Clinical trial NCT04093024
Conditions: Lung Diseases, Interstitial
Sponsor: Boehringer Ingelheim
Start date: 2019-12-03; Completion date: 2022-05-24
Enrollment: 39 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The main objective of the study is to evaluate dose-exposure and safety of nintedanib in children and adolescents with fibrosing Interstitial Lung Disease (ILD).

Detailed description:

Arms: arm 1: This arm shows Nintedanib randomised participants treated orally with Nintedanib in the DBP and OLNP twice daily with a dose interval of approximately 12 hours from one dose to the next dose.

Medication dosage was per administration 50 milligram (mg) \[2 capsules with strength 25 mg\],75 mg \[3 capsules with strength 25 mg\], 100 mg \[1 capsule with strength 100 mg or 4 capsules with strength 25 mg\] or 150 mg \[1 capsule with strength 150 mg or 6 capsules with strength 25 mg\] based on the participant's weight at baseline (= 0 weeks). The dosage was adjusted at subsequent visits if the participant's weight had changed.

In this arm participants received Nintedanib in both periods (DBP + OLNP). Participants in this arm do not entail participants from the 'randomised to placebo' arms.

DBP: Planned was from first randomised trial drug intake to last blinded drug intake.

OLNP: Planned was from first open-label Nintedanib intake to last open-label Nintedanib intake. arm 2: Placebo randomised participants were treated orally with a Nintedanib matching placebo soft capsule twice daily in the double-blind period (DBP).

Participants who continued with the open-label Nintedanib period (OLNP) after the DBP switched to active Nintedanib treatment in the OLNP and were treated orally with Nintedanib twice daily.

Medication dosage was per administration 50 milligram (mg) \[2 25 mg capsules (cap)\],75 mg \[3 25 mg cap\], 100 mg \[1 100 mg or 4 25 mg cap\] or 150 mg \[1 150 mg or 6 25 mg cap\] based on the participant's weight at baseline (= 0 weeks). The dosage was adjusted at subsequent visits if the participant's weight had changed.

The dose interval was approximately 12 hours between one and the next dose.

Here participants received placebo first (DBP) and then Nintedanib (OLNP). DBP: Planned was from first to last randomised blinded drug intake. OLNP: Planned was from first to last open-label Nintedanib intake.
Interventions: intervention 1: Nintedanib intervention 2: Placebo
Intervention descriptions: intervention 1: Capsule intervention 2: Capsule

Protocol documents:
Prot_002.pdf: 
MCS-40-106-RD-03 (16.0) / Saved on: 31 Aug 2018
Clinical Trial Protocol
TITLE PAGE
Document Number:
c26450188-03
EudraCT No.
EU Trial No.
2018-004530-14
BI Trial No.
1199-0337 (InPedILD™)
BI Investigational
Medicinal Product(s)
Ofev®, nintedanib
Title
A double blind, randomised, placebo-controlled trial to evaluate 
the dose-exposure and safety of nintedanib per os on top of 
standard of care for 24 weeks, followed by open label treatment 
with nintedanib of variable duration, in children and adolescents 
(6 to 17 year-old) with clinically significant fibrosing Interstitial 
Lung Disease
Lay Title
A study to find out how nintedanib is taken up in the body and 
how well it is tolerated in children and adolescents with 
Interstitial Lung Disease (ILD)
Clinical Phase
III
Clinical Trial Leader
Phone: +
Fax:
+
Coordinating 
Investigator
Phone: +
Fax:
+
Status
Final Protocol (Revised Protocol based on Global Amendment 2)
Version and Date
Version: 3.0
Date: 14 Jun 2021
Page 1 of 170
Proprietary confidential information.
2021 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.


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CLINICAL TRIAL PROTOCOL SYNOPSIS
Company name
Boehringer Ingelheim 
Protocol date
09 Jul 2019
Revision date
14 Jun 2021
BI trial number
1199-0337
Title of trial
A double blind, randomised, placebo-controlled trial to evaluate the 
dose-exposure and safety of nintedanib per os on top of standard of 
care for 24 weeks, followed by open label treatment with nintedanib 
of variable duration, in children and adolescents (6 to 17 year-old) 
with clinically significant fibrosing Interstitial Lung Disease
Coordinating 
Investigator
Trial sites
Multi-centre trial conducted in approximately 24 countries.
Clinical phase
III
Trial rationale
Some patients with childhood interstitial lung disease (chILD)
develop chronic lung fibrosis similar to adults with fibrosing lung 
disease, which is associated with significant morbidity and mortality. 
There are currently no approved therapies for the treatment of 
fibrosing interstitial lung disease in children.
Based on the presumed similarities in underlying pathophysiology 
resulting in fibrotic remodelling in adults and children, it is 
postulated that matching the dose exposure of nintedanib in children 
will lead to similar anti-fibrotic effects and clinical benefits in 
paediatric patients with fibrosing lung disease as demonstrated in 
adults with IPF and SSc-ILD.
As a powered efficacy study is not feasible, a focused 
pharmacokinetic (PK) and safety evaluation of nintedanib in 
children with clinically significant chronic fibrosing lung disease is 
planned to determine appropriate paediatric dosing of nintedanib in 
children and adolescents and to address this unmet need.
Trial objective(s)
The main objective of the study is to evaluate dose-exposure and 
safety of nintedanib in children and adolescents with fibrosing ILD.
Trial endpoints
Primary endpoints:

PK: AUCτ,ss based on sampling at steady state (at week 2 
and week 26);

N (%) of patients with treatment-emergent adverse events at 
week 24.
Secondary endpoints:


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
N (%) of patients with treatment-emergent pathological 
findings of epiphyseal growth plate on imaging at week 24, 
and week 52*;

N (%) of patients with treatment-emergent pathological 
findings on dental examination or imaging at week 24, and 
week 52*;

N (%) of patients with treatment-emergent adverse events 
over the whole trial;

Change in height, sitting height, leg length from baseline at 
week 24, week 52*, week 76*, and week 100*.

Change in Forced Vital Capacity (FVC) % predicted from 
baseline at week 24, and week 52*;

Absolute change from baseline in Pediatric Quality of Life 
Questionnaire™ (PedsQL™) at week 24, and week 52*;

Change in oxygen saturation (SpO2) on room air at rest from 
baseline at week 24, and week 52*.

Change in 6-min walk distance from baseline at week 24, 
and week 52*;

Patient acceptability based on the size of capsules at week 
24;

Patient acceptability based on the number of capsules at 
week 24;

Time to first respiratory-related hospitalization over the 
whole trial;

Time to first acute Interstitial Lung Disease (ILD)
exacerbation or death over the whole trial;

Time to death over the whole trial;
*52 weeks, 76 weeks, 100 weeks time points will not be available 
for all patients.
Trial design
Double blind, randomised, placebo-controlled on top of standard of 
care (SOC) over 24 weeks, followed by open label active treatment 
of variable duration.
Total number of 
patients randomised 
At least 30 randomised patients including at least 20 adolescents 
aged 12-17 years.
Number of patients on 
each treatment
Nintedanib: approx. 20*
Placebo: approx. 10*
*Patients will be allocated to the treatments in a ratio of 2:1 
(Nintedanib:Placebo).
Diagnosis
Clinically significant fibrosing Interstitial Lung Disease
Main in- and exclusion 
criteria
Main inclusion criteria:
Male or female 6 to 17 years old at Visit 2, with 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 evidence of 
clinical progression over time.


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Main exclusion criteria:
AST and/or ALT and/or bilirubin >1.5 x ULN, and/or creatinine 
clearance <30 mL/min (Schwartz formula), and/or underlying 
chronic liver disease (Child Pugh A, B or C hepatic impairment) at 
Visit 1; previous treatment with nintedanib, other investigational 
therapy received within 1 month or 5 half-lives (whichever is shorter
but ≥1 week) prior to Visit 2; significant pulmonary arterial 
hypertension, any cardiovascular disease excluded by protocol, 
history of thrombotic event within 12 months of Visit 1, other 
disease that may interfere with testing procedures or trial 
participation, or may put the patient at risk; bleeding risk; life 
expectancy for any concomitant disease other than ILD <2.5 years 
(investigator assessment); any diagnosed growth disorder or any 
genetic disorder associated with short stature and/or treatment with 
growth hormone therapy within 6 months before Visit 2; <13.5 kg of 
weight at Visit 1.
Test product(s)
Nintedanib
dose
Starting dose assigned based on patient’s weight at Visit 2:
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).
During treatment 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).
mode of 
administration
Per os
Comparator product(s)
Placebo
dose
Not applicable
mode of 
administration
Per os
Duration of treatment
24 weeks of double blind, randomised, placebo-controlled treatment
on top of SOC (Part A), followed by open label active treatment of 
variable duration (Part B).
During Part B patients will continue treatment with nintedanib on 
top of SOC until the end of the trial (i.e. the date of the last visit of 
the last patient in the whole trial) or premature discontinuation.
Patients who completed the treatment period according to protocol 
will be offered participation in a separate open label extension trial. 
The open label extension trial will be initiated if supported by the 
benefit-risk assessment from DBL 1 of the current trial.
Statistical methods
Descriptive statistics will be provided for PK and safety endpoints.
Analysis of secondary endpoints will be descriptive in nature using a 
mixed model with repeated measurements (MMRM) for continuous 
endpoints. Time-to-event endpoints will be displayed descriptively 
using the Kaplan-Meier method. Categorical endpoints, safety and 
tolerability will be displayed descriptively in frequency tables.


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FLOW CHART
Trial Periods
Screening
Treatment*
Follow-up
Randomised Part A
Open label Part B
Visit
1
2
3
4
5
5a
6
7
7a
8
8a
9
9a
X
Xa
EoT   
**
EoTrial 
***
Weeks****
-4
0
2
6
12
as 
needed
24
26
as 
needed
36
as 
needed
52
as 
needed
52
plus   
Q12w
as 
needed
Days****
Time window for 
visits (days)
Before 
or at
the latest 
at Visit 1
≤28d
before 
Visit 2
D 1
****
none
15
±3
43
±3
85
±3
na
169
±3
183
±3
na
253
±7
na
365
±7
na
365
plus 
Q84d
±7
na
EoT plus 
28 days
+3
Informed consent 
and assent1
X
HRCT sent to 
central review2
X
Biopsy sent to 
central review
(if required)2
X
Demographics
X
Medical history
X
Physical 
examination,
Vital signs3
X
X
X
X
X
X
X
X
X
X
X
X
Height (standing 
and sitting)4
X
X
X
X
X
X
X
X
(X)
Leg length
X
X
X
X
X
X 
/Q24w
X


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Trial Periods
Screening
Treatment*
Follow-up
Randomised Part A
Open label Part B
Visit
1
2
3
4
5
5a
6
7
7a
8
8a
9
9a
X
Xa
EoT   
**
EoTrial 
***
Weeks****
-4
0
2
6
12
as 
needed
24
26
as 
needed
36
as 
needed
52
as 
needed
52
plus   
Q12w
as 
needed
Days****
Time window for 
visits (days)
Before 
or at
the latest 
at Visit 1
≤28d
before 
Visit 2
D 1
****
none
15
±3
43
±3
85
±3
na
169
±3
183
±3
na
253
±7
na
365
±7
na
365
plus 
Q84d
±7
na
EoT plus 
28 days
+3
Weight4
X
X
X
X
X
X
X
X
X
X
(X)
12 lead-ECG 
(at rest)5
X
(X)
X
X
X 
/Q24w
X
Laboratory tests6,7,8
X7
X
X
X
X
(X)
X
X
(X)
X
(X)
X
(X)
X
(X)
X
(X)
Pregnancy tests9
X
X
X
X
X
X
X
X
X
X
X
X
Review with 
patient and 
dispense pregnancy 
test diary card 
together with urine 
dipstick pregnancy 
test (if applicable)9
X
X
X
X
X
X
X
X
SpO2 (room air, 
resting)
X
X
X
X
X
X
X
X
X
X
X
FVC11
X
X
X
X
X
X
X
X
X
X
X
DLCO11
X
Fan severity score
X
Review of in-/ 
exclusion criteria
X
X


