be done in the week immediately before or 
after the pre-defined time point. If it is not 
possible to conduct the follow-up at the 
predefined time points, please refer also to 
footnotes 21, 22, and 23 in the Flow Chart. 
Rationale for change 
 
Updated time windows for specific safety 
procedures (bone imaging, dental imaging, dental 
examination)  
Section to be changed 
 
Section 6.2.2 Treatment period(s) – End of 
Treatment 
Description of change 
 
One sentence added and one sentence adapted and 
corrected as below: 
Patients who discontinue trial treatment 
prematurely should undergo the EoT visit as soon 
as possible.  
If a patient discontinues the study during a 
scheduled treatment visit, then the visit will be 
considered as an EoT visit. As consequence, 
roll-over patients that discontinue trial treatment at 
week 104 should perform EoT visit instead of Visit 
11visit 12. 
Rationale for change 
 
Clarification (and correction of typo to be 
consistent with Flow Chart) 
Section to be changed 
 
Section 6.2.3 Follow-up period and trial 
completion 
Description of change 
 
Following sentence updated/added: 
At week 104, for roll-over patients who 
prematurely discontinued trial treatment before 
Visit 11 and were able to stay in the trial until 
week 104. 
Sentence added: 
At the end of the EoS Visit for new patients who 
prematurely discontinued trial treatment and 
were able to stay in the trial until the overall 
end of trial or, if earlier, until alternative 
treatment options become or are made 
available. 
At F-up visit, for roll-over patients who 

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prematurely discontinued trial treatment before 
Visit 11 and were not able to stay in the trial until 
week 104 or for patients who prematurely 
discontinued trial treatment after week 104 and for 
new patients who prematurely discontinued 
trial treatment and were not able to stay in the 
trial until the overall end of trial or, if earlier, 
until alternative treatment options become 
available. 
Rationale for change 
 
Clarification related to trial completion 
Section to be changed 
 
Section 7.2.1 General considerations 
Description of change 
 
Patients’ groups for analysis updated: 
Patients will be analysed depending if and when 
they rolled over from the parent trial (Group 1: 
New Patients [including patients who 
prematurely discontinued treatment 
permanently in 1199-0337, and completed 
patients from the parent trial not able to roll 
over into the extension trial within 12 weeks 
following their End of Treatment visit in the 
parent trial] and patients from 1199-0337 placebo 
arm Part A –, Group 2: patients from 1199-0337 
Part B and from 1199-0337 nintedanib arm Part A) 
and overall. 
Rationale for change 
 
To include all types of patients in the analysis 
Section to be changed 
 
Section 7.2.6 Safety analyses 
Description of change 
 
Sentence below updated: 
TreatmentPatient groups will be compared 
descriptively with regard to distribution parameters 
as well as with regard to frequency and percentage 
of patients with abnormal values or clinically 
relevant abnormal values. 
Rationale for change 
 
Correction as treatment is the same in all groups 
Section to be changed 
 
Section 7.2.8 Interim analyses 
Description of change 
 
Sentences updated as follow: 
One Iinterim analyseis areis planned after 1 and 2 
years, i.e. after all roll-over patients completed 
the 52 weeks visit and the 104 weeks visit 
respectively or prematurely discontinued from the 
trial. Additional interim analyses could be 
performed upon request from Health 
Authorities or for publication purposes. All the 
previously mentioned analysies may be presented 
at each interim analysis. Further details will be 
provided in the TSAP. 

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Rationale for change 
 
Removal of second interim analysis due to 
reduction of trial duration. 
Section to be changed 
 
Section 8.3.1 Source documents  
Description of change 
 
The list of relevant committee/vendor to which 
copies of source documents may be provided has 
been updated with: 
and to any other radiology/clinical experts or to 
any other external dentist/experts in pediatric 
dentistry selected by the sponsor for 
consultancy. 
Rationale for change 
 
To allow any additional external expert’s review if 
needed 
Section to be changed 
 
Section 10.4 Equation for Dlco adjustement for 
heamoglobin 
Description of change 
 
The following formulas have been revised as 
below: 
In adolescents (and adult males) 
DLCO predicted corrected for Hb = DLCO predicted 
x (1.7Hb)/(10.22+Hb) 
Percent predicted DLCO corrected for Hb = 
[actual DLCO/ DLCO predicted corrected for 
Hb] x 100% 
In children <15 years of age and females 
DLCO predicted corrected for Hb = DLCO predicted 
x (1.7Hb)/(9.38+Hb) 
Percent predicted DLCO corrected for Hb = 
[actual DLCO/ DLCO predicted corrected for 
Hb] x 100% 
Rationale for change 
 
Correction 
Section to be changed 
 
All sections in the protocol 
Description of change 
 
Editorial, grammatical updates  
Rationale for change 
 
Editorial, grammatical corrections throughout the 
document. 
 
11.2 
GLOBAL AMENDMENT 2 
Date of amendment 
 
18 Apr 2023 
EudraCT number 
EU number 
 
2020-005554-23 
BI Trial number 
 
1199-0378 
BI Investigational Medicinal 
Product(s) 
 
Ofev®, nintedanib 
Title of protocol 
 
An open-label trial of the long-term safety and 
tolerability of nintedanib per os, on top of standard 
of care, over at least 2 years, in children and 

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adolescents with clinically significant fibrosing 
Interstitial Lung Disease (InPedILD®-ON) 
Global Amendment due to urgent safety reasons 
 
Global Amendment 
x 
 
Section to be changed 
 
Flow Chart – footnote 21 Bone imaging 
Description of change 
 
For new patients: 
Sentence adapted and sentences added: 
Imaging follow-up will be conducted only in 
patients with open physes at predefined time 
points. Imaging follow-up will be conducted, if 
applicable, at 12 weeks, 24 weeks, 36 weeks, 52 
weeks, 76 weeks, 104 weeks and every 24 weeks 
thereafter until the end of study or closure of the 
physes. If it’s not possible to conduct the follow-
up at the predefined time points, the procedure 
can be done within 1 week before or after this 
time point with always minimum 10 weeks (first 
year)/22 weeks (thereafter) and always 
maximum 16 weeks (first year)/28 weeks 
(thereafter) from the previous procedure. 
Timepoints may be adapted on a case-by-case 
basis after discussion with the sponsor if 
appropriate for patient’s safety. 
Rationale for change 
 
Clarification and alignment of time window (with 
visit’s time window) 
Section to be changed 
 
Flow Chart – footnote 21 Bone imaging 
Description of change 
 
For roll-over patients: 
Sentence adapted: 
Within this timeframe, tTimepoints may be 
adapted on a case-by-case basis after discussion 
with the sponsor if appropriate for patient’s safety. 
Rationale for change 
 
Clarification 
Section to be changed 
 
Flow Chart – footnote 21 Bone imaging 
Description of change 
 
For roll-over patients: 
Sentence added: 
Preponement or postponement of one follow-up 
procedure within – 2 months to +2 months to 
the planned timepoint will be allowed once to 
align this procedure and the subsequent ones 
with the regular clinic visits planned in the 
protocol. After this alignment, the acceptable 
time window will be +/-1 week for this 
procedure 
Rationale for change 
 
To align the schedule of safety procedures with 
patient’s visit 

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Section to be changed 
 
Flow Chart – footnote 21 Bone imaging 
Description of change 
 
For all patients: 
Sentence added: 
For all patients, if the follow-up procedure 
cannot be conducted at least every 16 weeks 
(first year)/28 weeks (second year), the 
individual patient treatment needs to be 
interrupted upon discussion with the sponsor 
(except at the one time alignment with clinic 
visits mentioned above) 
Rationale for change 
 
Clarification to be consistent with instructions 
mentioned in the appendice 10.9  
Section to be changed 
 
Flow Chart – footnote 22 clinical dental 
examination 
Description of change 
 
For new patients: 
Sentence adapted and sentences added: 
Follow-up will be conducted, if applicable, at 12 
weeks, 24 weeks, 36 weeks, 52 weeks, 76 weeks, 
104 weeks and every 24 weeks thereafter until the 
end of the study. If it’s not possible to conduct 
the follow-up at the predefined time points, the 
procedure can be done within 1 week before or 
after this time point with always maximum 16 
weeks (first year)/28 weeks (thereafter) from the 
previous procedure. Timepoints may be 
adapted on a case-by-case basis after discussion 
with the sponsor if appropriate for patient’s 
safety. 
Rationale for change 
 