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Trial Periods
Screening
Treatment*
Follow-up
Randomised Part A
Open label Part B
Visit
1
2
3
4
5
5a
6
7
7a
8
8a
9
9a
X
Xa
EoT   
**
EoTrial 
***
Weeks****
-4
0
2
6
12
as 
needed
24
26
as 
needed
36
as 
needed
52
as 
needed
52
plus   
Q12w
as 
needed
Days****
Time window for 
visits (days)
Before 
or at
the latest 
at Visit 1
≤28d
before 
Visit 2
D 1
****
none
15
±3
43
±3
85
±3
na
169
±3
183
±3
na
253
±7
na
365
±7
na
365
plus 
Q84d
±7
na
EoT plus 
28 days
+3
IRT call/ 
notification
X12
X
X
X
X
X12
X
X
X
X
Randomisation
X
Administer 
trial drug
X
X
X
X
Dispense PK diary 
card13
X
X
PK Sampling13
X
X
Dispense 
trial drug
X
X
X
X
X
X
X
X
Collect trial drugs
X
X
X
X
X
X
X
X
Compliance check/ 
drug accountability
X
X
X
X
X14
X
X
X
X
Criteria for dose 
reduction/ 
interruption check
X
X
X
X
X
X
X
X
X
Acceptability 
questionnaire
X
X
PedsQL™15
X
X
X
6MWT, Borg CR-
10 scale®, SpO2
X
X
X


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Trial Periods
Screening
Treatment*
Follow-up
Randomised Part A
Open label Part B
Visit
1
2
3
4
5
5a
6
7
7a
8
8a
9
9a
X
Xa
EoT   
**
EoTrial 
***
Weeks****
-4
0
2
6
12
as 
needed
24
26
as 
needed
36
as 
needed
52
as 
needed
52
plus   
Q12w
as 
needed
Days****
Time window for 
visits (days)
Before 
or at
the latest 
at Visit 1
≤28d
before 
Visit 2
D 1
****
none
15
±3
43
±3
85
±3
na
169
±3
183
±3
na
253
±7
na
365
±7
na
365
plus 
Q84d
±7
na
EoT plus 
28 days
+3
ILD exacerbations
X
X
X
X
X
X
X
X
X
X
X
Hospitalizations
(respiratory-
related)
X
X
X
X
X
X
X
X
X
X
X
Bone imaging 
(if applicable)16
X
X
X
X
X
X 
/Q24w
X
Dental 
examination16
X
X
X
X
X
X 
/Q24w
X
Dental imaging16
X
X
X
X 
/Q48w
X
All AEs/ 
SAEs/AESIs17
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant 
therapy
X
X
X
X
X
X
X
X
X
X
X
X
Completion of 
patient 
participation 
X
Vital status data18
X
X
X


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(*)
In case of dose change (reduction or re-escalation) additional visits have to be included.
(**)
Patients who discontinue trial treatment prematurely should undergo the End of Treatment (EoT) visit as soon as possible, and follow the trial schedule thereafter, 
if possible. The patient will be asked to attend all visits (except for the laboratory a-visits) as originally planned until the end of the trial. Please also see Flow 
Chart footnote 18 for instructions, should the patient be unable to complete the scheduled visits; see Section 6.2.3 for details on trial procedures at these visits. 
The first visit after the EoT visit will be skipped if the EoT visit occurs within 4 weeks prior to scheduled visit.
Patients who did not discontinue trial treatment prematurely should undergo the EoT visit as soon as the timing of final DBL (DBL 2) and EoT visit has been
communicated (see Section 3.1 for details). If a regular study visit is scheduled in the period when the EoT visit should be conducted, all procedures required at 
this regular study visit and the additional procedures, if any, required at the EoT visit will be conducted during the same visit.
(***) After the EoT visit, patients who completed the treatment period according to protocol will enter a 4-week follow-up period, unless they roll-over into an open 
label extension trial. See Section 3.1 for details.
(****) Weeks and Days from the Day of Randomisation, i.e. Day of first intake of randomised medication (D 1).
1Informed 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 after the informed consent have to be recorded, including those occurred 
between informed consent and Visit 1. 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 (informed consent to Visit 2) must not be 
longer than 12 weeks. Upon obtaining informed consent, the patient and parent(s)/legal guardian will be instructed on procedures to be followed until the next study 
visit.
2Central review of high resolution computed tomography (HRCT) for meeting inclusion criteria. HRCT should not be older than 12 months. If the patient does not have 
a 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 for the purposes of participation in the trial, provided the patient meets all other in-/exclusion criteria. For details about HRCT and biopsy 
review see Section 3.3.2.1.
3Measurements of vital signs should precede blood sampling; except at Visit 3 and Visit 7 (as blood sampling for PK will start upon patient’s arrival).
4At 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 electronic 
Case Report Form (eCRF). An average of the 3 measurements will be calculated. Height and weight will be repeated at follow-up in case of clinically relevant changes 
at EoT. Height and weight assessed in the 2 years prior to screening (Visit 1) will also be collected, if available.
5Electrocardiogram (ECG) at rest (if possible prior to blood sampling) will be performed at Visit 1. It will be repeated at Visit 2 prior to randomization only if abnormal 
at Visit 1, and at visits specified in the Flow Chart thereafter.
6Safety laboratory tests will be conducted on blood and urine. Tests will be repeated at follow-up (unless patients roll-over into the open label extension trial) in case of 
clinically relevant changes at EoT.
7The safety laboratory tests of Visit 1 must be repeated if screening is longer than 6 weeks.
8Intermediate 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). Laboratory kits for blood and urine sampling done locally (e.g. by the general practitioner or a nurse) and for shipping to central 
laboratory will be provided. Analyses will be conducted by central laboratory.


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9Beta-Human Chorionic Gonadotropin (HCG) testing will be conducted in all female patients, even pre-menarche, on blood collected at each scheduled visit until EoT. 
Pregnancy testing should be repeated every 4-6 weeks, i.e. at least at every visit and additionally at home or at a local laboratory / local doctor from Visit 4 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. If applicable, urine dipstick pregnancy tests will be dispensed 
from Visit 4 until EoT, and use of pregnancy test diary card will be explained with the patient and/or parent(s)/legal guardian. Retuned diary card will be reviewed with
patient or parent(s)/legal guardian from Visit 5 until EoT, 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. At the Follow-up Visit the pregnancy test will be conducted on urines (if acceptable), and 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.
11Order of lung function measurements at Visit 2: 1. FVC followed by patient’s rest; 2. DLCO. After Visit 2 FVC measurements to be done at approximately the same 
time each visit, with reference time at Visit 2.
12Interactive Response Technology (IRT) should be notified upon obtaining informed consent, at Visit 1 at the latest. At Visit 6 IRT will assign open label treatment, and
Part B will start once the first open label dose has been taken in the morning during the visit.
13PK samples will be taken before drug administration at the clinic and at 6 timepoints post-dose (see Flow Chart for PK blood sampling for details). In exceptional 
cases, where extensive PK sampling is not possible and only in paediatric patients with an age < 12 years, a sparse sampling approach might be applied with a minimum 
blood sampling before (PTM of -0:05), 1 h (+/- 15 min) and 3 h (+/- 15 min) after nintedanib administration. Date and exact clock time of drug administration and blood 
sampling must be recorded in the eCRF. The patient and parent(s)/legal guardian will be provided (Visit 2 and Visit 6) with a PK diary card to support the record of the 
exact clock time of medication intake on the three days preceding PK sampling. At the beginning of the PK sampling visit (Visit 3 and Visit 7) the site personnel will 
check the PK diary card and confirm that the trial medication has been taken in the three days preceding the visit. If this is not confirmed, the visit will be rescheduled.
14At this visit drug accountability is to be completed only in case of dose reduction / increase.
15The PedsQL™ questionnaire should always be administered in a quiet place prior to any other visit procedure.
16Bone imaging (Magnetic Resonance Imaging (MRI) examination; if MRI cannot be performed, x-ray assessment) will be conducted in all patients who qualified for 
randomisation at baseline. Imaging follow-up will be conducted only in patients with open physes at 12 weeks, 24 weeks, 36 weeks, 52 weeks and every 24 weeks
thereafter until the end of the study or closure of the physes. At EoT the MRI/x-ray should not be repeated if the last MRI/x-ray was conducted within 12 weeks in the 
first year, 24 weeks thereafter.
Dental examination (clinical) will be conducted in all patients who qualified for randomisation at baseline. Follow-up will be conducted in all patients at 12 weeks, 24 
weeks, 36 weeks, 52 weeks and every 24 weeks thereafter until the end of the study. At EoT the dental examination will not be repeated if the last examination was 
conducted within 12 weeks.
Dental imaging (panoramic x-ray) will be conducted in all patients who qualified for randomisation at baseline. Follow-up will be conducted in all patients at 24 weeks, 
52 weeks and every 48 weeks thereafter until the end of the study. At EoT the dental imaging should not be repeated if the last dental imaging was conducted within 24
weeks.
If it’s not possible to conduct the baseline bone imaging, and/or dental examination, and/or dental imaging on the day of Visit 2, the procedure can be done in the 2 
weeks (until study day 15) immediately after the visit. If it’s not possible to conduct the follow-up bone imaging, and/or dental examination, and/or dental imaging on 
the day of the visit, the procedure can be done in the week immediately before or after the visit. Please refer to the image acquisition guideline available in the ISF for 
details.


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17After 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.
18Patients who prematurely discontinue trial medication will be asked to remain in the study and return to all regularly scheduled visits until the end of the trial. For 
those patients who are unable to complete the scheduled visits, every attempt will be made to get information on vital status at 24 weeks after randomization, i.e. the 
time of the data cut-off for the primary analysis of safety, at 52 weeks and at the end of the trial.
In the event of force majeure or other disruptive circumstances (e.g. pandemic) the investigational plan as per this clinical trial protocol may 
not be feasible at a site. With the consent of the patient’s parent(s)/legal guardian (and assent by the patient where applicable), sponsor and 
investigator may implement risk mitigation measures and modifications to CTP standard procedures as described in Appendix 10.9. See also 
Section 4.1.4, Section 6.1 and ISF for details. 


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FLOW CHART FOR PK BLOOD SAMPLING
Visit
Week
(±days)
Time Point 
[hh:min]
CRF Time
/PTM
Event
3
(Part A)
2
(±3)
-0:051
-0:05
PK Blood
0:00
---
Drug 
administration
1:002
1:00
PK Blood
2:002
2:00
PK Blood
3:002
3:00
PK Blood
4:003
4:00
PK Blood
6:003
6:00
PK Blood
8:003
8:00
PK Blood
7
(Part B)
26
(±3)
-0:051
-0:05
PK Blood
0:00
---
Drug 
administration
1:002
1:00
PK Blood
2:002
2:00
PK Blood
3:002
3:00
PK Blood
4:003
4:00
PK Blood
6:003
6:00
PK Blood
8:003
8:00
PK Blood
1Upon patient’s arrival at the clinic, just before drug administration.
2Time window for 1:00, 2:00 and 3:00 hour post-dose PK sampling: +/-15 min.
3Time window for 4:00, 6:00 and 8:00 hour post-dose PK sampling: +/-30 min.
Extensive blood sampling will be done for the primary PK analysis. In exceptional cases of 
paediatric patients aged <12 years, where extensive PK sampling is not possible, a sparse 
sampling approach should be applied with a minimum blood sampling before (PTM of -0:05) 
and 1 h (+/- 15 min) as well as 3 h (+/- 15 min) after nintedanib administration.
In rare circumstances PK sampling might need to be repeated (e.g. blood samples not taken at 
required timepoint, wrong medication taken in the days before PK sampling or on the day of 
PK sampling, destroyed/lost sample during shipment). In such cases PK sampling will be 
repeated close before the end of treatment visit, to allow the maximum possible interval from 
the previous PK sampling.
A total blood volume of 1.2 mL per time point is required.