Clarification and alignment of time window (with 
visit’s time window) 
Section to be changed 
 
Flow Chart – footnote 22 clinical dental 
examination 
Description of change 
 
For roll-over patients: 
Sentence adapted: 
Within this timeframe, tTimepoints may be 
adapted on a case-by-case basis after discussion 
with the sponsor if appropriate for patient’s safety. 
Rationale for change 
 
Clarification 
Section to be changed 
 
Flow Chart – footnote 22 clinical dental 
examination 
Description of change 
 
For roll-over patients: 
Sentence added: 
Preponement or postponement of one follow-up 
procedure within – 2 months to +2 months to 
the planned timepoint will be allowed once to 
align this procedure and the subsequent ones 

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with the regular clinic visits planned in the 
protocol. After this alignment, the acceptable 
time window will be +/-1 week for this 
procedure 
Rationale for change 
 
To align the schedule of safety procedures with 
patient’s visit 
Section to be changed 
 
Flow Chart – footnote 22 clinical dental 
examination 
Description of change 
 
For all patients: 
Sentence added: 
For all patients, if the follow-up procedure 
cannot be conducted at least every 16 weeks 
(first year)/28 weeks (second year), the 
individual patient treatment needs to be 
interrupted upon discussion with the sponsor 
(except at the one time alignment with clinic 
visits mentioned above) 
Rationale for change 
 
Clarification to be consistent with instructions 
mentioned in the appendice 10.9 
Section to be changed 
 
Flow Chart – footnote 23 Dental imaging 
Description of change 
 
For new patients: 
Sentence adapted and sentences added: 
Follow-up will be conducted, if applicable, at 24 
weeks, 52 weeks,104 weeks and every 48 weeks 
thereafter until the end of the study. If it’s not 
possible to conduct the follow-up at the 
predefined time points, the procedure can be 
done within 1 week before or after this time 
point with always minimum 22 weeks (first 
year)/46 weeks (thereafter) and always 
maximum 28 weeks (first year)/52 weeks 
(thereafter) from the previous procedure. 
Timepoints may be adapted on a case-by-case 
basis after discussion with the sponsor if 
appropriate for patient’s safety. 
Rationale for change 
 
Clarification and alignment of time window (with 
visit’s time window) 
Section to be changed 
 
Flow Chart – footnote 23 Dental imaging 
Description of change 
 
For roll-over patients: 
Sentence adapted: 
Within this timeframe, tTimepoints may be 
adapted on a case-by-case basis after discussion 
with the sponsor if appropriate for patient’s safety. 
Rationale for change 
 
Clarification 
Section to be changed 
 
Flow Chart – footnote 23 Dental imaging 
Description of change 
 
For roll-over patients: 

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Sentence added: 
Preponement or postponement of one follow-up 
procedure within – 2 months to +2 months to 
the planned timepoint will be allowed once to 
align this procedure and the subsequent ones 
with the regular clinic visits planned in the 
protocol. After this alignment, the acceptable 
time window will be +/-1 week for this 
procedure 
Rationale for change 
 
To align the schedule of safety procedures with 
patient’s visit 
Section to be changed 
 
Flow Chart – footnote 23 Dental imaging 
Description of change 
 
For all patients: 
Sentence added: 
For all patients, if the follow-up procedure 
cannot be conducted at least every 28 weeks 
(first year)/52 weeks (second year), the 
individual patient treatment needs to be 
interrupted upon discussion with the sponsor 
(except at the one time alignment with clinic 
visits mentioned above) 
Rationale for change 
 
Clarification to be consistent with instructions 
mentioned in the appendice 10.9 
Section to be changed 
 
Flow Chart – footnote 24  
Description of change 
 
Sentence added: 
Only one additional regular follow-up for bone 
imaging and for dental imaging procedures will 
be needed after the EOT visit if there is no 
pathological finding. If there is a pathological 
finding, follow-up procedures will be conducted 
on individual basis upon discussion with the 
sponsor and with the investigator. Follow –up 
procedures for clinical dental examination will 
be conducted as initially planned by the 
protocol. 
Rationale for change 
 
To limit the burden for the patient while assuring 
patient safety 
Section to be changed 
 
Section 1.4.2 Risk - Table 1.4.2:1 Overview of trial 
related risks  
Description of change 
 
Sentence below adapted for “Impact on bone 
development and growth”: 
The follow-up bone imagings will be planned, 
irrespective of scheduled visits, in order to respect 
the frequency of around every 12 weeks for first 
year and around every 24 weeks thereafter, taking 
in account, for roll-over patients, the participation 

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in the parent trial. 
Rationale for change 
 
To be consistent with update in the flowchart 
footnote related to bone imaging procedures 
Section to be changed 
 
Section 1.4.2 Risk - Table 1.4.2:1 Overview of trial 
related risks 
Description of change 
 
Sentences below have been replaced for “Impact 
on dentition”:  
The follow-up dental examinations will be 
planned, irrespective of scheduled visits, in order 
to respect the frequency of around every 12 weeks 
for first year and around every 24 weeks 
thereafter, taking in account, for roll-over patients, 
the participation in the parent trial. 
… 
The follow-up dental imagings will be planned, 
irrespective of scheduled visits, in order to respect 
the frequency of around every 24 weeks for first 
year and around every 48 weeks thereafter, taking 
in account, for roll-over patients, the participation 
in the parent trial. 
Rationale for change 
 
To be consistent with the update of the flowchart 
footnotes related to clinical dental examination and 
to dental imaging procedure.  
Section to be changed 
 
Section 1.4.2 Risk - Table 1.4.2:1 Overview of trial 
related risks 
Description of change 
 
Sentences below have been adapted for “radiation 
exposure”:  
Bone MRI/x-ray required with always minimum 
10 weeks (first year)/22 weeks (thereafter) and 
dental X-ray required with always minimum 22 
weeks (first year)/46 weeks (thereafter) and always 
minimum 16 weeks (first year)/28 weeks 
(thereafter) from the previous procedure, taking 
into account, for roll-over patients, the 
participation in the parent trial (except at the one 
time alignment of these safety procedures with 
clinic visits). Similarly, Bone MRI/x-ray at EoT 
required only if previous MRI/x-ray not available 
within 12 weeks in the first year, 24 weeks 
thereafter. Within this timeframe, tTimepoints may 
be adapted on a case-by-case basis after discussion 
with the sponsor if appropriate for patient’s safety. 
Rationale for change 
 
Clarification and to be consistent with the update 
of the flowchart footnotes related to bone imaging 
and to dental imaging procedures. 
Section to be changed 
 
Section 2.2.2 further endpoints 

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Description of change 
 
Further safety endpoint below updated: 
• Change in height, sitting height, leg length 
from baseline at week 24, week 52, week 76, 
and week 104; 
Rationale for change 
 
Endpoints removed and data to be provided in 
listings due to inconsistent method of measurement 
impacting comparability of data 
Section to be changed 
 
Section 5.2.5 Assessment of pathological findings 
of epiphyseal growth plate 
Description of change 
 
Sentences below have been adapted: 
The follow-up will be planned, irrespective of 
scheduled visits, in order to respect the frequency 
of around every 12 weeks for first year and 
around every 24 weeks thereafter, taking in 
account, for roll-over patients, the participation in 
the parent trial. If it is not possible to cnduct the 
follow-up at the predefined time points, the 
procedure can be done within 2 weeks before or 4 
weeks after this time point with always minimum 
10 weeks (first year)/22 weeks (thereafter) and 
always maximum 16 weeks (first year)/28 weeks 
(thereafter) from previous procedure. Please refer 
to Flow Chart footnotes for more details. Within 
this timeframe, tTimepoints may be adapted on a 
case-by-case basis after discussion with the 
sponsor if appropriate for patient’s safety. 
Rationale for change 
 
To be consistent with the update of the flowchart 
footnotes related to bone imaging procedures. 
Section to be changed 
 
Section 5.2.6 Assessment of pathological on dental 
examination or imaging 
Description of change 
 
Sentences below have been adapted: 
Dental examination follow-ups will be planned, 
irrespective of scheduled visits, in order to respect 
the frequency of around every 12 weeks for first 
year and around every 24 weeks thereafter, taking 
in account, for roll-over patients, the participation 
in the parent trial. If it is not possible to cnduct the 
follow-up at the predefined time points, the 
procedure can be done within 2 weeks before or 4 
weeks after this time point with always maximum 
16 weeks (first year)/28 weeks (thereafter) from 
previous procedure. Please refer to Flow Chart 
footnotes for more details. Within this timeframe, 
timepoints may be adapted on a case-by-case basis 
after discussion with the sponsor if appropriate for 
patient’s safety. 