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TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS .....................................................................2
FLOW CHART........................................................................................................................5
FLOW CHART FOR PK BLOOD SAMPLING................................................................12
TABLE OF CONTENTS ......................................................................................................15
ABBREVIATIONS................................................................................................................19
1.
INTRODUCTION...............................................................................................25
1.1
MEDICAL BACKGROUND.............................................................................25
1.2
DRUG PROFILE................................................................................................25
1.3
RATIONALE FOR PERFORMING THE TRIAL.........................................28
1.3.1
Similarities and differences in the condition between populations and 
pharmacological rationale..................................................................................28
1.4
BENEFIT - RISK ASSESSMENT.....................................................................30
1.4.1
Benefits.................................................................................................................30
1.4.2
Risks .....................................................................................................................30
1.4.3
Discussion.............................................................................................................35
2.
TRIAL OBJECTIVES AND ENDPOINTS......................................................36
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS........36
2.1.1
Main objectives....................................................................................................36
2.1.2
Primary endpoints...............................................................................................36
2.1.3
Secondary endpoints...........................................................................................36
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.........................39
3.1
OVERALL TRIAL DESIGN AND PLAN .......................................................39
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP...........................................................................................40
3.3
SELECTION OF TRIAL POPULATION .......................................................42
3.3.1
Main diagnosis for trial entry ............................................................................42
3.3.2
Inclusion criteria .................................................................................................43
3.3.2.1
Evidence of fibrosing ILD ....................................................................................44
3.3.3
Exclusion criteria ................................................................................................44
3.3.4
Withdrawal of patients from treatment or assessments..................................46
3.3.4.1
Discontinuation of trial treatment .........................................................................47
3.3.4.2
Withdrawal of consent to trial participation .........................................................48
3.3.4.3
Discontinuation of the trial by the sponsor...........................................................48


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4.
TREATMENTS...................................................................................................49
4.1
INVESTIGATIONAL TREATMENTS ...........................................................49
4.1.1
Identity of the Investigational Medicinal Products..........................................49
4.1.2
Selection of doses in the trial and dose modifications......................................50
4.1.3
Method of assigning patients to treatment groups...........................................56
4.1.4
Drug assignment and administration of doses for each patient......................56
4.1.5
Blinding and procedures for unblinding...........................................................57
4.1.5.1
Blinding.................................................................................................................57
4.1.5.2
Unblinding and breaking the code ........................................................................58
4.1.6
Packaging, labelling, and re-supply...................................................................59
4.1.7
Storage conditions...............................................................................................59
4.1.8
Drug accountability.............................................................................................59
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS ................................................................................................60
4.2.1
Other treatments and emergency procedures..................................................60
4.2.2
Restrictions ..........................................................................................................60
4.2.2.1
Restrictions regarding concomitant treatment ......................................................60
4.2.2.2
Restrictions on diet and life style..........................................................................62
4.2.2.3
Contraception requirements..................................................................................62
4.3
TREATMENT COMPLIANCE........................................................................63
5.
ASSESSMENTS..................................................................................................64
5.1
ASSESSMENT OF EFFICACY........................................................................64
5.1.1
Assessment of FVC..............................................................................................64
5.1.2
Assessment of SpO2.............................................................................................65
5.1.3
Time to first respiratory-related hospitalization..............................................65
5.1.4
Time to first acute ILD exacerbation or death.................................................65
5.1.5
Time to death.......................................................................................................66
5.1.6
Six-minute walk test............................................................................................66
5.2
ASSESSMENT OF SAFETY.............................................................................66
5.2.1
Physical examination ..........................................................................................67
5.2.1.1
Body weight ..........................................................................................................67
5.2.1.2
Height, leg length..................................................................................................67
5.2.2
Vital signs.............................................................................................................68
5.2.3
Safety laboratory parameters ............................................................................68
5.2.4
Electrocardiogram ..............................................................................................71
5.2.5
Assessment of pathological findings of epiphyseal growth plate....................71
5.2.6
Assessment of pathological findings on dental examination or imaging........71
5.2.7
Assessment of adverse events.............................................................................72
5.2.7.1
Definitions of AEs ................................................................................................72
5.2.7.2
Adverse event collection and reporting ................................................................76
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS...................................................................................77
5.3.1
Assessment of pharmacokinetics .......................................................................77
5.3.2
Methods of sample collection .............................................................................78
5.3.3
Analytical determinations ..................................................................................78


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5.4.2
Pharmacogenomics biomarkers.........................................................................79
5.5
BIOBANKING ....................................................................................................79
5.6
OTHER ASSESSMENTS...................................................................................79
5.6.1
Assessment of quality of life via PedsQL™......................................................79
5.6.3
Patient’s acceptability of the investigational product based on the size and 
number of capsules..............................................................................................80
5.6.4
Assessment of DLCO.............................................................................................81
5.6.5
Fan severity score................................................................................................81
5.6.6
Assessment of HRCT ..........................................................................................82
5.7
APPROPRIATENESS OF MEASUREMENTS..............................................83
6.
INVESTIGATIONAL PLAN.............................................................................84
6.1
VISIT SCHEDULE.............................................................................................84
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS .................85
6.2.1
Screening..............................................................................................................85
6.2.2
Treatment period ................................................................................................87
6.2.3
Follow-up period and trial completion..............................................................93
7.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE
...............................................................................................................................96
7.1
NULL AND ALTERNATIVE HYPOTHESES ...............................................96
7.2
PLANNED ANALYSES.....................................................................................96
7.2.1
General considerations .......................................................................................96
7.2.2
Primary endpoint analyses.................................................................................98
7.2.3
Secondary endpoint analyses .............................................................................98
7.2.5
Safety analyses.....................................................................................................98
7.2.7
Interim Analyses .................................................................................................99
7.3
HANDLING OF MISSING DATA .................................................................100
7.4
RANDOMISATION .........................................................................................100
7.5
DETERMINATION OF SAMPLE SIZE .......................................................100
8.
INFORMED CONSENT, TRIAL RECORDS, DATA PROTECTION, 
PUBLICATION POLICY, AND ADMINISTRATIVE STRUCTURE ......103
8.1
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED 
CONSENT .........................................................................................................103
8.2
DATA QUALITY ASSURANCE ....................................................................104
8.3
RECORDS.........................................................................................................104
8.3.1
Source documents .............................................................................................104
8.3.2
Direct access to source data and documents...................................................106
8.3.3
Storage period of records .................................................................................106


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8.4
EXPEDITED REPORTING OF ADVERSE EVENTS ................................107
8.5
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY......107
8.5.1
Collection, storage and future use of biological samples and corresponding 
data.....................................................................................................................107
8.6
TRIAL MILESTONES.....................................................................................107
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL .................................108
9.
REFERENCES..................................................................................................111
9.1
PUBLISHED REFERENCES..........................................................................111
9.2
UNPUBLISHED REFERENCES....................................................................117
10.
APPENDICES...................................................................................................119
10.1
FAN SEVERITY SCORE ................................................................................119
10.2
CREATININE CLEARANCE.........................................................................120
10.3
EQUATIONS FOR DLCO ADJUSTMENT FOR HAEMOGLOBIN...........121
10.4
RECOMMENDATIONS FOR AMBULATORY (OFFICE) BLOOD 
PRESSURE MEASUREMENTS IN CHILDREN AND ADOLESCENTS 122
10.5
SIX-MINUTE WALK TEST ...........................................................................127
10.6
BORG CR-10 SCALE ......................................................................................128
10.7
PEDSQL.............................................................................................................129
10.8
ACCEPTABILITY QUESTIONNAIRES......................................................144
10.9
VISIT MODIFICATION IN EXCEPTIONAL CIRCUMSTANCES .........147
11.
DESCRIPTION OF GLOBAL AMENDMENTS..........................................150
11.1
GLOBAL AMENDMENT 1 ............................................................................150
11.2
GLOBAL AMENDMENT 2 ............................................................................158


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ABBREVIATIONS
ABCA3
ATP Binding Cassette Subfamily A Member 3
AC
Adjudication Committee
AE
Adverse Event
AESI
Adverse Event of Special Interest
ALK
Alkaline Phosphatase
ALT
Alanine Aminotransferase
AP
Antero Posterior
aPTT
Activated Partial Thromboplastin Time
AST
Aspartate Aminotransferase
ATP
Adenosine Triphosphate
ATS / ERS
American Thoracic Society / European Respiratory Society
AUCτ,ss
Area under the Plasma Concentration-Time Curve at Steady State
b.i.d.
bis in die (twice daily dosing)
ß-HCG
Beta- Human Chorionic Gonadotropin
Beta-HCG
Beta- Human Chorionic Gonadotropin
BI
Boehringer Ingelheim
BLQ
Below the Limit of Quantification
CA
Competent Authority
chILD
Childhood Interstitial Lung Disease
cHP
Chronic Hypersensitivity Pneumonitis
CL/Fss
Apparent Clearance of the Analyte in the Plasma at Steady-State
following extravascular multiple dose administration
CK
Creatine Kinase
Cmax
Maximum Concentration in Plasma
Cmax,ss
Maximum Measured Concentration of the Analyte in Plasma at Steady 
State
CNS
Central Nervous System
COHb
Carboxyhaemoglobin
COVID-19
Coronavirus Disease 2019
Cpre,ss
Predose Concentration of the Analyte in Plasma at Steady State 
immediately before administration of the next dose
CRA
Clinical Research Associate


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CRF
Case Report Form, paper or electronic (sometimes referred to as “eCRF”)
CRA
Contract Research Associate
CRO
Contract Research Organisation
CSF1R
Colony-Stimulating Factor 1 Receptor
CTCAE
Common Terminology Criteria for Adverse Events
CT Leader
Clinical Trial Leader
CT Manager
Clinical Trial Manager
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
CV
Coefficient of Variation
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
DRC
Disease Review Committee
EC
Ethics Committee
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
eDC
Electronic Data Capture
EDTA
Ethylenediamine-Tetraacetic Acid
EoT
End of Treatment
EoTrial
End of Trial
EudraCT
European Clinical Trials Database
FC
Flow Chart
FDA
Food and Drug Administration
FGFR
Fibroblast Growth Factor Receptor
FPE
First Patient Enrolled
FPI
First Patient In
FUP
Follow-up
FVC
Forced Vital Capacity


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GCP
Good Clinical Practice
gCV
Geometric Coefficient of Variation
GFR
Glomerular Filtration Rate
GGT
Gamma-Glutamyl Transferase
GI
Gastro-Intestinal
GLI
Global Lung Initiative
GMP
Good Manufacturing Practice
h
hour
HA
Health Authority
Hb
Haemoglobin
Hct
Haematocrit
HP
Hypersensitivity Pneumonitis
HRCT
High-Resolution Computed Tomography
HSCT
Haematopoietic Stem Cell Transplant
i.v.
intravenous
IB
Investigator’s Brochure
ICH
International Conference 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
IQRMP
Integrated Quality and Risk Management Plan
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
LDH
Lactate Dehydrogenase
LFT
Liver Function Test


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LPI
Last Patient In
LPLT
Last Patient Last Treatment
LPLVPE
Last-Patient-Last-Visit-Primary-Endpoint
Lyn
Tyrosine-protein Kinase Lyn
MACE
Major Adverse Cardiovascular Events
MCTD
Mixed Connective Tissue Disease
MedDRA
Medical Dictionary for Drug Regulatory Activities
MMRM
Mixed Model with Repeated Measurements
MRI
Magnetic Resonance Imaging
n.a.
Not Applicable
NOA
Not Analysed
NOP
No Peak Detectable
NOR
No Valid Result
NOS
No Sample
NSIP
Non-Specific Interstitial Pneumonia
OPU
Operative Unit
PAH
Pulmonary Arterial Hypertension
PBMC
Peripheral Blood Monocytic Cells
PD
Pharmacodynamic(s)
PDGFR
Platelet-Derived Growth Factor Receptor
PedsQL™
Pediatric Quality of Life Questionnaire™
per os
Oral
PF-ILD
Progressive Fibrosing Interstitial Lung Disease
P-gp
Permeability Glycoprotein
PIP
Paediatric Investigation Plan
PK
Pharmacokinetic(s)
PKS
Pharmacokinetic Set
PM
Polymyositis
PopPK
Population Pharmacokinetics
PT
Prothrombin Time
PTM
Planned Time
Q
Quaque, i.e. every
RA
Regulatory Authority


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RA-ILD
Rheumatoid Arthritis associated ILD
RBC
Red Blood Count
REP
Residual Effect Period
s.c.
subcutaneous
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SFTPC
Surfactant Protein Deficiency
SI
International System of units
SMC
Safety Monitoring Committee
SMQ
Standard MedDRA Query
6MWT
Six-Minute Walk Test
SARS-CoV2
Severe Acute Respiratory Syndrome Coronavirus 2
SOC
Standard of Care
SOP
Standard Operating Procedure
SpO2
Oxygen Saturation
Src
Proto-oncogene Tyrosine-protein Kinase
SSc-ILD
Systemic Sclerosis associated ILD
SUSARs
Suspected Unexpected Serious Adverse Reactions
t1/2,ss
Terminal Half-life of the Analyte in Plasma at Steady State
tmax,ss
Time from Dosing to Maximum Measured Concentration of the Analyte 
in Plasma at Steady State
TKI
Tyrosine Kinase Inhibitor
TMF
Trial Master File
TS
Treated Set
TSAP
Trial Statistical Analysis Plan
UIP
Usual Interstitial Pneumonia
ULN
Upper Level of Normal
US
United States
VEGFR
Vascular Endothelial Growth Factor receptor
w
Week(s)
WHO
World Health Organisation
WOCBP
Woman of childbearing potential


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Vz/Fss
Apparent Volume of Distribution during the Terminal Phase λz at Steady 
State following extravascular administration