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Rationale for change 
 
To be consistent with the update of the flowchart 
footnotes related to clinical dental examination. 
Section to be changed 
 
Section 5.2.6 Assessment of pathological on dental 
examination or imaging 
 
 
Sentences below have been adapted: 
Dental imaging follow-ups will be planned, 
irrespective of scheduled visits, in order to respect 
the frequency of around every 24 weeks for first 
year and around every 48 weeks thereafter, taking 
in account, for roll-over patients, the participation 
in the parent trial. If it is not possible to cnduct the 
follow-up at the predefined time points, the 
procedure can be done within 2 weeks before or 4 
weeks after this time point with always minimum 
22 weeks (first year)/46 weeks (thereafter) and 
always maximum 28 weeks (first year)/52 weeks 
(thereafter) from previous procedure. Please refer 
to Flow Chart footnotes for more details. Within 
this timeframe, timepoints may be adapted on a 
case-by-case basis after discussion with the 
sponsor if appropriate for patient’s safety. 
Rationale for change 
 
To be consistent with the update of the flowchart 
footnotes related to to dental imaging procedures. 
Section to be changed 
 
Section 6.2.2 Treatment period(s) – Visits 3, 4, 5, 
6, 7, 8, 9, 10, 11, X (treatment period) 
Description of change 
 
Sentences below have been adapted: 
Follow-up bone imaging (MRIs or x-rays if 
baseline MRI was not possible) will be planned, in 
order to follow the frequency of around every 12 
weeks for first year and around every 24 weeks 
thereafter, taking in account, for roll-over patients, 
the participation in the parent trial: 
•For new patients, imaging follow-up will be 
conducted, if applicable, at 12 weeks, 24 weeks, 
36 weeks, 52 weeks, 76 weeks, 104 weeks and 
every 24 weeks thereafter until the end of the study 
or closure of the physes.  
•For roll-over patients, imaging follow-up will be 
conducted around every 12 weeks in the following 
year after the MRI/x-ray considered as baseline for 
parent trial (when applicable) and around every 24 
weeks thereafter until the end of the study or 
closure of the physes.  
Rationale for change 
 
To be consistent with the update of the flowchart 
footnotes related to bone imaging procedures. 
Section to be changed 
 
Section 6.2.2 Treatment period(s) – Visits 3, 4, 5, 

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6, 7, 8, 9, 10, 11, X (treatment period) 
Description of change 
 
Sentences below have been adapted: 
Follow-up dental examination will be planned in 
order to follow the frequency of around every 12 
weeks for first year and around every 24 weeks 
thereafter, taking in account, for roll-over patients, 
the participation in the parent trial: 
•For new patients, follow-up will be conducted, if 
applicable, at 12 weeks, 24 weeks, 36 weeks, 52 
weeks, 76 weeks, 104 weeks and every 24 weeks 
thereafter until the end of the study. 
•For roll-over patients, follow-up will be 
conducted around every 12 weeks in the following 
year after the dental examination considered as 
baseline in parent trial (when applicable) and 
around every 24 weeks thereafter until the end of 
the study. 
Rationale for change 
 
To be consistent with the update of the flowchart 
footnotes related to clinical dental examination. 
Section to be changed 
 
Section 6.2.2 Treatment period(s) – Visits 3, 4, 5, 
6, 7, 8, 9, 10, 11, X (treatment period) 
Description of change 
 
Sentences below have been adapted: 
Follow-up dental imaging will be planned in order 
to follow the frequency of around every 24 weeks 
for first year and around every 48 weeks 
thereafter, taking in account, for roll-over patients, 
the participation in the parent trial: 
•For new patients, follow-up will be conducted, if 
applicable, at 24 weeks, 52 weeks,104 weeks and 
every 48 weeks thereafter until the end of the 
study. 
•For roll-over patients, follow-up will be 
conducted, irrespective of scheduled visits, around 
every 24 weeks in the following year after the 
dental imaging considered as baseline for parent 
trial (when applicable) and around every 48 weeks 
thereafter until the end of the study.  
Rationale for change 
 
To be consistent with the update of the flowchart 
footnotes related to dental imaging procedures. 
Section to be changed 
 
Section 6.2.2 Treatment period(s) – Patients who 
prematurely discontinued trial medication 
Description of change 
 
At remaining scheduled visits, all procedures and 
assessments planned to be done under treatment 
need to be followed by the patient 
 
 
The first visit after the EoT will be skipped if the 

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EoT Visit occurs within 4 weeks prior to the 
scheduled visit but if MRI and/or dental 
examinations were planned at this visit, then they 
should be performed as planned. Only one 
additional regular follow-up for bone imaging 
and for dental imaging procedures will be 
needed after the EOT visit if there is no 
pathological finding. If there is a pathological 
finding, follow-up procedures will be conducted 
on individual basis upon discussion with the 
sponsor and with the investigator. Follow –up 
procedures for clinical dental examination will 
be conducted as initially planned by the 
protocol. 
Rationale for change 
 
To be consistent with the update of the flowchart 
footnotes related to bone imaging and dental 
imaging procedures. 
Section to be changed 
 
Section 10.9 Visit modification in exceptional 
circumstances – Table 10.9:1 Modification to visit 
procedures in exceptional circumstances 
Description of change 
 
Section related to follow-up monitoring of bone 
and teeth: 
Sentence adapted: 
If bone MRI/x-ray and/or dental examination cannot be 
conducted at least every 16 weeks (first year)/28 weeks 
(second year), and/or if dental panoramic x-ray cannot 
be conducted at least every 28 weeks (first year)/1 year 
(thereafter) (, the individual patient treatment needs to 
be interrupted upon discussion with the sponsor (except 
at the one time alignment with clinic visits). 
Rationale for change 
 
Clarification to be consistent with the update of the 
flowchart footnotes related to bone imaging and 
dental imaging procedures. 
 
11.3 
GLOBAL AMENDMENT 3 
Date of amendment 
 
29 Nov 2023 
EudraCT number 
EU number 
 
2020-005554-23 
BI Trial number 
 
1199-0378 
BI Investigational Medicinal 
Product(s) 
 
Ofev®, nintedanib 
Title of protocol 
 
An open-label trial of the long-term safety and 
tolerability of nintedanib per os, on top of standard 
of care, over at least 2 years, in children and 
adolescents with clinically significant fibrosing 

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Interstitial Lung Disease (InPedILD®-ON) 
Global Amendment due to urgent safety reasons 
 
Global Amendment 
x 
 
Section to be changed 
 
Title page, Synopsis-Title 
Description of change 
 
An open-label trial of the long-term safety and 
tolerability of nintedanib per os, on top of standard 
of care, over at least 2 3 years, in children and 
adolescents with clinically significant fibrosing 
Interstitial Lung Disease (InPedILD®-ON) 
Rationale for change 
 
Change of study treatment duration by adding an 
additional year of study treatment 
Section to be changed 
 
Synopsis-Trial rationale and section 1.3 Rationale 
for performing the trial 
Description of change 
 
The rationale of this open label trial is to collect 
additional safety and efficacy data of nintedanib in 
children and adolescents with clinically significant 
fibrosing ILD for at least 2 3 years (applies to 
patients rolling over from the parent trial) or until 
alternative treatment options become available or 
are made available (e.g., via marketing 
authorization, via compassionate use or via similar 
process) (applies to new patients and to roll-over 
patients after 2 3 years). 
Rationale for change 
 
Change of study treatment duration by adding an 
additional year of study treatment 
Section to be changed 
 
Synopsis –Duration of treatment 
Description of change 
 
Treatment duration for each patient will be 
variable. 
For roll-over patients: at least 2 3 years; variable 
treatment duration afterwards, or until alternative 
treatment options become or are made available 
(e.g., via marketing authorization, via 
compassionate use, or via similar process) to the 
patient outside of the clinical trial. 
Rationale for change 
 
Change of study treatment duration by adding an 
additional year of study treatment and 
simplification of the sentence 
Section to be changed 
 
Synopsis –Duration of treatment 
Description of change 
 
Treatment duration for each patient will be 
variable. 
… 
For new patients: until the overall end of the trial 
(with expected minimum treatment duration of 24 
76 weeks) or, if earlier, until alternative treatment 
options become or are made available (e.g. via 