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1.
INTRODUCTION
1.1
MEDICAL BACKGROUND
Childhood interstitial lung disease (chILD) comprises a complex and heterogeneous spectrum 
of rare respiratory disorders affecting infants and children [P19-02553] associated with 
varying prognosis. There is scant data in the literature on the epidemiology of paediatric 
ILDs. Overall, the prevalence of paediatric ILD is considered to be substantially lower than in 
adults [R11-5060, R12-0299, R12-0358, R12-0974, R14-4379, R17-2810, R17-2902, R17-
2907, R03-2090, R03-2075, P16-01479], ranging from 1.5 to 3.8 per million [R12-2794,
R16-4790, R17-2776] and incidence rates ranging from 1.32 to 162 per million person-years 
for children [R16-1141, R12-0299, R18-1147].
Similar to adults with ILD, some of whom can develop a progressive phenotype characterized 
by worsening symptoms, lung function decline and increased morbidity [P17-10582], some 
patients with chILD develop chronic lung fibrosis that is associated with significant 
morbidity and mortality. Although some ILDs (e.g. rheumatoid arthritis [RA]-ILD) can occur 
in both children and adults, certain ILDs occur more frequently in children (e.g. surfactant 
protein deficiency) [R16-4788] while others are almost exclusively found in adults (e.g. IPF). 
As a result, the composition of the clinical diagnoses associated with lung fibrosis in 
paediatric patients, though overlapping differs from that seen in adults. Potential paediatric 
conditions likely to be associated with fibrosing ILD include, but are not limited to, the 
following:

surfactant protein deficiency (SFTPC and ATP binding cassette subfamily A member 
3 [ABCA3] mutations); 

chronic hypersensitivity pneumonitis (cHP); 

toxic/radiation/drug induced pneumonitis; 

post hematopoietic stem cell transplant (HSCT) fibrosis;

connective tissue disease related disorders (e.g. juvenile rheumatoid arthritis [RA]/ 
juvenile idiopathic arthritis; Systemic Sclerosis [SSc], dermatomyositis/polymyositis 
[DM/PM]; mixed connective tissue disease [MCTD]) and sarcoidosis.
There are currently no approved therapies for the treatment of fibrosing interstitial lung 
disease associated with any of these conditions in children.
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 


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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 [c01783972-16].
A soft gelatin capsule formulation of nintedanib is used in humans. Maximum plasma 
concentrations (Cmax) occur between 2 to 4 hours after oral administration. Steady state is 
reached at the latest within one week of dosing. The absolute bioavailability of nintedanib is 
slightly below 5%. After food intake, a trend towards an increased systemic exposure (around 
20%) and a delayed absorption is observed compared to administration under fasted 
conditions. Therefore nintedanib is recommended to be taken with food. Nintedanib is 
preferentially distributed in plasma with a blood to plasma ratio of 0.87; the terminal half-life 
is in the range of 7 to 19 h. Nintedanib is mainly eliminated via faeces (~93%), with minimal 
renal excretion (0.7%).
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 4.1.2:2) [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 [U13-1478-01, 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 paediatric programme is 28 days. 


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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].
Data from clinical studies
Based on the demonstrated pre-clinical effects noted above, the potential benefits of 
nintedanib have been investigated in adults with idiopathic pulmonary fibrosis [P14-07514],
SSc-ILD [P17-07763, P19-04387], and progressive fibrosing interstitial lung disease (PF-
ILD) [P17-10582, P19-08802].
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 
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 forced vital capacity (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 decreased 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 


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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 IB
Nintedanib in Idiopathic Pulmonary Fibrosis, Systemic Sclerosis and Progressive Fibrosing 
Interstitial Lung Disease [c01783972-16].
1.3
RATIONALE FOR PERFORMING THE TRIAL
This study is part of the Paediatric Investigation Plan (PIP) agreed with EMA for nintedanib 
in the treatment of chronic fibrosing ILDs with a progressive phenotype.
The study is conducted in patients 6 to 17 years old with clinically significant fibrosing ILD.
Based on the presumed similarities in underlying pathophysiology in fibrotic lung 
remodelling in adults and children and observed clinical efficacy in adults with fibrosing 
interstitial lung disease, e.g. systemic sclerosis associated ILD, idiopathic pulmonary fibrosis,
and other progressive fibrosing ILDs, it is postulated that the anti-fibrotic effect of nintedanib 
may lead to similar benefit in a paediatric population with similar underlying 
pathophysiology.
As the conduct of a confirmatory efficacy study is deemed not feasible based on the low 
disease prevalence in children, a focused PK and safety evaluation of nintedanib in children 
and adolescents with clinically significant fibrosing interstitial lung disease is planned. Due 
to small patient numbers, a basket approach [P17-10582, R18-2970] will be used to group 
children and adolescents according to demonstrated evidence of lung fibrosis and clinical 
disease severity irrespective of clinical diagnosis to optimise feasibility. Supportive data on 
efficacy in the proposed paediatric programme will be collected to support inferences of 
clinical benefit and evaluation of the benefit-risk of nintedanib in the target population.
1.3.1
Similarities and differences in the condition between populations and 
pharmacological rationale
Fibroblast proliferation, migration and transformation have been shown to be fundamental 
processes in the common final path of fibrotic remodelling and several diseases resulting in 
lung fibrosis including IPF, chronic HP, SSc-ILD and RA-ILD [c01783972-16]. As such, the 
prevailing underlying hypothesis is that a similar final common pathway in fibrosing ILDs 
can be targeted with nintedanib and lead to clinical benefit (see pharmacologic rationale). 
Accordingly, clinical programmes with nintedanib have targeted patients with presumed 
similarities in pathophysiology based on demonstrated evidence of chronic fibrosing lung 
disease, irrespective of the underlying trigger [P17-07763; P17-10582].


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While there is overlap between clinical diagnoses associated with lung fibrosis in paediatrics
and adults, some diagnoses associated with lung fibrosis are specific to each population. The 
following paediatric conditions can be most frequently associated with lung fibrosis in 
paediatrics: 

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.
In addition to difference in clinical diagnoses associated with fibrosing lung disease, the 
clinical course of fibrotic lung disease also differs between paediatrics and adults.
The data on the natural history of chronic fibrosing interstitial lung disease in children is 
limited. The available evidence suggests overall that the clinical course is associated with 
better outcome compared to adult ILDs with survival at 2, 4 and 5 years after symptom onset 
reported to be 83%, 72% and 64%, respectively [R09-5337]. This is compared to a median 
survival of 2.5–3.5 years from diagnosis in IPF [P11-07084], the most progressive form of 
fibrosing lung disease in adults. However, as previously mentioned there is a subgroup of 
children with fibrosing lung disease who experience significant morbidity and mortality 
[R09-5337].
Accelerated decline in lung function over time is one of the key clinical findings in adults 
with fibrotic ILDs and is considered one of the best predictors of disease progression and
mortality [R10-6539, R06-4127, R10-2727, P12-09611, R14-1149, R12-3648, R14-1150,
R06-4129, R17-1625, R18-3409, R18-3555]. Other independent predictors of mortality that 
have been identified in adults with fibrosing lung disease include older age, male gender, 
worse pulmonary function and radiological or histopathological extent of fibrosis, as well as 
presence of usual interstitial pneumonia (UIP) pattern on HRCT [P06-05020, R16-0754,
R16-0756, R16-0758, R16-0752, R16-0755, R16-0560]. While there is limited data in 
paediatrics, a study assessed predictors of survival in a small cohort of children with various 
fibrosing ILDs and found a severity-of-illness score based on symptoms and oxygenation to 
be significantly associated with decreased survival [R09-5337]. There is limited data on serial 
lung function in children with fibrosing ILD available in the literature. Clinical parameters 
such as weight, crackles, digital clubbing, symptom duration or family history were not found 
to be associated with survival. As such, evaluation of clinically significant disease and 
evaluation of potential therapies in paediatric patients need to be tailored accordingly.


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1.4
BENEFIT - RISK ASSESSMENT
1.4.1
Benefits
Based on a comprehensive clinical development programme in adult patients with 3 phase II 
and III studies in IPF (TOMORROW®, INPULSIS1® and INPULSIS2®), 1 phase III study in 
SSc-ILD (SENSCIS®) [P17-07763], and 1 phase III study in chronic fibrosing interstitial 
lung disease with progressive phenotype (INBUILD®) [P17-10582], nintedanib has been
approved for the treatment of IPF in more than 70 countries and for the treatment of SSc-ILD 
in Europe, US, Japan, Australia, Canada, China and several other countries. In addition,
nintedanib has been approved for the treatment of adults with chronic fibrosing interstitial 
lung diseases with a progressive phenotype in the US, Canada, Japan and has received a 
positive opinion in Europe. Nintedanib has shown a consistent benefit in slowing the rate of 
decline in lung function over 52 weeks across these indications [P14-07514, P19-04387, P19-
08802].
Based on its mode of action and demonstrated effect in various pre-clinical models of ILD
and demonstrated clinical benefit in various adult fibrosing ILDs (e.g. IPF, fibrosing ILDs 
with a progressive phenotype, and SSc-ILD), treatment of fibrosing ILDs with nintedanib in 
children and adolescents is expected to lead to similar clinical benefit as observed in adults.
1.4.2
Risks
Currently there is no experience with nintedanib in the paediatric population except for the 
current trial. However, the known risks of use in adults are 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 risks specific for the paediatric 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 (see Table 1.4.2:1 for 
details).
The most frequently reported adverse reactions associated with the use of nintedanib in 
adults, and the potential risks specific to the paediatric population, will be carefully 
monitored.
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 the risk for worsening the disease course of COVID-19. However, 
patients with chronic fibrosing interstitial lung diseases may be at risk of severe clinical 
courses due to the underlying disease, associated co-morbidities and potential use of 
immunosuppressive co-medications.


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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 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.
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
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 (Clinical 
Trial Protocol [CTP]
Section 4.1.2), regular 
monitoring by SMC.

Decreased appetite
Same as above.
Weight check every 12 
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 4.1.2), 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).


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Potential risks of clinical 
relevance for this trial
Summary of data, rationale 
for the risk
Mitigation strategy

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 (AESI).
Careful monitoring of liver 
function. 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, 
may result in fatal outcome.
Increased awareness and 
expedite reporting (AESI).
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 conducted 
in all female patients at each 
visit on blood until end of 
treatment, and between 
visits on urines from Visit 4 
until end of trial and at the 
Follow-up Visit (if 
acceptable), to ensure 
testing every 4-6 weeks.
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.


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Potential risks of clinical 
relevance for this trial
Summary of data, rationale 
for the risk
Mitigation strategy
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 in 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 weeks. Regular 
evaluation by SMC.

Impact in bone 
development and growth
In animal models, 
nintedanib has been shown 
to alter the epiphyseal 
growth plates of large bones 
(femur and tibia). These 
changes were reported 
during bone growth, and 
were reversible after 
discontinuation.
Monitor potential reversible 
effects on bone 
development and growth by:
Regular evaluation by 
radiology expert, with 
skeletal growth monitoring 
(MRIs or x-rays of 
epiphyseal growth plates) at 
baseline and follow-up in 
patients with open physes at 
12, 24, 36, 52 weeks and 
every 24 weeks thereafter 
until end of the study or 
closure of the physes. 
Expedited reporting of 
pathological findings 
identified on bone imaging 
(AESI).
Regular evaluation by SMC.

Impact on dentition
In animal models, 
nintedanib has been shown 
to impact tooth 
development. Tooth 
changes were major with 
altered tooth structure and 
Monitor potential 
severe/irreversible effects
on dentition by:
Regular evaluation by 
dentist, with dental 
examination at baseline and 


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Potential risks of clinical 
relevance for this trial
Summary of data, rationale 
for the risk
Mitigation strategy
function which were 
irreversible. Changes 
occurred only during the 
growth phase of the teeth.
follow-up at 12, 24, 36, 52 
weeks and every 24 weeks
thereafter until end of the 
study.
Expedited reporting of 
stunted growth identified on 
dental imaging (AESI).
Regular evaluation by 
paediatric dentistry expert, 
with panoramic x-ray at 
baseline and follow-up at 
24, 52 and every 48 weeks
thereafter until end of the 
study. 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.
HRCT at baseline required 
only if acceptable HRCT 
not available within 12 
months of Visit 1.
 
 
 
MRI/x-ray at EoT required 
only if previous MRI/x-ray 
not available within 12
weeks in the first year, 24 
weeks thereafter.
Panoramic x-ray at EoT
required only if previous 
panoramic x-ray not 
available within 24 weeks.


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Potential risks of clinical 
relevance for this trial
Summary of data, rationale 
for the risk
Mitigation strategy
Other risks

Placebo treatment
Allow for blinded 
evaluation of safety over 
first 24 weeks of study 
(Part A)
Patients will be allowed to 
use SOC as determined by 
treating physician.

Risk of contracting a 
SARS-CoV-2 infection
The number of site visits is 
limited to the minimum 
required for the successful 
conduct of the 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 4.1.4, Section 
6.1 and Appendix 10.9 for 
details).
An external Safety Monitoring Committee (SMC) will ensure monitoring of safety 
throughout the conduct of the study. The SMC will review individual and aggregated PK and 
safety data at regular intervals, advise the study team about the appropriateness of further 
enrolment and continuation/modification/premature interruption of the study, and might 
recommend dose modification and/or additional assessments (e.g. intermediate checks in 
those patients who switched from placebo to nintedanib at the end of the initial 24 weeks of 
treatment).
Investigational Medicinal Product (IMP) withdrawal criteria throughout the treatment phase 
of the study as defined by protocol should be adhered to (see Section 3.3.4.1).
Patients with co-morbidities associated with potentially increased risk to nintedanib will be 
excluded (see Section 3.3.3).
1.4.3
Discussion
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 benefit-risk of nintedanib in the 
target population is considered acceptable. The planned trial procedures and the associated-
risk are deemed acceptable as they allow for timely identification of potential risks, 
discontinuation of treatment and possible reversal of adverse drug reactions.


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2.
TRIAL OBJECTIVES AND ENDPOINTS
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS
2.1.1
Main objectives
The main objective of the study is to evaluate dose-exposure and safety of nintedanib in 
children and adolescents with fibrosing ILD.
2.1.2
Primary endpoints
Primary endpoints:

PK: AUCτ,ss based on sampling at steady state (at week 2 and week 26);

N (%) of patients with treatment-emergent adverse events at week 24.
2.1.3
Secondary endpoints
Secondary endpoints:

N (%) of patients with treatment-emergent pathological findings of epiphyseal growth 
plate on imaging at week 24, and week 52*;

N (%) of patients with treatment-emergent pathological findings on dental 
examination or imaging at week 24, and week 52*;

N (%) of patients with treatment-emergent adverse events over the whole trial;

Change in height, sitting height, leg length from baseline at week 24, week 52*, week 
76*, and week 100*.

Change in Forced Vital Capacity (FVC) % predicted from baseline at week 24, and 
week 52*;

Absolute change from baseline in Pediatric Quality of Life Questionnaire™ 
(PedsQL™) at week 24, and week 52*;

Change in oxygen saturation (SpO2) on room air at rest from baseline at week 24, and 
week 52*;

Change in 6-min walk distance from baseline at week 24, and week 52*;

Patient acceptability based on the size of capsules at week 24;

Patient acceptability based on the number of capsules at week 24;

Time to first respiratory-related hospitalization over the whole trial;

Time to first acute Interstitial Lung Disease (ILD) exacerbation or death over the 
whole trial;

Time to death over the whole trial.
*52 weeks, 76 weeks, 100 weeks time point will not be available for all patients.


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN AND PLAN
This is a multi-centre, multi-national, prospective, double blind, randomised, placebo-
controlled clinical trial to evaluate the dose-exposure and safety of nintedanib per os on top 
of standard of care for 24 weeks, followed by open label treatment with nintedanib of 
variable duration, in children and adolescents (6 to 17 years old) with clinically significant 
fibrosing interstitial lung disease.
All patients recruited for the study will enter a 4-week screening period (Visit 1 to Visit 2)
(see Flow Chart and footnotes for permitted time window). At Visit 2 patients meeting in-
/exclusion criteria will be randomised and enter the treatment period of the study. This period 
will consist of two parts: Part A and Part B (Figure 3.1: 1).
Figure 3.1: 1 Trial design
FPE: First Patient Enrolled; FPI: First Patient In (i.e. randomized); LPI: Last Patient In; EoT: End of Treatment.
During Part A patients will receive blinded randomised treatment (nintedanib or placebo 2:1) 
for 24 weeks. Following completion of Part A (Visit 6), patients will be switched to open 
label nintedanib (Part B) and will remain on treatment until the end of the study, or premature 
discontinuation. The duration of treatment in Part B is “variable” from patient to patient, 
depending on when the patient has entered the treatment period of the study. For the 
definition of “the end of the study” see Section 8.6. 
The study will include two database locks (DBL 1 and DBL 2). The first DBL will be 
announced once 30 patients (at least 20 adolescents aged 12-17 years, and if feasible at least 
10 children aged 6-11 years) have completed PK sampling at 26 weeks, or prematurely 
discontinued the trial (last-patient-last-visit-primary-endpoint). At this timepoint patient 
recruitment will close. Based on the data from DBL 1 (or updated DBL 1 data once the 
number of patients with sufficient PK data has been reached), the primary analysis and a 
benefit-risk assessment will be done and the clinical trial report for the primary analysis will 
be written. The timing of final DBL (DBL 2) and EoT visit will be communicated after 
confirming adequacy of PK data from DBL 1 (or updated DBL 1 data).


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If no additional PK data are needed, all patients, including those who may have entered the 
study after targeted number (30 patients) have been randomised, will be scheduled for an EoT 
visit.
After the EoT visit, patients will enter a 4-week follow-up period (see Flow Chart and 
footnotes for permitted time window), unless they subsequently roll-over into the open label 
extension trial. The open label extension trial (1199-0378) will be initiated if supported by 
the benefit-risk assessment from DBL 1.
In the rare case that additional PK data is deemed necessary to complete the primary PK 
assessment, data from DBL 1 will be updated and the administrative DBL 2 will be 
postponed. Additional PK will be collected by switching ongoing study participants in Part A 
to Part B and/or recruiting new patients directly to Part B following screening if supported by 
the benefit-risk assessment. This decision will be made after discussion with the Safety 
Monitoring Committee (SMC) and properly documented. Once the decision is taken, all 
patients who did not yet complete Visit 6 (and were not prematurely discontinued) will be 
scheduled for Visit 6, complete all visit procedures (see Section 6.2.2 for details) and enter 
Part B. After two weeks of open label treatment each patient will attend Visit 7, and blood 
samples for PK analyses will be collected per standard procedures (see Flow Chart for PK 
blood sampling for details). If the number of patients in Part A is not sufficient, further 
patients will be screened and entered to Part B at the end of the screening period, if meeting 
eligibility criteria (see Section 3.3.2 and Section 3.3.3 for details).
Patients who prematurely discontinued trial medication will be asked to remain in the study 
and return to all regularly scheduled visits until the end of the trial. For details about 
procedures to be conducted at these visits please refer to Section 6.2.3. For those patients who 
are unable to complete the scheduled visits, every attempt will be made to get information on 
vital status at 24 weeks after randomization (i.e. the time of the data cut-off for the primary 
analysis), at 52 weeks and at the end of the trial. 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).
For each patient, the study period is from the signature of the informed consent by the 
parent(s)/legal guardian until the patient’s last visit of the study. Adverse events will be 
collected during the entire study period and considered treatment-emergent from first study 
drug intake until 28 days after drug discontinuation.
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP
Placebo design and treatment allocation
A placebo-controlled design is considered necessary for evaluating and interpreting the AE 
reporting.
While the safety profile is presumed to be similar to that observed in the adult studies 
including IPF, SSc-ILD and fibrosing ILDs with progressive phenotype, the availability of a 


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placebo arm will assist in the interpretation of any potential unexpected findings in this 
paediatric population.
In addition, though limited, use of a placebo group may allow for exploratory evaluation of 
the natural course of lung function and assess comparability of the study population to 
historical controls if available by then.
To minimise the potential negative impact of a placebo-control design on recruitment and 
taking into account the disease severity, use of standard of care as deemed clinically indicated 
by the treating physician will be allowed. In addition, as there are limited treatment options
for the target population, after 24 weeks of double blind, placebo-controlled treatment all 
patients will be switched to open label nintedanib treatment. 
Consistent with the primary objective of evaluating the safety of nintedanib in the target 
population, a 2:1 allocation is planned to minimize exposure to placebo and allow for more 
robust safety evaluation of active treatment.
Treatment duration
The planned duration of the placebo-controlled treatment is considered sufficient to evaluate 
the primary endpoint of PK as well as assess the incidence of the most frequent drug related 
AEs associated with nintedanib in the adult population, and potential AEs related to use of 
nintedanib in the paediatric population.
The most frequent AEs associated with nintedanib treatment in adults (e.g. increases in liver 
transaminase levels and/or bilirubin, diarrhoea, nausea, vomiting) can be adequately assessed 
with a treatment duration of 3 months. Since a comparable safety profile is expected in 
children and adolescents, a study duration of 6 months is considered acceptable. While there 
is no previous clinical experience of nintedanib in the paediatric population, review of the 
literature of the effect of VEGF inhibition in children suggest that 6-month observation is 
adequate to evaluate potential acute effects on growth [R18-1476, R18-1477].
Moreover, the overall exposure to active treatment based on the proposed study design allows 
for collection of long term safety monitoring data of potential paediatric specific AEs (i.e. 
bone and teeth effects), which may take longer to develop. Based on to the current design, 
assuming a recruitment time of 18 months, the treatment period for the minimum targeted 30 
subjects is expected to be minimum 26 weeks, with an average nintedanib exposure of 
approximately 12 months, and >2-year exposure in early enrolled patients. As such, data 
collected beyond 6 months will provide longer term safety and efficacy information.
Sample Size 
The target sample size of a minimum of 30 patients is based on the sample size estimation for 
the primary evaluation of PK and feasibility. Although the planned basket approach makes it 
feasible to evaluate this extremely rare patient population, one of the limitations of this 
approach is the heterogeneity of the study populations, especially in evaluating efficacy 
outcomes of potential interest (e.g. lung function). Given the high unmet medical need, lack 
of therapeutic option and the potential for more robust assessment of efficacy, study 
enrolment into the treatment phase will remain open until 30 patients (at least 20 adolescents 


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aged 12-17 years, and if feasible at least 10 children aged 6-11 years) have completed PK 
sampling at 26 weeks, or prematurely discontinued the trial. This approach will allow for any 
eligible patients identified beyond the minimum targeted 30 subjects to have access to study 
drug. All PK and clinical data available at DBL 1 (or updated DBL 1) will be used in the 
primary analysis to allow for more robust estimates of exposure and potential treatment 
effect. 
3.3
SELECTION OF TRIAL POPULATION
At least 30 paediatric patients (male and female 6 years old and older, including at least 20 
adolescents aged 12-17 years) with documented clinically significant fibrosing interstitial 
lung disease will be randomised.
Patients under the age of 6 years will be excluded from the current study. This is based on the 
potential higher risk of nintedanib administration in children younger than 6 years, limited 
evidence to support the scientific rationale of potential benefit of nintedanib, and challenges 
in evaluating potential clinical benefit as established in adults, in this paediatric subset.
A log of all patients enrolled into the trial (i.e. who have an informed consent signed by the 
parent(s)/legal guardian) will be maintained in the Investigator Site File (ISF) at the 
investigational site irrespective of whether patients have been treated with investigational 
drug or not. 
Re-enrolment of screen failed patients will be permitted. Patients who did not qualify for 
randomisation during the early months of the recruitment period might qualify for 
randomisation during the late months of the recruitment period of the study. A previous 
‘screening failure’ patient will sign a new informed consent and get a new unique patient 
number. The previous patient number will be collected via the electronic Case Report Form 
(eCRF).
If a patient is enrolled by error (does not meet all inclusion criteria or meets one or more 
exclusion criteria on the day of enrolment), the sponsor should be contacted immediately.
Patient recruitment is expected to be conducted in approximately 24 countries and 
approximately 70 sites. Each site is expected to enrol 1-2 patients, some sites might not be 
able to randomize any patients.
3.3.1
Main diagnosis for trial entry
The study will be conducted in paediatric patients with clinically significant fibrosing 
interstitial lung diseases as defined in protocol (refer to Section 3.3.2 and Section 3.3.3). 
Given the low prevalence of individual (and even grouped) diagnoses, a basket approach 
grouping patients based on similarity in underlying pathophysiology in fibrotic remodelling is 
considered required for the feasibility of the current study.
Potential diagnoses likely to be associated with a chronic fibrosing lung pathology include,
but are not limited to:


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
Surfactant protein deficiency (SFTPC, 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
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
1. Children and adolescents 6 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 (WOCBP)1 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 Section 4.2.2.3.
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. [See Section 3.3.2.1 for details.]
5. Patients with FVC % predicted ≥25% at Visit 2.
[Note: Predicted normal values will be calculated according to GLI (Global Lung 
Initiative), see Section 5.1.1 for details.]
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
                                                
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.
A postmenopausal state is defined as no menses for 12 months without an alternative medical cause.