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marketing authorization, via compassionate use, or 
via similar process) to the patient outside of the 
clinical trial. 
Rationale for change 
 
To increase the collection of long-term data  
Section to be changed 
 
Synopsis –Duration of treatment  
Description of change 
 
Sentences added: 
Exception: patients aged 21 years must 
complete the trial before their 22nd birthday. 
Consequently, a treatment duration of at least 3 
years might not be reached by some patients 
aged 21. 
Rationale for change 
 
After longterm follow-up adult patients of 21 years 
should leave the trial.These patients should be able 
to have nintedanib available outside the study. 
Section to be changed 
 
Synopsis –Duration of treatment and section 3.1 
Overall trial design 
Description of change 
 
The overall end of trial will take place 
approximately when last roll-over patient still on-
treatment reaches 3 2 years of treatment 
) ensuring 
that nintedanib or alternative treatment options 
(e.g., via marketing authorization, via 
compassionate use, or via similar process) will be 
available for all remaining patients (roll-over or 
new patients) outside the trial at this time 
 
. 
Rationale for change 
 
Change of study treatment duration by adding an 
additional year of study treatment and clarification 
added for last roll-over patient 
Section to be changed 
 
Flow Chart 
Description of change 
 
Additional visits added related to additional year: 
V12 to V15 
Rationale for change 
 
Change of study treatment duration by adding an 
additional year of study treatment 
Section to be changed 
 
Flow Chart 
Description of change 
 
Additional information collected mentioned in the 
flow chart:  
 
Rationale for change 
 
To collect with minor burden 
 
 
Section to be changed 
 
Flow Chart - Bone imaging 
Description of change 
 
Information updated: 
On regular basis (Q12W to Q48WQ24W) 
Rationale for change 
 
Safety procedure only needed yearly for patients 
aged 19 or older. 
Section to be changed 
 
Flow Chart 

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Description of change 
 
Additional information collected mentioned in the 
flow chart:  
Concomitant medication 
 
Rationale for change 
 
Section to be changed 
 
Description of change 
 
Rationale for change 
 
Change of study treatment duration 
Section to be changed 
 
Flow Chart 
Description of change 
 
Rationale for change 
 
Change of study treatment duration 
Section to be changed 
 
Flow Chart –footnote 3 
Description of change 
 
Sentence updated: 
- 
Additional visits/ Phone calls (if appropriate) 
have to be included, in case of dose change 
(reduction or re-escalation) or in case of 
capsule’s size change. Please refer to Section 
6.2.2.  
Rationale for change 
 
To avoid patient to travel if not needed 
Section to be changed 
 
Flow Chart –footnote 3 
Description of change 
 
Sentence added: 
- 
Patients aged 21 years must complete the 
trial while being 21 years old. They should 
perform EoT visit and EoS visit (28 days 
after) before their 22nd birthday. 
Rationale for change 
 
After longterm follow-up adult patients of 21 years 
should leave the trial.These patients should be able 
to have nintedanib available outside the study. 
Section to be changed 
 
Flow Chart –footnote 16 
Description of change 
 
Rationale for change 
 
Change of study treatment duration 
Section to be changed 
 
Flow Chart –footnote 21 
Description of change 
 
Sentence added: 
For patients aged 19 and older, please see 
additional information at the end of the 
footnote. 
Rationale for change 
 
Safety procedure only needed yearly for patients 
aged 19 or older. 
Section to be changed 
 
Flow Chart –footnote 21 
Description of change 
 
Sentences adapted: 

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For new patients: 
… 
Imaging follow-up will be conducted, if 
applicable, at 12 weeks, 24 weeks, 36 weeks, 52 
weeks, 76 weeks, 104 weeks, 128 weeks, 156 
weeks, and every 24 weeks thereafter until the end 
of study or closure of the physes. 
…. 
For all patients, if the follow-up procedure cannot 
be conducted at least every 16 weeks (during the 
first year)/28 weeks (second year thereafter), the 
study treatment of this individual patient needs to 
be interrupted upon discussion with the sponsor 
(except for the one-time alignment with clinic 
visits mentioned above for roll-over patients).  
Rationale for change 
 
Change of study treatment duration by adding an 
additional year of study treatment 
Section to be changed 
 
Flow Chart –footnote 21, section 5.2.5, Section 
6.2.2 Treatment period(s) – follow-up bone 
imaging  
Description of change 
 
Sentence added: 
For patients aged 19 and older, bone imaging 
follow-up procedures will be performed around 
every 48 weeks (instead of around every 24 
weeks) until the end of the study or closure of 
the physes. 
Rationale for change 
 
Safety procedure only needed yearly for patients 
aged 19 or older. 
Section to be changed 
 
Flow Chart –footnote 21,  
Description of change 
 
Paragraph reviewed to be clearer without adding 
any additional change than those previously 
mentioned 
Rationale for change 
 
Clarifications 
Section to be changed 
 
Flow Chart –footnote 22 
Description of change 
 
Sentences adapted: 
For new patients: 
… 
Follow-up will be conducted, if applicable, at 12 
weeks, 24 weeks, 36 weeks, 52 weeks, 76 weeks, 
104 weeks, 128 weeks, 156 weeks, and every 24 
weeks thereafter until the end of study or closure 
of the physes. 
…. 
For all patients, if the follow-up procedure cannot 

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be conducted at least every 16 weeks (during the 
first year)/28 weeks (second year thereafter), the 
study treatment of this individual patient needs to 
be interrupted upon discussion with the sponsor 
(except for the one-time alignment with clinic 
visits mentioned above for roll-over patients). 
Rationale for change 
 
Change of study treatment duration by adding an 
additional year of study treatment 
Section to be changed 
 
Flow Chart –footnote 22 
Description of change 
 
Paragraph reviewed to be clearer without adding 
any additional change than those previously 
mentioned 
Rationale for change 
 
Clarifications 
Section to be changed 
 
Flow Chart –footnote 23 
Description of change 
 
Sentences adapted: 
For new patients: 
… 
Follow-up will be conducted, if applicable, at 24 
weeks, 52 weeks,104 weeks, 156 weeks, and every 
48 weeks thereafter until the end of the study. 
…. 
For all patients, if the follow-up procedure cannot 
be conducted at least every 16 weeks (during the 
first year)/28 weeks (second year thereafter), the 
study treatment of this individual patient needs to 
be interrupted upon discussion with the sponsor 
(except for the one-time alignment with clinic 
visits mentioned above for roll-over patients). 
Rationale for change 
 
Change of study treatment duration by adding an 
additional year of study treatment 
Section to be changed 
 
Flow Chart –footnote 23 
Description of change 
 
Paragraph reviewed to be clearer without adding 
any additional change than those previously 
mentioned 
Rationale for change 
 
Clarifications 
Section to be changed 
 
Flow Chart –footnote 24 
Description of change 
 
2 sentences removed according to flow chart 
update: 
At the EoT visit:  

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• the MRI/x-ray should not be repeated if the last 
MRI/x-ray was conducted within 24 weeks,  
• the dental examination will not be repeated if 
the last examination was conducted within 12 
weeks and  
• the dental imaging will not be repeated if the 
last examination was conducted within 24 
weeks.  
Rationale for change 
 
Procedures to be always done at EOT following 
change of study duration  
Section to be changed 
 
Flow Chart –footnote 24 
Description of change 
 
If EoT occurs before Visit 15 11 (week 156 104), 
roll-over patients will be asked to remain in the 
study and to return to all regularly scheduled visits 
until week156 104.  
Rationale for change 
 
Change of study treatment duration 
Section to be changed 
 
Flow Chart –footnote 24 
Description of change 
 
New patients who prematurely discontinued trial 
drug will be asked to remain in the study and to 
return to all regularly scheduled visits until the 
overall end of trial or, if earlier, until alternative 
treatment options become or are made available to 
the patient outside the clinical trial.  
Rationale for change 
 
To increase the collection of long-term data 
Section to be changed 
 
Flow Chart –footnote 25 
Description of change 
 
For patients who discontinue trial treatment 
prematurely and are not able to complete the 
scheduled visits, a follow-up (FU) visit should be 
planned 28 days after EoT. In addition, every 
attempt will be made to get information on vital 
status, when applicable, at 24 weeks, 52 weeks, 76 
weeks, 104 weeks, 128, 156, and every 24 weeks 
thereafter until the end of the study and for new 
patients at EoS. Please see Section 5.2.7.2.1  
Rationale for change 
 
Change of study treatment duration 
Section to be changed 
 
Flow Chart –footnote 28 
Description of change 
 
For patients who discontinue permanently trial 
treatment before Visit 15 11 and who accepted to 
attend further scheduled visits as per protocol, then 
the patient’s trial completion will be at initial 
planned date of Visit 15 11 (at week 156 104) for 
roll-over patients and at the overall end of trial or, 

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if earlier, when treatment options become or are 
made available for new patients. 
Rationale for change 
 
Change of study treatment duration and to increase 
the collection of long-term data  
Section to be changed 
 
Flow Chart – footnote 30 
Description of change 
 
footnote 30 added: 
Rationale for change 
 
To collect with minor burden a 
 
 
Section to be changed 
 
Section 1.3 Rationale of the trial 
Description of change 
 
It is expected that availability of nintedanib via 
marketing authorization, or via compassionate use 
or via similar process, as offered/provided by the 
sponsor (depending on local laws) occurs 
approximately when last roll-over patient reaches 
3 years of treatment 
). 
However, roll-over patients should stay in the 
trial for at least 3 years and new patients should 
stay in the trial until the end of (with the 
exception of patients > 22 years of age) to 
ensure collection of patient data for a prolonged 
period of time. 
Rationale for change 
 
Study prolongation  
Section to be changed 
 
Description of change 
 
Rationale for change 
 
Section to be changed 
 
Description of change 
 
Rationale for change 
 
Clarification 

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Section to be changed 
 
Section 3.1 Overall trial design 
Description of change 
 
Trial design graph updated to reflect the increase 
of treatment duration 
Rationale for change 
 
Study treatment prolongation 
Section to be changed 
 
Section 3.1 Overall trial design 
Description of change 
 
Roll-over patients will be requested to stay in the 
trial for at least 156 104 weeks (until Visit 15 11).  
At week 156, roll-over patients who can be treated 
with nintedanib or alternative treatment options 
outside the clinical trial will have their EoT Visit 
instead of Visit 15 11). 
Rationale for change 
 
Study treatment prolongation 
Section to be changed 
 
Section 3.1 Overall trial design 
Description of change 
 
New patients will be requested to stay in the trial 
until the end of trial (with expected minimum 
treatment duration of 76 24 weeks) or, if earlier, 
until alternative treatment options become or are 
made available (e.g. via marketing authorization, 
via compassionate use, or via similar process) to 
the patient outside the trial.  
When nintedanib or alternative treatment options 
become or are made available for patients outside 
the trial, then patients will perform their EoT Visit 
and enter in the 28-days follow-up period off-
treatment until End of Study Visit (EOS). 
Rationale for change 
 
Change of study treatment duration and to increase 
the collection of long-term data 
Section to be changed 
 
Section 3.1 Overall trial design 
Description of change 
 
Exception: patients aged 21 years must 
complete the trial before their 22nd birthday. 
Consequently, a treatment duration of at least 3 
years might not be reached for by patients aged 
21. 
Patients completing trial while being 21 years 
old, even with a treatment duration less than 3 
years, will be considered as completed patients. 
Rationale for change 
 
After longterm follow-up adult patients of 21 years 
should leave the trial.These patients should be able 
to have nintedanib available outside the study. 
Section to be changed 
 
Section 3.1 Overall trial design 
Description of change 
 
At this time, all the remaining patients will 
perform their EoT Visit.  
For logistical reasons, it may be planned that EoT 
visit of all remaining patients will occur within 6 
weeks before the latest Visit 15 11 of roll-over 
patients. If regular scheduled visit is planned for a 

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patient during this period of 6 weeks, then the 
patient will skip this regular visit and will perform 
directly the EoT visit instead. After the EoT visit, 
all remaining patients will enter a 4-week follow-
up period. 
Rationale for change 
 
Study treatment prolongation 
Section to be changed 
 
Section 3.1 Overall trial design 
Description of change 
 
Roll-over patients will be considered as 
prematurely discontinued from trial treatment if 
they stop trial medication before week 156 104 
(except at the age of 21) or if they stop trial 
medication after week 104 but without any 
other treatment option available. 
New patients will be considered as prematurely 
discontinued from trial treatment if they 
discontinue trial treatment before nintedanib or 
alternative treatment options are available outside 
the clinical trial the overall end of trial (except at 
the age of 21). 
Rationale for change 
 
Study treatment prolongation, change for patients 
aged 21 years old and change to increase the 
collection of long-term data 
Section to be changed 
 
Section 3.1 Overall trial design 
Description of change 
 
Roll-over patients prematurely discontinued from 
trial treatment before week 156 104 will be asked 
to remain in the study and return to all regularly 
scheduled visits until Visit 15 11 (individual 
planned date of week 156 104). 
New patients prematurely discontinued from trial 
treatment will be asked to remain in the study until 
the overall end of trial (expected to occur 
approximately when last roll-over patient still on-
treatment reaches 3 2 years of treatment) or, if 
earlier, until alternative treatment options become 
available.  
Rationale for change 
 
Study treatment prolongation and change to 
increase the collection of long-term data 
Section to be changed 
 
Section 3.1 Overall trial design 
Description of change 
 
For patients who prematurely discontinued trial 
drug and who are unable to complete the 
scheduled visits, a follow-up (FU) visit should be 
planned for 28 days after EoT. In addition, every 
attempt will be made to collect information on 
vital status, when applicable, at weeks 24, 52, 76, 
104, 128 and 156 and for new patients at EoS.  
Rationale for change 
 
Study treatment prolongation 

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Section to be changed 
 
Section 3.1 Overall trial design and Section 6.2.2 
Treatment period(s) – Patients who prematurely 
discontinued trial medication 
Description of change 
 
Sentence removed: 
For new patients who prematurely discontinued 
trial drug, if nintedanib or alternative treatment 
options become or are made available outside the 
clinical trial before the overall end of trial, then 
vital status will be collected for the last time at that 
time and this will define the end of patient’s 
participation in the trial (trial completion). 
Rationale for change 
 
To increase the collection of long-term data 
Section to be changed 
 
Section 3.1 Overall trial design and Section 3.3.4.1 
Discontinuation of trial treatment and Section 
4.2.2.1 Restrictions regarding concomitant 
treatment  
Description of change 
 
Sentence added: 
If it is intended by a treatment discontinued 
patient to use available nintedanib outside the 
trial after trial treatment discontinuation, the 
patient should directly undergo the EoS visit 28 
days after the EOT visit (no vital status will be 
required for this patient). 
Rationale for change 
 
Clarification 
Section to be changed 
 
Section 3.3.4 Discontinuation of patients from 
treatment or assessments 
Description of change 
 
However, if the patients agree, they should stay in 
the trial even if continued trial treatment is not 
possible: roll-over patients should attend further 
trial visits until Visit 15 11 and new patients 
should attend until the overall end of trial or, if 
earlier, until treatment options become or are made 
available to ensure their safety and to collect 
important trial data. 
Rationale for change 
 
Study treatment prolongation and to increase the 
collection of long-term data 
Section to be changed 
 
Section 3.3.4.1 Discontinuation of trial treatment  
Description of change 
 
The patient can no longer receive trial treatment 
for medical reasons such, adverse events, other 
diseases, or pregnancy. 
If a patient becomes pregnant during the trial the 
investigational product must be interrupted 
discontinued immediately, and the patient will be 
followed up until birth of the child/children or 
otherwise termination of the pregnancy. The study 
medication may be only re-introduced once the 

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child has been born and the mother is no longer 
nursing, if supported by individual benefit risk 
as judged by the investigator. 
Rationale for change 
 
To give patients the possibility to restart trial 
treatment after pregnancy 
Section to be changed 
 
Section 3.3.4.1 Discontinuation of trial treatment  
Description of change 
 
In case of permanent discontinuation of trial 
medication, it is of utmost importance for the 
robustness and integrity of the trial results that the 
patient remains in the study and returns to all 
regularly scheduled visits until the end of the 
planned observation period. For those patients who 
are unable to complete the remaining scheduled 
visits, every attempt will be made to get 
information on vital status every 24 weeks after 
Visit 2 until the individual planned observation 
period of 104 weeks as outlined in the Flow Chart 
and Section 6.2.3. 
Rationale for change 
 