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o
other measures of clinical worsening attributed to progressive lung disease (e.g. 
increased oxygen requirement, decreased diffusion capacity).
Instructions on Fan score are given in Appendix 10.1.
3.3.2.1
Evidence of fibrosing ILD
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 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. Co-existing 
multifocal non-fibrotic, non-dependent consolidations (e.g. organizing pneumonia, infection) 
will not be allowed.
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.
For patients without any documented lung biopsy or whose biopsy results do not meet the 
biopsy criteria for fibrosis listed above, at least two of the following imaging findings are 
required on at least two HRCT scan (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.
3.3.3
Exclusion criteria
1. AST and/or ALT >1.5 x ULN at Visit 1.
2. Bilirubin >1.5 x ULN at Visit 1.
3. Creatinine clearance <30 mL/min calculated by Schwartz formula at Visit 1.
[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 


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randomization. In case at Visit 2 the results 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. 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. Previous treatment with nintedanib.
6. Other investigational therapy received within 1 month or 5 half-lives (whichever is 
shorter but ≥1 week) prior to Visit 2.
7. 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
8. In the opinion of the Investigator, other clinically significant pulmonary abnormalities.
9. 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)
ii. In adolescents 13 to 17 years old: systolic blood pressure ≥140 mm Hg or 
diastolic blood pressure ≥90 mm Hg
b. Myocardial infarction within 6 months of Visit 1
c. Unstable cardiac angina within 6 months of Visit 1
10. 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 (e.g. enoxaparin 4000 I.U. s.c. 
per day), as well as prophylactic use of antiplatelet therapy (e.g. acetyl salicylic 
acid up to 325 mg/day, or clopidogrel at 75 mg/day, or equivalent doses of other 
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: 


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i. International normalized ratio (INR) >2
ii. Prolongation of prothrombin time (PT) by >1.5 x ULN
iii. Prolongation of activated partial thromboplastin time (aPTT) by >1.5 x ULN 
11. History of thrombotic event (including stroke and transient ischemic attack) within 12 
months of Visit 1.
12. Known hypersensitivity to the trial medication or its components (i.e. soya lecithin).
13. Patients with documented allergy to peanut or soya.
14. 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.
15. Life expectancy for any concomitant disease other than ILD <2.5 years (investigator 
assessment).
16. Female patients who are pregnant, nursing, or who plan to become pregnant while in
the trial.
17. Patients not able or willing to adhere to trial procedures, including intake of study 
medication.
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).
Instructions about how to assess creatinine clearance are given in Appendix 10.2. 
Recommendations for blood pressure measurements in children and adolescents are given in 
Appendix 10.4.
3.3.4
Withdrawal of patients from treatment or assessments
Patients may discontinue trial treatment or have withdrawn consent (and/or withdrawn assent,
where applicable) to trial participation as a whole (“withdrawal of consent”) with very 
different implications; please see Section 3.3.4.1 and Section 3.3.4.2 below.
Every effort should be made to keep the patients in the trial: if possible on treatment, or at 
least 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 and reporting (please see Section 5.2.7.2.1 and 
Section 5.2.7.2.2).
All data collected will be reported, including data of patients who discontinue/withdraw from 
treatment or assessments after randomization/entering the active treatment phase of the study.
If consent/assent to trial participation is withdrawn, data collection will stop at time of 
consent/assent withdrawal.


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3.3.4.1
Discontinuation of trial treatment
An individual patient will discontinue trial treatment if:

The patient wants to discontinue trial treatment, and or the parent(s)/legal guardian
wants the patient to discontinue trial treatment, without the need to justify the 
decision.

The patient has repeatedly shown to be non-compliant with important trial procedures 
and, in the opinion of both, the investigator and sponsor representative, 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’s 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 (e.g. enoxaparin 4000 I.U. s.c. per 
day), as well as prophylactic use of antiplatelet therapy (e.g. acetyl salicylic acid up to 
325 mg/day, or clopidogrel at 75 mg/day, or equivalent doses of other 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 gastro-intestinal bleeding or GI-ulcers.
The trial medication has to be permanently discontinued in the following circumstances:

The patient experiences signs of hepatic injury, 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 is restricted as defined in 
Section 4.2.2.

The patient can no longer receive trial treatment for medical reasons (such as adverse 
events, other diseases, or pregnancy).
If a patient becomes pregnant during the trial the investigational product must be 
discontinued immediately, and the patient will be followed up until birth or otherwise 
termination of the pregnancy. 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 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 


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regularly scheduled visits until the end of the trial. For those patients who are unable to 
complete the scheduled visits, every attempt will be made to get information on vital status at 
24 weeks after randomization, i.e. the time of the data cut-off for the primary analysis, at 52 
weeks after randomization and at the end of the trial, as outlined in the Flow Chart and 
Section 6.2.3.
3.3.4.2
Withdrawal of consent to trial participation
Patient’s parent(s)/legal guardian may withdraw their consent to trial participation (and/or the 
patient may withdraw assent, where applicable) at any time without the need to justify the 
decision.
If a patient’s parent(s)/legal guardian wants to withdraw consent (and/or the patient wants to 
withdraw assent, where applicable), the investigator should be involved in the discussion with 
the parent(s)/legal guardian (and/or the patient) 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.
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. Emergence of any efficacy/safety information invalidating the earlier positive benefit-
risk-assessment that could significantly affect the continuation of the trial.
3. Deviations from GCP, the trial protocol, or the contract impairing the appropriate conduct
of the trial.
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, 25 mg, 
and matching placebo capsules.
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 this trial in the paediatric population. The 75 mg and 50 
mg doses will be provided as multiples of the newly developed 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
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.
Mode of administration:
Oral (swallowed)
Table 4.1.1:2 Test product 2
Substance:
Placebo
Pharmaceutical formulation:
Soft gelatin capsule
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG
Unit strength:
Placebo to 150 mg, 100 mg, 25 mg
Posology:
Placebo to 150 mg, or 100 mg, or 3x25 mg, or 2x25
mg, or 25 mg, each b.i.d.
Mode 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 [c01783972-16] for details). This approach is 
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 as 
provided in Table 4.1.2: 1.
The patient’s weight will be measured at screening, at randomization and at each IMP 
dispensing visit thereafter (see Flow Chart for details). At randomization 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.
Table 4.1.2: 1
Dose assignment and dose reduction possibilities based on body 
weight bins according to ICH E11
* Patients <13.5 kg of weight are excluded from the trial
Based on population anthropometric measures of weight by age, most children younger than 
10 are expected to fall into body weight bin 1–2, younger adolescents in bin 3 and older ones 
in bin 4.
Similar to the adult dosing schedule [P17-10582], treatment interruption and dose reduction 
are allowed as medically indicated.
Body 
weight 
bin 
Weight 
range
Dose (b.i.d.) 
Capsule 
strengths 
Dose 
reduction 
possibility 
(b.i.d.)
Capsule 
strengths 
1
13.5* to 
<23.0 kg
50 mg 
25 mg (2x)
25 mg
25 mg (1x) 
2
23.0 to 
<33.5 kg
75 mg 
25 mg (3x)
50 mg
25 mg (2x)
3
33.5 to 
<57.5 kg
100 mg 
100 mg (1x) 
or 25 mg (4x)
75 mg
25 mg (3x) 
4
≥57.5 kg
150 mg 
150 mg (1x) 
or 25 mg (6x)
100 mg
100 mg (1x)  
or 25 mg (4x)


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Criteria for dose reduction / treatment interruption
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-started after recovery. The dose reduction scheme in Table 
4.1.2: 1 should be considered to manage adverse events.
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.
Dose reduction and re-increase are allowed at multiple occasions.
No further dose reduction outside of those listed will be allowed. In case of persistent adverse 
events observed at the reduced dose, or severe effects at the starting dose, permanent 
treatment discontinuation should be considered.
Temporary treatment interruption is allowed to manage adverse events (see below for 
details).
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.
The criteria to be followed for treatment interruption, re-start and re-escalation are shown in 
Table 4.1.2: 2.
Table 4.1.2: 2 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.


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To manage diarrhoea and liver enzyme elevations guidelines similar to the adult programme 
are provided in the paediatric programme.

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 
antidiarrheal symptomatic treatment, e.g. loperamide.
If diarrhoea persists despite optimal symptomatic treatment, treatment interruption and/or 
dose reduction of nintedanib should be considered. Table 4.1.2: 3 shows the 
recommendations for children and adolescents with the appropriate age and weight-adjusted 
dosing.


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Table 4.1.2: 3 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 
4.1.2:4) 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 randomization.


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Table 4.1.2: 4
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

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 4.1.2: 5.


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Table 4.1.2: 5
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
Visit 2
(randomization)
Permanently 
discontinue
trial 
medication or 
justify 
continuation1
Permanently 
discontinue
trial medication 
Permanently 
discontinue
trial medication 
Permanently discontinue
trial medication 
Any other 
Visit
Continue as 
planned2
Reduce dose or 
interrupt trial 
medication3
Interrupt trial 
medication
Permanently discontinue
trial medication
CLINICAL 
EVALUATION OF 
HEPATIC INJURY5
Close 
observation4
After 2 weeks 
or any time 
later
Close 
observation4
After 2 weeks 
or any time 
later
<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
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 by using intermediate visit lab kit.


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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 with specific trial lab kits and sent to the central 
laboratory for analysis.

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).
4.1.3
Method of assigning patients to treatment groups
After the assessment of all in- and exclusion criteria, each eligible patient will be randomised 
to treatment groups according to a randomisation plan in a 2:1 ratio (nintedanib:placebo) at 
Visit 2 (i.e. at start of Part A) via Interactive Response Technology (IRT) stratified by age 
group (6 - <12 years; 12 - <18 years). Access to the codes will be controlled and 
documented. A validated randomisation software will be used to generate the randomisation. 
Technical and statistical features of the process of treatment allocation are described in 
Section 7.4.
After completion of 24 weeks of blinded treatment, at Visit 6 (i.e. at start of Part B) each 
patient will be assigned via IRT to open label treatment with nintedanib, until EoT or 
premature discontinuation.
4.1.4
Drug assignment and administration of doses for each patient
For the individual patient the start of treatment period is planned on the day of randomization
at Visit 2, and the end of treatment period is planned at the EoT visit; 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 by means 
of an IRT contact during scheduled clinic visits detailed in the Flow Chart.
The investigational product should only be dispensed to parents/caregiver(s) (or patients if 
applicable based on their maturity) if the patient was entered to the treatment phase of the 
study, during clinic visits as defined by protocol and by authorized personnel as documented 
in the “Trial Staff List”.
In the event of force majeure or other disrupting circumstances (e.g. pandemic, 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, 
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.