Study treatment prolongation 
Section to be changed 
 
Section 3.3.4.1 Discontinuation of trial treatment 
Description of change 
 
Sentence added: 
If it is intended by the patient to use 
commercial nintedanib after trial treatment 
discontinuation, the patient should directly 
undergo the EoS visit 28 days after the EOT 
visit. 
Rationale for change 
 
Clarification 
Section to be changed 
 
Section 4.1.4 Drug assignment and administration 
of dose for each patient - Section 6.2.2 Treatment 
period(s) - Dose reduction visit / dose increase 
visit/ Change of capsule size visit 
Description of change 
 
Sentence added: 
In case the start/end of an AE requires a dose 
reduction/increase without the need of a change 
in capsule size and without requiring a meeting 
with the investigator in person, the unscheduled 
visit for the patient can be replaced by a phone 
call. The investigator will register the phone call 
in IRT as an unscheduled visit and register the 
dose reduction/increase on the respective page 
in the eCRF. 
Rationale for change 
 
To avoid patient to travel if not needed 
Section to be changed 
 
Section 4.2.1 Other treatments and emergency 
procedures  
Description of change 
 
Sentence added: 
 

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during the trial will be recorded in the eCRF. 
Rationale for change 
 
Section to be changed 
 
Section 4.2.2.1 Restrictions regarding concomitant 
treatment 
Description of change 
 
Sentence added: 
The use of nintedanib other than the 
investigational product is prohibited throughout 
the study, including the follow-up period (if any). 
If it is intended by the patient to use 
commercial nintedanib after trial treatment 
discontinuation, the patient should directly 
undergo the EoS visit 28 days after the EOT 
visit. 
Rationale for change 
 
Clarification 
Section to be changed 
 
 
Description of change 
 
Physician reported Fan severity score [R09-5337] 
at Visit 2 will be used to determine eligibility of 
new patient.
For 
instructions on how to assign the severity-of-
illness score see Appendix 10.2 
Rationale for change 
 
 
Section to be changed 
 
Section 6.2.1 Screening and run-in period(s) - Visit 
1 (Screening) for new patients 
Description of change 
 
• Medical history including pre-existing 
conditions (including 
 
 if applicable) 
will be recorded. 
• Concomitant therapy including previous 
medications 
 will be 
recorded 
Rationale for change 
 
To reflect the update of the flow chart 
Section to be changed 
 
Section 6.2.2 Treatment period(s) – Visit 1/Visit 2 
for roll-over patients  
Description of change 
 
Sentence updated: 
Baseline Conditions/Medical History:  
• Medical history including pre-existing 
conditions (including 
 
 if applicable) 
will be recorded. 
Concomitant therapy including previous 
medications 
 will be 
recorded. 

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Rationale for change 
 
To reflect the update of the flow chart 
Section to be changed 
 
Section 6.2.2 Treatment period(s) –Visits 3, 4, 5, 
6, 7, 8, 9, 10, 11, 12, 13, 14, 15, X (treatment 
period)  
Description of change 
 
Sentence adapted: 
Additional clinic visits will be scheduled after 12, 
24, 36, 52, 64, 76, 88 and 104 weeks of treatment 
(Visits 4 to 11) and when applicable, every 12 
weeks (Visit X) thereafter on regular basis from 
Visit 2 until End of Treatment (EOT) visit. 
Detailed procedures and assessment to be 
performed at each Visit are described in Flow 
Chart and Section 5. 
Sentence added: 
As the treatment duration for each patient will 
be variable, some visits may not apply (to some 
new patients and to some patients aged 21) 
Rationale for change 
 
Study treatment prolongation, change for patients 
aged 21 years old and clarification 
Section to be changed 
 
Section 6.2.2 Treatment period(s) - Visits 3, 4, 5, 
6, 7, 8, 9, 10, 11, 12, 13, 14, 15, X (treatment 
period) 
Description of change 
 
Visits 12 to 15 added in the description of 
procedures during treatment period 
Rationale for change 
 
Study treatment prolongation 
Section to be changed 
 
Section 6.2.2 Treatment period(s) – Visit 2 for new 
patients – and Visits 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 
13, 14, 15, X (treatment period) and Dose 
reduction visit / dose increase visit/ Change of 
capsule size visit 
Description of change 
 
Sentence updated: 
Adverse events
 and 
concomitant therapy 
 
since last visit will be reviewed and recorded 
Rationale for change 
 
To reflect the update of the flow chart 
Section to be changed 
 
Section 6.2.2 Treatment period(s) – follow-up 
bone imaging 
Description of change 
 
Sentence updated: 
•For new patients, follow-up will be conducted, if 
applicable, at 12 weeks, 24 weeks, 36 weeks, 52 
weeks, 76 weeks, 104 weeks, 128 weeks, 156 
weeks, and every 24 weeks thereafter until the end 
of the study. 
Rationale for change 
 
Study treatment prolongation 

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Section to be changed 
 
Section 6.2.2 Treatment period(s) – follow-up 
dental examination 
Description of change 
 
Sentence updated: 
For new patients, follow-up will be conducted, if 
applicable, at 12 weeks, 24 weeks, 36 weeks, 52 
weeks, 76 weeks, 104 weeks, 128 weeks, 156 
weeks, and every 24 weeks thereafter until the end 
of the study. 
Rationale for change 
 
Study treatment prolongation 
Section to be changed 
 
Section 6.2.2 Treatment period(s) – follow-up 
dental imaging 
Description of change 
 
•For new patients, follow-up will be conducted, if 
applicable, at 24 weeks, 52 weeks,104 weeks, 156 
weeks, and every 48 weeks thereafter until the end 
of the study. 
Rationale for change 
 
Study treatment prolongation 
Section to be changed 
 
Section 6.2.2 Treatment period(s) - treatment 
period duration 
Description of change 
 
Treatment duration for each patient will be 
variable. 
Roll-over patients will be requested to stay in the 
trial for at least 156 104 weeks (until Visit 15 11). 
At week 156 104, roll-over patients who can be 
treated with nintedanib or alternative treatment 
options outside the clinical trial will have their 
EoT Visit. The remaining roll-over patients will 
continue in the trial until nintedanib, or alternative 
treatment options become available to them 
outside the clinical trial. 
 
Trial treatment will be stopped prematurely if a 
reason for withdrawal is met (refer to Section 
3.3.4).  
 
After week 156 104, if reason for study treatment 
discontinuation is that nintedanib or alternative 
treatment options become available for patient 
outside the clinical trial, then the patient will not 
be considered as early discontinued for treatment. 
Rationale for change 
 
Study treatment prolongation 
Section to be changed 
 
Section 6.2.2 Treatment period(s) - treatment 
period duration 
Description of change 
 
New patients will stay in the trial until the overall 
end of the trial (with expected minimum treatment 
duration of 76 24 weeks) or, if earlier, until 
alternative treatment options become or are made 

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available (e.g. via marketing authorization, via 
compassionate use, or via similar process) to the 
patient outside of the clinical trial, then patients 
will perform the EoT Visit. 
Rationale for change 
 
Study treatment prolongation and change to 
increase the collection of long-term data 
Section to be changed 
 
Section 6.2.2 Treatment period(s) – End of 
Treatment Visit 
Description of change 
 
Sentence removed as repetition: 
Patients who discontinued trial treatment 
prematurely will undergo the EoT visit as soon as 
possible. 
Sentence adapted for clarification: 
If a patient discontinues the study during a 
scheduled treatment visit, then the scheduled visit 
will be considered as an replaced by the EoT 
visit. 
Rationale for change 
 
Clarification 
Section to be changed 
 
Section 6.2.2 Treatment period(s) – End of 
Treatment Visit 
Description of change 
 
Sentence updated: 
As consequence, roll-over patients that discontinue 
trial treatment at week 156 104 should perform 
EoT visit instead of Visit 15 11. 
Rationale for change 
 
Study treatment prolongation 
Section to be changed 
 
Section 6.2.2 Treatment period(s) – End of 
Treatment Visit 
Description of change 
 
Observation and procedures updated as follow: 
• 
• Adverse events, 
, 
 and 
 
since last visit will be reviewed and recorded 
 
Added: 
• 
• 
if applicable and if not 
collected before. 
Rationale for change 
 
To reflect the update of the flow chart 

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Rationale for change 
 
Section 6.2.2 Treatment period(s) – End of 
Treatment Visit  
Section to be changed 
 
Sentence added: 
Exception: patients aged 21 years must 
complete the trial before their 22nd birthday.  
The EoT visit followed by EoS visit must be 
performed before the 22nd birthday.  
Description of change 
 
After longterm follow-up adult patients of 21 years 
should leave the trial.These patients should be able 
to have nintedanib available outside the study. 
Rationale for change 
 
Section 6.2.2 Treatment period(s) – Patients who 
prematurely discontinued trial medication 
Section to be changed 
 
Sentence added: 
Exception: patients aged 21 years must 
complete the trial before their 22nd birthday. 
Remaining scheduled visits or vital status will 
be replaced by the EoS visit which must be 
performed before the 22nd birthday.  
Description of change 
 
After longterm follow-up adult patients of 21 years 
should leave the trial.These patients should be able 
to have nintedanib available outside the study. 
Section to be changed 
 
Section 6.2.2 Treatment period(s) – Patients who 
prematurely discontinued trial medication 
Description of change 
 
Roll-over patients who discontinued trial treatment 
prematurely before week156, patient will be asked 
to remain in the study and to return to remaining 
scheduled visits until the initial planned week 
156 104 (Visit 15 11) 
New patients who discontinued treatment 
prematurely will be asked to remain in the study 
and to return to remaining scheduled visits until 
the overall end of trial or, if earlier, until 
alternative treatment options become or are made 
available. 
Rationale for change 
 
Study treatment prolongation and change to 
increase the collection of long-term data 
Section to be changed 
 
Section 6.2.2 Treatment period(s) – Patients who 
prematurely discontinued trial medication 
Description of change 
 
The last visit to be performed by prematurely 
discontinued roll-over patients will be the Visit 15 
11 including trial completion and the last visit to 
be performed by new patients prematurely 
discontinued will be EoS including trial 
completion. 
 
If patients are not able to complete the remaining 

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scheduled visits, a follow-up (FU) visit should be 
planned for 28 days after EoT. In addition, every 
attempt will be made to get information on vital 
status, when applicable, at 24 weeks, 52 weeks, 76 
weeks and 104 weeks, 128 weeks, 156 weeks, and 
for new patients at EoS.  
Rationale for change 
 
Study treatment prolongation 
Section to be changed 
 
Section 6.2.2 Treatment period(s) – Patients who 
prematurely discontinued trial medication 
Description of change 
 
Sentence added: 
Additionally, for treatment discontinued 
patients, if it is intended by the patient to use 
commercial nintedanib after trial treatment 
discontinuation, the patient should directly 
undergo the EoS visit 28 days after the EOT 
visit. 
Rationale for change 
 
Clarification 
Section to be changed 
 
Section 6.2.2 Treatment period(s) – Patients who 
prematurely discontinued trial medication 
Description of change 
 
Sentence removed: 
For roll-over patients who discontinued trial 
treatment prematurely after week 156 104 but 
before alternative treatment options become or are 
made available, a FU visit should be planned for 
28 days after EoT. This will be the last visit for the 
patient. 
For roll-over patients who discontinued trial 
treatment prematurely after week 104 but before 
alternative treatment options become or are made 
available, a FU visit should be planned for 28 days 
after EoT. This will be the last visit for the patient. 
Rationale for change 
 
Patients can directly do the EoS visit 
Section to be changed 
 
Section 6.2.2 Treatment period(s) – Follow-up 
visit 
Description of change 
 
Sentence added: 
F-up visit should be conducted 28 days (+7 
days) after the EoT visit for all discontinued 
patients who are able to complete the remaining 
visits or who accepted the vital status collection. 
Rationale for change 
 
Clarification 
Section to be changed 
 
Section 6.2.3 Follow-up and trial completion End 
of Study Visit - End of Study visit 
Description of change 
 
EoS visit should be conducted 28 days (+7 days) 
after the EoT visit for all patients except 
discontinued patients who are able to complete 
the remaining visits or who accepted the vital 

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status collection who didn’t prematurely 
discontinue trial treatment.  
Rationale for change 
 
Clarification 
Section to be changed 
 
Section 6.2.3 Follow-up and trial completion - End 
of Study visit 
Description of change 
 
Sentence updated: 
• Adverse events, 
 
 
concomitant therapy 
 
since last visit will be reviewed and recorded. 
Sentence updated: 
• 
 
if applicable and if not 
collected before. 
Rationale for change 
 
To reflect the update of the flow chart  
Section to be changed 
 
Section 6.2.3 Trial completion 
Description of change 
 
Update and clarification: 
The trial completion CRF page must be filled-in 
when the patient has terminated the trial. 
The trial completion (individual patient’s end of 
trial) is: 
• At the end of the EoS Visit for patients who 
have completed the trial on treatment as 
planned (including patients aged 21). 
• At week 156 104, for roll-over patients who 
prematurely discontinued trial treatment before 
Visit 15 11 and were able to stay in the trial 
until week 156 104. 
• At the overall end of the trial EoS Visit for 
new patients who prematurely discontinued 
trial treatment and were able to stay in the trial 
until the overall end of trial or, if earlier, until 
alternative treatment options become or are 
made available. 
• At F-up/EoS visit, for roll-over patients who 
prematurely discontinued trial treatment before 
Visit 15 11 and were not able to stay in the trial 
until week 156 104 or who prematurely 
discontinued trial treatment after week 156 104 
and for new patients who prematurely 
discontinued trial treatment and were not able 
to stay in the trial until the overall end of trial 
or, if earlier, until alternative treatment options 
become available. 
• At last contact, for other cases. 
Rationale for change 
 
Update and clarification needed following other 

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changes previously introduced 
Section to be changed 
 
Section 8 infromed consent, trial records, data 
protection, publication policy, and administrative 
structure 
Description of change 
 
The trial will be carried out in accordance with the 
Medical Devices Directive (93/42/EEC) Medical 
Device Regulation (EU) 2017 / 745 and the 
harmonised standards for Medical Devices (ISO 
14155, current version). 
Rationale for change 
 
Change in regulation 
 
11.4 
GLOBAL AMENDMENT 4 
Date of amendment 
 
15 Apr 2024 
EudraCT number 
EU number 
 
2020-005554-23 
 
BI Trial number 
 
1199-0378 
BI Investigational Medicinal 
Product(s) 
 
Ofev®, nintedanib 
Title of protocol 
 
An open-label trial of the long-term safety and 
tolerability of nintedanib per os, on top of standard 
of care, over at least 3 years, in children and 
adolescents with clinically significant fibrosing 
Interstitial Lung Disease (InPedILD®-ON) 
Global Amendment due to urgent safety reasons 
 
Global Amendment 
x 
 
Section to be changed 
 
Title page 
Description of change 
 
The Universal Trial Number (UTN) was added 
Rationale for change 
 
Updated information. 
Section to be changed 
 
Clinical protocol synospsis, section 3.3.2. 
Inclusion criteria, section 3.3.3. Exclusion criteria 
Description of change 
 
Trial population in France is limited to adolescents 
12 to 17 years old at Visit 2. 
Rationale for change 
 
Harmonisation of the CTP for the transition to EU 
Clinical Trials Regulation with inclusion of current 
Local Amendment 1 France requested by French 
Health Authority (ANSM) and already approved to 
limit the age groups to be enrolled in France. 
Section to be changed 
 
Flowchart footnote 13, Section 1.4.2. Table 1.4.2:1 
overview of trial related risks, Section 5.2.3. Safety 
laboratory parameters, Section 6.2.2. treatment 
period(s), Section 10.9 Visit modification in 
exceptional circumstances– Table 10.9:1 
Modification to visit procedures in exceptional 

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circumstances 
Description of change 
 
Pregnancy testing will be done every 4 weeks for 
female patients in Poland and in Norway. 
Rationale for change 
 
Harmonisation of the CTP for the transition to EU 
Clinical Trials Regulation with inclusion of current 
Local Amendment 1 Poland (requested by Polish 
Authorities and already approved) and current 
local amendment 1 Norway (requested by the 
Norvegian Medecines Agency and already 
approved). 
Section to be changed 
 
Flow Chart:V3a and footnote 4 
Description of change 
 
For new patients in Norway, the Visit 3a is also 
applicable and should be performed at Week 6 
(Day 43). 
Rationale for change 
 
Harmonisation of the CTP for the transition to EU 
Clinical Trials Regulation with inclusion of current 
Local Amendment 1 Norway requested and 
already approved by the Norvegian Medecines 
Agency. 
Section to be changed 
 