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Wallets each containing 84 capsules (25 mg), or 56 capsules (100 mg and 150 mg) will be 
dispensed to the patient, with sufficient coverage until the next dispensing visit. One reserve 
wallet will be dispensed at Visit 2 and at Visit 6 and replaced as needed (e.g. in case of dose 
change requiring unit strength change, or use-by-date before the date planned for the next 
clinic visit) thereafter. At Visit 6 any remaining wallet, including reserve, dispensed to the 
patient while the patient was taking part in the double-blind part of the study will be 
collected, and open label wallets will be dispensed.
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. Once smaller capsules have been assigned, IRT will not allow to switch back to 
bigger capsules.
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 following dose should be taken according to the protocol. 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 and instruct the patient and 
parent(s)/legal guardian on the number of capsules to be taken in the morning and in the 
evening until the next visit. Drug accountability will be completed carefully. Please refer to 
Section 6.2.2 for instructions.
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
The randomisation codes will be provided to bioanalytics for analysis purpose during conduct 
of the study to allow for the exclusion from the analyses of pharmacokinetic (PK) samples 


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taken from placebo patients. Bioanalytics will not disclose the randomisation code or the 
results of their measurements until DBL 1.
At DBL 1 the trial will be unblinded by the sponsor. 
In order to enable early analysis of PK, selected non-trial personnel from the sponsor 
involved in the PK analyses will be unblinded. The planned preliminary analyses will be 
conducted on a continuous basis and will focus purely on PK (no efficacy or safety outcomes 
will be analysed at that time). Available PK data will be provided to the SMC for 
consideration when evaluating the safety of the trial. Measures will be taken to ensure the 
integrity of the ongoing trial at the time of PK unblinding until the time of DBL 1. No 
individual unblinding information will be shared, however it could be communicated to the 
trial team how many patients with evaluable PK data are missing to reach the target. The 
process for unblinding as well as the trial team functions to be unblinded will be defined in 
the preliminary PK analysis logistics plan. In addition, a dedicated database snapshot (no 
partial DBL) will be generated after ‘last-patient-last-visit-primary-endpoint’ (LPLVPE) prior 
to DBL 1 to allow for development and refinement of exposure-response models (“Fast-
track” PK/PD analysis) referring to FVC and the most relevant safety variables (e.g. 
diarrhoea and liver enzyme elevations). Only personnel involved in the exposure-response 
analyses will be granted access to the unblinded data before DBL 1, whereas the trial team 
and all other functions not involved in the exposure response analyses will remain blinded.  
The analysis plan for the exposure-response analysis as well as the Trial Statistical Analysis 
Plan (TSAP) will be finalized and signed prior to the database snapshot for ‘fast-track PK/PD 
analyses’. No formal interim report will be generated. 
The SMC will review unblinded data. The independent statistician of the SMC will receive 
the randomization code to allow the required analyses on unblinded data. The independent 
statistician will ensure that all unblinded information remains within the SMC.
Patients, investigators and any other site personnel will remain blinded with regard to the 
randomised treatment assignments until after the final database lock (DBL 2).
For rules of breaking the code for an individual or for all patients in emergency situations see 
Section 4.1.5.2.
4.1.5.2
Unblinding and breaking the code
Emergency unblinding will be available to the investigator via IRT. In case the automated 
unblinding option via the IRT system is malfunctioning, the IRT service provider can be 
contacted (24 hours a day coverage) and the treatment allocation can be obtained. IRT 
support has direct access to the database and the treatment information can be manually 
obtained in case the automated process is not working properly. Details about this process 
will be included in the ISF.
Emergency unblinding must only be used in an emergency situation when the identity of the 
trial drug must be known to the investigator in order to provide appropriate medical treatment 
or otherwise assure safety of trial participants. The reason for unblinding must be 
documented in the source documents and/or appropriate CRF page.


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Due to the high unmet medical need and lack of therapeutic options, a patient which is 
unblinded during Part A may be given the option to continue the trial and receive active 
treatment (nintedanib) until the end of the study, if there are no safety concerns and after 
approval by the sponsor.
Due to the requirements to report Suspected Unexpected Serious Adverse Reactions 
(SUSARs), it may be necessary for a representative from BI’s Pharmacovigilance group to 
access the randomisation code for individual patients during trial conduct. The access to the 
code will only be given to authorised Pharmacovigilance representatives for processing in the 
PV database system and not be shared further. 
4.1.6
Packaging, labelling, and re-supply
The investigational medicinal products will be provided by BI or a designated Contract 
Research Organisation (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 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 Trial 
Manager (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
when the following requirements are fulfilled:

Approval of the clinical trial protocol by the Institutional Review Board (IRB) / Ethics 
Committee (EC),

Availability of a signed and dated clinical trial contract between the sponsor and the 
investigational site,

Approval/notification of the regulatory authority (RA), e.g. competent authority (CA),

Availability of the curriculum vitae of the Principal Investigator,

Availability of a signed and dated clinical trial protocol,

In countries where it is required, availability of the proof of a medical license for the 
Principal Investigator,

In the US, availability of FDA Form 1572.


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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 / 
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
There are no special emergency procedures to be followed, nor any specific requirements for 
handling of trial medication in case of emergency (e.g. no specific antidote to be given, no 
other particular medical intervention required in connection with overdose).
Treatment interruption and dose reduction should be considered to manage adverse events, as 
detailed in Section 4.1.2.
4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
As detailed in the exclusion criteria, 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).
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.


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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
Ketoconazol, cyclosporine A (or 
ciclosporin), boceprevir, clarithromycin, 
conivaptan, erythromycin, indinavir, 
itraconazole, lopinavir, mibefradil, 
nefazodone, nelfinavir, posaconazole, 
ritonavir, saquinavir, telaprevir, 
telithromycin, voriconazole.
NOT permitted:
stop at least 7 days prior to PK sampling 
day until respective PK sampling is 
completed
P-gp and CYP3A4 strong inducers
Avasimibe, carbamazepine, phenytoin, 
rifampin
NOT permitted:
stop at least 7 days prior to PK sampling 
day until respective PK sampling is 
completed
Products including St. John’s wort
NOT permitted:
stop at least 7 days prior to PK sampling 
day until respective PK sampling is 
completed
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, by using intermediate (a-visit) trial lab kit are recommended.
4.2.2.2
Restrictions on diet and life style
There are no restrictions 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 3.3.2) 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, 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.


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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 capsule counts, treatment compliance will be calculated as the number of capsules 
taken, divided by the number of capsules which should have been taken according to the 
scheduled period, multiplied by 100, as shown below. Compliance will be verified by the 
Clinical Research Associate (CRA) authorised by the sponsor.
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 and 
the parent(s)/legal guardian the importance of treatment compliance.


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5.
ASSESSMENTS
For the assessment of primary endpoints see Section 5.2 (assessment of safety) and Section 
5.3 (drug concentration measures and pharmacokinetics).
5.1
ASSESSMENT OF EFFICACY
This Section describes the assessment of secondary and further endpoints of efficacy.
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.
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). 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.
Further instructions regarding FVC measurements will be provided in the ISF.


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5.1.2
Assessment of SpO2
Oxygen saturation (SpO2) will be measured after minimum 5 minutes on room air by 
standard pulse oximetry at rest.
SpO2 with exertion will be measured during the 6MWT. See Section 5.1.6 for details.
A pulsoximeter and sensors suitable for the paediatric population should be used. Forehead
probe is recommended; if not available, earlobe and finger probe are also allowed; once 
chosen, the probe should be used consistently in the same patient.
Measurements will be recorded in source documents and transcribed into the CRF by 
designated site personnel.
5.1.3
Time to first respiratory-related hospitalization
Time to first respiratory-related hospitalization assessment will be based on the date of 
hospitalization collected on a specific hospitalization CRF page. The CRF page will capture 
whether the hospitalization was due to respiratory cause, and the primary admission 
diagnosis.
5.1.4
Time to first acute ILD exacerbation or death
Consistent with recent publication, acute exacerbation will be defined as significant 
worsening of the patient’s respiratory condition that necessitates a change in regular 
management, based on more than 2 of the following criteria over 4 weeks [R19-0805]:

Increase in respiratory rate ≥20% from baseline

Increase in or development of dyspnoea

Newly developing or increased abnormalities on chest imaging

Onset/increase of oxygen demand to attain the individual baseline saturation (at rest 
and/or during exercise)

Need for an additional level of ventilatory support (in addition to oxygen)

Decrease in spirometry in children able to perform the tests (≥10%) from baseline for 
vital capacity

Reduced exercise tolerance in children able to perform the tests (includes 
desaturation).
Events that are clinically considered to meet the definition of acute exacerbation but fail to 
meet the required criteria due to missing imaging data should be termed “suspected acute 
exacerbations”.
For the endpoints 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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5.1.5
Time to death
Time to death (all-cause mortality) will be based either on the date of death on the AE report 
for patients with AEs leading to death, or will be based on the information from the vital 
status assessment.
Analysis of time to death due to respiratory cause will be based on the adjudicated cause of 
death as determined by the Adjudication Committee (AC).
5.1.6
Six-minute walk test
Exercise capacity will be assessed conducting the 6-minute walk test (6MWT).
The 6MWT is a self-paced test of walking capacity. Patients are asked to walk as far as 
possible in 6 minutes along a flat corridor. The distance in metres is recorded. Standardised 
instructions and encouragement are commonly given during the test.
The 6MWT should be conducted as much as possible according to the methodology referred 
to in Appendix 10.5. 
The 6MWT exhibits good test-retest reliability; however, there is strong evidence of a 
learning effect. At visits when the 6MWT is requested (see Flow Chart for details) the 
6MWT will be conducted only once (not in duplicate). Training of site staff and patients 
before start of test at baseline (Visit 2) is important. Training materials and instructions will 
be provided in the ISF.
At visits when the 6MWT is requested the 6MWT should be preferably performed 
approximately at the same time of day to minimize intraday variability. Please refer to 
Section 6.2.2 for preferred order of completion of assessments during a clinic visit.
Prior to and at the end of the 6MWT, patients will be asked to rate their breathing discomfort 
and overall fatigue using the Borg CR-10 Scale® (see Appendix 10.6). During the test 
continuous pulse oximetry (SpO2) will be performed.
The distance covered in 6 minutes, possible premature discontinuations and oxygen use, 
oxygen saturation measured by SpO2, vital signs and symptoms of the patient will be 
recorded in the eCRF.
5.2
ASSESSMENT OF SAFETY
The primary and secondary endpoints of safety will be based on data at timepoints defined in 
Section 2.1.2 and Section 2.1.3. The 52 weeks time point will not be available for all patients, 
depending on the time of enrolment into the study. 


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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.
The results must be included in the source documents available at the site.
All abnormal findings at baseline will be recorded on the Baseline Condition CRF 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 CRF page.
5.2.1.1
Body weight
Measurement of body weight will be performed at the time points specified in the Flow 
Chart. 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.
Body weight measurements will be recorded in the source documents and transcribed into the 
CRF.
These measurements will be used to assess safety, and to assign the proper dose of trial 
medication at randomisation 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. 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.
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.
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 CRF.
These measurements will be used to assess safety and be periodically reviewed by the Safety 
Monitoring Committee.


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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. See also Appendix
10.4 for details.
The results must be included in the source documents available at the site.
All abnormal findings at baseline will be recorded on the Baseline Condition CRF 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 CRF page.
5.2.3
Safety laboratory parameters
Safety laboratory parameters to be assessed 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. 
Patients do not have to be fasted for the blood sampling for the safety laboratory. 
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
5.2.7.1.1).
In case the criteria for hepatic injury are fulfilled, a number of additional measures will be 
performed (please see Section 5.2.7.1.4 and the DILI Checklist provided in the electronic 
Data Capture (eDC) system. The amount of blood taken from the patient concerned will be 
increased due to this additional sampling.
The central laboratory will transfer the results of the analysis to the sponsor.


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Table 5.2.3: 1 
Safety laboratory tests at regular site visits
The laboratory tests at regular site visits will include:
Category
Laboratory test 
Haematology
Red blood cell count (RBC)
Haemoglobin (Hb)
Haematocrit (Hct)
Mean corpuscular volume
White blood cell count including differential count
Platelet count
Biochemistry 
Aspartate aminotransferase (AST)
Alanine transaminase (ALT)
Gamma-glutamyl transferase (GGT)
Alkaline phosphatase (ALK)
Creatine kinase (CK)
Lactate dehydrogenase (LDH)
Total protein
Total bilirubin
Creatinine
Glucose (non fasting, V1 and V2 only)
Uric acid
Thyroid stimulating hormone
ß-HCG (at all visits requiring blood sampling for laboratory tests until EoT–
in all and only female patients)*
Electrolytes
Sodium
Potassium
Calcium
Chloride
Inorganic phosphorus
Coagulation
International normalized ratio (INR)
Activated partial thromboplastin time (aPTT)
Prothrombin time (PT)
Urinalysis 
pH, glucose, erythrocytes, leukocytes, protein, nitrite (semi-quantitative 
measurements; -, +, ++, +++)
*Pregnancy test is required in all female patients every 4-6 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. Locally provided urine dipstick pregnancy tests will be dispensed for use 
between clinic visits starting from Visit 4. A urine dipstick pregnancy test will be conducted
at the Follow-up Visit (if acceptable) and test results will be documented in the patient’s 
records. In case of positive results, procedures defined in Section 5.2.7.2.3 should be 
followed.


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Table 5.2.3:2 
Safety laboratory tests at intermediate ‘a’-visits
The laboratory tests at intermediate ‘a’-visits will include:
Category
Laboratory test 
Biochemistry
Total protein, creatinine, electrolytes and liver function (AST, ALT, GGT, 
alkaline phosphatase, and total bilirubin)
Urinalysis 
pH, glucose, erythrocytes, leukocytes, protein, nitrite (semi-quantitative 
measurements; -, +, ++, +++)
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).
The samples may be collected at the office of a local doctor using trial specific lab kits that 
will be sent to a central laboratory for analyses. These kits will be provided to patients at 
study visits as applicable. 
A maximum total amount of approximately 38 mL blood will be taken for standard safety 
laboratory tests during the course of Part A. In Part B, a maximum total amount of 
approximately 44 mL blood will be taken for standard laboratory (this is based on a 76-week 
duration of Part B, but it might be less depending of the time the patient will stay in Part B).
Creatinine clearance will be calculated based on serum creatinine according to Schwartz 
formula [R10-0828, R11-4789] (see Appendix 10.2).
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.
Laboratory analysis will be done using central laboratory services. 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.
Details regarding centrifuge, processing, storage and shipment of samples will be determined 
by the central laboratory in accordance with the sponsor. The Investigators will be informed 
and instructed by the central laboratory and detailed documentation will be included in the 
ISF.