Flow Chart V12 - End of study 
Description of change 
 
V12 should be performed at Day 813 +/- 7 days 
V13 should be performed at Day 897 +/- 7 days 
V14 should be performed at Day 981 +/- 7 days 
V15 should be performed at Day 1093 +/- 7 days 
VX should be performed at Day 1093+Q84 with 
time window of +/- 7 days 
Rationale for change 
 
Correction of calculation (1 day was missing) 
Section to be changed 
 
Flow chart – footnote 25 and Section 6.2.2 
treament period(s) – follow-up visit 
Description of change 
 
Sentences added: 
If the EoT visit has been delayed and has been 
done 28 days or more after the treatment 
discontinuation, the follow-up (FU) visit can be 
skipped. 
Rationale for change 
 
To limit the burden for the patient 
Section to be changed 
 
Flow chart – footnote 26 and Section 6.2.3 Follow-
up and trial completion - End of Study visit 
Description of change 
 
Sentences added: 
In exceptional cases, when the patient is not 
able to come at site for medical reason, the EoS 
visit can be replaced by a phone call. If the EoT 
visit has been delayed and has been done 28 
days or more after the treatment 
discontinuation, the EoS visit can be skipped. 
Rationale for change 
 
To limit the burden for the patient. 
Section to be changed 
 
Flow chart – footnote 28 

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Description of change 
 
For patients who discontinue permanently trial 
treatment before Visit 15 and who accepted to 
attend further scheduled visits as per protocol, then 
the patient’s trial completion will be at initial 
planned date of Visit 15 (at week 156) for roll-over 
patients and at the overall end of trial or, if earlier, 
when treatment options become or are made 
available for new patients. 
Rationale for change 
 
Correction following previous CTP revision 
Section to be changed 
 
Flow chart – footnote 28 
Description of change 
 
Sentence added: 
Completion of trial participation will be 
conducted at EoT visit, if FU/EoS visit is 
skipped due to delayed EoT for more than 28 
days. 
Rationale for change 
 
To limit the burden for the patient  
Section to be changed 
 
Section 6.2.2 treament period(s) –follow-up visit 
Description of change 
 
Sentence corrected: 
F-up visit should be conducted 28 days (+7 days) 
after the EoT visit for all discontinued patients who 
are not able to complete the remaining visits or 
who accepted the vital status collection. 
Rationale for change 
 
Correction 
Section to be changed 
 
Section 6.2.3 Follow-up period and trial 
completion – End of study visit 
Description of change 
 
Sentence updated: 
EoS visit should be conducted 28 days (+7 days) 
after the EoT visit for patients who have 
completed the trial on treatment as planned all 
patients except discontinued patients who are 
able to complete the remaining visits or who 
accepted the vital status collection. 
…. 
Sentence added: 
The EoS should be conducted at week 156 for 
prematurely discontinued roll-over patients 
who were able to complete the remaining visits 
off-treatment until week 156 and at the overall 
end of the trial for new patients who 
prematurely discontinued trial treatment and 
were able to stay in the trial until the overall 
end of trial. 
Rationale for change 
 
clarification 
Section to be changed 
 
Section 11.3 Global Amendment 3 description of 
change- change in section 3.1 (page 190) 
Description of change 
 
Roll-over patients will be considered as 

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prematurely discontinued from trial treatment if 
they stop trial medication before week 156 (except 
at the age of 21) or if they stop trial medication 
after week 104 but without any other treatment 
option available. 
Rationale for change 
 
Correction in the description of the change 
 
11.5 
GLOBAL AMENDMENT 5 
Date of amendment 
 
27 Nov 2024 
EU Clinical Trial No  
 
2024-515743-27-00 
BI Trial number 
 
1199-0378 
BI Investigational Medicinal 
Product(s) 
 
Ofev®, nintedanib 
Title of protocol 
 
An open-label trial of the long-term safety and 
tolerability of nintedanib per os, on top of standard 
of care, over at least 3 years, in children and 
adolescents with clinically significant fibrosing 
Interstitial Lung Disease (InPedILD®-ON) 
Global Amendment due to urgent safety reasons 
 
Global Amendment 
x 
 
Section to be changed 
 
Title page 
Description of change 
 
The EU Clinical Trial Number was added 
Rationale for change 
 
Updated information. 
Section to be changed 
 
Synopsis –Duration of treatment  
Description of change 
 
The overall end of trial will take place 
approximately when last roll-over patient still on 
treatment is expected to reach reaches 3 years of 
treatment (
) 
ensuring that nintedanib or alternative treatment 
options (e.g., via marketing authorization, via 
compassionate use, or via similar process) will be 
available for all remaining patients (roll-over or 
new patients) outside the trial at this time. 
Rationale for change 
 
Clarification to avoid changing the timelines of 
overall end of trial in the last months of the study. 
In addition, as patients may travel long distances to 
expert centers, longer term planning needs to 
occur. 
Section to be changed 
 
Flow Chart - footnote 3, Section 4.2.1.2 
Management of liver enzymes elevations, Table 
4.2.1.2:1 Recommendations for managing liver 
enzyme elevations - footnote 4, Section 4.2.2.1. 
Restrictions regarding concomitant treatment, 

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Section 5.2.3 Safety laboratory parameters –‘a-
Visits’ section, Section 6.2.2. Intermediate “a-
Visits” 
Description of change 
 
Sentences adapted to clarify that the specific lab kit 
(visit-a) should be preferably used to monitor 
hepatic parameters, but local lab will be also 
acceptable. 
Rationale for change 
 
Clarification to limit the burden for the patient 
enable timely availability of safety lab and to give 
flexibility 
Section to be changed 
 
Flowchart – footnote 13, Section 1.4.2. Risks – 
table 1.4.2:1 Overview of trial related risks – 
Feotal harm, Section 5.2.3 Safety laboratory 
parameters – Pregnancy tests and Table 5.2.3:1 
Safety laboratory tests at scheduled site visits, 
Section 6.2.2. other observations and procedures, 
Section 6.2.2. Intermediate pregnancy tests, 
Section 6.2.2. End of Treatment Visit, Section 
6.2.2. Patients who prematurely discontinued trial 
treatment, section, Section 10.9 Visit modification 
in exceptional circumstances– Table 10.9:1 
Modification to visit procedures in exceptional 
circumstances 
Description of change 
 
frequency of pregnancy testing harmonised:  
every 4-6 weeks (with every 4 weeks for female 
patients in Poland and Norway) 
 
Changed for all countries to: 
every 4 weeks. 
Rationale for change 
 
Harmonisation requested by Italian H.A. following 
transition to new regulation in Europe 
Section to be changed 
 
Flowchart – footnote 24 and section 6.2.2. 
Treatment period(s) - Patient who prematurely 
discontinued trial medication 
Description of change 
 
One sentence adapted to clarify that at remaining 
visits off-treatment visits, IRT call/notification is 
not needed anymore 
Rationale for change 
 
Clarification 
Section to be changed 
 
Flowchart –footnote 13 and footnote 24 and 
section 6.2.2. Treatment period(s) - Patient who 
prematurely discontinued trial medication 
Description of change 
 
In case of treatment discontinuation when a female 
patient continues with visits off treatment, then the 
urine pregnancy tests at home are only required to 
be continued every 4 weeks for the 3 months after 
last trial drug intake. 

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Rationale for change 
 
To limit the burden of the patient. 
Section to be changed 
 
Description of change 
 
Rationale for change 
 
Change following authorities’ interactions 
Section to be changed 
 
section 3.1 Overall trial design 
Description of change 
 
The overall end of trial will take place 
approximately when last roll-over patient still on 
treatment is expected to reach reaches 3 years of 
treatment 
) 
ensuring that nintedanib or alternative treatment 
options (e.g., via marketing authorization, via 
compassionate use, or via similar process) will be 
available for all remaining patients (roll-over or 
new patients) outside the trial at this time. 
At this time, all the remaining patients will 
perform their EoT Visit.  
For logistical reasons, it may be planned that EoT 
visit of all remaining patients will occur within 6 
weeks before the planned date of latest Visit 15 
of last roll-over patient. 
… 
New patients prematurely discontinued from trial 
treatment will be asked to remain in the study until 
the overall end of trial (expected to occur 
approximately when last roll-over patient still on 
treatment is expected to reach reaches 3 years of 
treatment). 
Rationale for change 
 
Clarification  
 

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