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5.2.4
Electrocardiogram
Resting 12 lead Electrocardiograms (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 (rate, rhythm and repolarization changes have to be 
evaluated, compared to previous tracings) 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.
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.
MRIs/x-rays of growth plates will be conducted in all patients who qualified for 
randomisation at baseline. Imaging follow-up will be conducted only in patients with open 
physes, at 3 months, 6 months, 9 months, 12 months after start of trial medication, and every 
6 months thereafter until end of the study or closure of physes.
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 a blinded external expert 
in radiology. In addition, all MRI/x-ray assessments and height measurements (see Section 
5.2.1.2) will be periodically reported to the Safety Monitoring Committee.
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 who qualified for randomisation to assess the potential severe/irreversible 
effects of nintedanib on teeth in the study population.


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Dental examination will be conducted at baseline. Follow-up will be conducted at 12 weeks, 
24 weeks, 36 weeks, 52 weeks after start of trial medication, and every 24 weeks thereafter
until end of the study.
A panoramic x-ray will be conducted at baseline. Dental imaging follow-up will be 
conducted at 24 weeks, 52 weeks after start of trial medication, and every 48 weeks thereafter 
until end of the study.
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.
Dental examination and imaging will be periodically reported to the Safety Monitoring 
Committee.
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.
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 or not considered related to the medicinal product.
The following should also be recorded as an AE in the CRF 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;


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Changes in vital signs, ECG, physical examination (including changes in standing 
and/or sitting height, changes in leg length) 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.
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 further 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 above.
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 
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.


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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 immediately stop the trial medication and be followed up according to 
the “DILI checklist” provided in the eDC system. The investigator is asked to collect 
requested information within 48 hours upon laboratory hepatic injury alert/notification.
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.
The intensity (severity) of diarrhoea adverse events should be classified and recorded in the 
CRF according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5
[R18-1357], Table 5.2.7.1.5: 1.


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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 whether there is a reasonable possibility of a 
causal relationship between the adverse event and the given study treatment, 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 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 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).
Of note, this criterion may not be applicable to events whose time course is prolonged 
despite removing the original trigger.


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
Additional arguments amongst those stated before, like 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 CRF(s) by the 
investigator:

From signing the informed consent onwards until the individual patient’s end of trial: 
all AEs (serious and non-serious) and all AESIs.

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 treatment related SAEs and trial 
treatment 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 (see Section 5.2.7.2.2), but not on the CRF.
Vital Status Data Collection
Patients who discontinue trial medication prematurely, whose parents/legal guardians 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 all deaths/fatal AEs regardless of relationship, and 
trial treatment related SAEs and trial treatment 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 immediately (within 24 hours) to the sponsor’s 
unique entry point (country specific reporting process will be provided 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 and send the BI SAE form.
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.


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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 Trials (Part B).
The ISF will contain the Pregnancy Monitoring Form for Clinical Trials (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 Trials 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

A blinded external expert in radiology will review all MRI/radiological assessments
(bone imaging).

A blinded external expert in paediatric dentistry will review all panoramic x-rays
(dental imaging).

An independent Safety Monitoring Committee (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.

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’.
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS
5.3.1
Assessment of pharmacokinetics
Pharmacokinetics will be one primary endpoint of this study. For this reason extensive PK 
sampling is planned, which is considered appropriate for the targeted age range of ≥6 years.
In exceptional cases of paediatric patients aged <12 years a sparse sampling approach should 
be applied; for details refer to the Flow Chart for PK blood sampling.
PK plasma sampling will be conducted at Visit 3 and Visit 7 at steady state, just before drug 
administration and 1h, 2h, 3h, 4h, 6h, 8h post-dose (see Flow Chart for PK blood sampling).


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In rare circumstances PK sampling might need to be repeated (e.g. blood samples not taken at 
required timepoint, wrong medication taken in the days before PK sampling or on the day of 
PK sampling, destroyed/lost sample during shipment). In such cases PK sampling will be 
repeated close before the end of treatment visit, to allow the maximum possible interval from 
the previous PK sampling.
Based on this PK sampling, the area under the plasma concentration-time curve at steady 
state (AUCτ,ss) and further PK parameters (see Section 2.2.2) will be calculated by non-
compartmental analyses. The pharmacokinetic parameters will be included in the clinical trial 
report. In addition, population pharmacokinetics analyses will be conducted to further 
characterize PK (see Section 7.2.6), which will be reported separately. 
5.3.2
Methods of sample collection
A detailed description of sample collection and handling is provided in the laboratory
manual. For quantification of drug plasma concentrations of nintedanib, venous blood will be 
collected using a pre-labelled potassium ethylenediamine-tetraacetic acid (EDTA) containing 
blood drawing tube. 
5.3.3
Analytical determinations
Nintedanib (in form of its free base BIBF 1120 BS) plasma concentrations will be determined 
by a validated assay based on liquid chromatography-tandem-mass spectrometry (LC-MS /
MS). The procedures and specifications of the analytical method are available at the 
bioanalytical site (Nuvisan GmbH & Co KG, Wegenerstraße 13, 89231 Neu-Ulm, Germany).
5.4
ASSESSMENT OF BIOMARKERS


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5.4.2
Pharmacogenomics biomarkers
n.a.
5.5
BIOBANKING
n.a.
5.6
OTHER ASSESSMENTS
5.6.1
Assessment of quality of life via PedsQL™
Health-related quality of life will be assessed using the PedsQL™ questionnaire [R19-0760].
The PedsQL™ questionnaires will be administered according to the PedsQL™ 
Administration GuidelinesSM (for questionnaires to be administered in the different age 
groups and the administration guidelines see Appendix 10.7).
The PedsQL™should be completed in a quiet area/room before the respondents complete 
any other health data forms and before they see the investigator.
Parents, Children (8-12 year-old) and Teens (>12 year-old) may self-administer the 
PedsQL™ targeted for their age group after introductory instructions from the administrator.  
If the administrator determines that the child or teen is unable to self-administer the 
PedsQL(e.g., due to illness, fatigue, reading difficulties), the PedsQLshould be read 
aloud to the child or teen.  For the Young Child (<8 year-old), the PedsQL™ should be 
administered by reading the instructions and each item to the young child word for word.
If during the trial a patient changes age group, then the questionnaire appropriate for that age 
group should be administered.


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If a patient has difficulty understanding the age-appropriate PedsQL, the preceding age 
group version may be administered to the patient (e.g., administering the Young Child (5-7) 
Self-Report version with the three faces response choices to an 8 year-old).  However, if a 
patient presents with severe cognitive impairments (as determined by the administrator), the 
PedsQLmay not be appropriate for that patient.  In such cases, only the Parent-Proxy 
Report should be administered to the patient’s parent.
The parent and the patient must complete the questionnaires independently of one another. 
Consulting with one another during the completion of the questionnaire should be 
discouraged.  The patient answering the questionnaire should be facing away from the parent.
The parent and the patient will be provided with a pen or pencil and a solid writing surface. If 
a table is not available, the participant should be provided with an item such as a clipboard.  
The administrator will remain nearby should questions or concerns arise.
If the patient or parent has a question about what an item means or how they should answer 
it, the administrator should not interpret the question for them, just repeat the item to them 
verbatim, ask them to answer the item according to what they think the question means and
choose the response that comes closest to how they feel. The patient and/or the parent has the 
option of not answering a question if they truly do not understand the question.
When the parent/patient returns the PedsQL™, the administrator will look it over, check to 
see that all answers have been completed and verify that no item has more than one response. 
If any responses are incomplete, illegible, or there are multiple responses for an item, the 
administrator will ask the parent or patient to indicate their response.
The responses will be transcribed into the CRF by designated site-personnel.
For further instructions and details see Appendix 10.7.
5.6.3
Patient’s acceptability of the investigational product based on the size and 
number of capsules
Acceptability is defined as the overall ability and willingness of the patient to use the 
medicinal product as intended.
In this study acceptability of the investigational product based on the size and number of 
capsules will be assessed.
The assessment of acceptability will be performed by the patient using the acceptability 
questionnaire for the patient. If the patient is considered not old enough per investigator 
judgment, the parent/caregiver can assist with completion of the questionnaire (see Appendix 
10.8 for details).


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In between study visits, the parent/legal guardian will be asked to record any failed or missed 
intake of medication (e.g. the patient did not swallow the medication, or doses were missed, 
etc.) and provide this documentation to the investigator at the next study visit. The 
parent/legal guardian will be instructed to inform the investigator immediately if two or more 
consecutive doses of trial medication are missed or not taken correctly.
Moreover, to collect the investigator / site staff impression about the patient’s acceptability of 
the study medication intake, the treatment acceptability questionnaire for the investigator or 
investigational site staff will be completed by the investigator / site staff (see Appendix 10.8
for details).
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 patient.
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.
DLCO will be measured at Visit 2 and corrected for haemoglobin (Hb) measured at Visit 1 (see 
Appendix 10.3 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.
The DLCO assessment should be performed after the FVC measurement.
5.6.5
Fan severity score
Physician reported Fan severity score [R09-5337] at Visit 2 will be used to determine 
eligibility of the patient. For instructions on how to assign the severity-of-illness score see 
Appendix 10.1.
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.
Fan score as an outcome measure will be calculated by the sponsor based on response to Borg
CR-10 scale® and oxygen saturation at rest and after 6-minute walk test. This will be further 
defined in TSAP.


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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 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 
research.


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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 parameters 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
The trial consists of a screening period (from informed consent to Visit 2), a treatment period 
divided into double blind Part A of 24 weeks (from Visit 2 to Visit 6) and open label Part B
of variable duration (from Visit 6 to EoT), and a follow-up period (from EoT to End of trial 
visit; this period is only for those patients who are not enrolled into the separate open label 
extension study).
If additional PK data are needed after DBL 1, patients meeting in-/exclusion criteria at Visit 2 
will be directly entered into Part B, and patients undergoing double blind treatment will be 
directly switched to Part B.
All study visits should be scheduled according to the visit schedule defined in the Flow Chart. 
Windows of ±3 days for Visits 3 to 7, ±7 days for the following visits are defined to 
accommodate scheduling problems.
All efforts should be made to perform all visits as requested.
If a delay is observed for a particular visit, the original calendar schedule should be kept for 
subsequent visits (delays should not accumulate).
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.
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. The morning 
dose at Visit 2, Visit 3, Visit 6 and Visit 7 should be taken at the site.

The pre-dose PK sampling (Visit 3 and Visit 7) should be conducted immediately 
before intake of the morning dose of trial medication; the post-dose PK sampling 
should be conducted 1h, 2h, 3h, 4h, 6h, 8h after the morning dose of trial medication.

Spirometric measurements should always be conducted at approximately the same 
time of the day, with reference to baseline measurement (Visit 2).
In the event of force majeure or other disruptive circumstances (e.g. pandemic) the 
investigational plan as per this clinical trial protocol may not be feasible at a site. With the 
consent of the patient’s parent(s)/legal guardian (and assent by the patient where applicable), 
sponsor and investigator may implement risk mitigation measures and modifications to CTP 
standard procedures which may include, but are not 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 


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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 the patient’s parent(s)/legal guardian (and in the patient information where 
applicable). The implementation of these measures will depend on consent from the patient’s 
parent(s)/legal guardian, operational feasibility, local law and regulations. If alternative 
procedures are 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
Trial procedures and observations will be completed at study visits according to the Flow 
Chart and instructions given in the Flow Chart footnotes as well as in Sections 6.2.1, 6.2.2,
6.2.3. Explanations of procedures and observations are given in Section 5.
Before start of each visit 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 patient during the visit.
6.2.1
Screening
Informed consent (before or at the latest at Visit1)

Informed consent (and assent where applicable) will be obtained before any procedure 
related to the study, including HRCT transfer to central review.

A preliminary check of in-/exclusion criteria is recommended at time of informed 
consent to avoid unnecessary wash-out procedures in non-eligible patients.
Upon obtaining informed consent:

Site personnel will perform a screening call/notification in IRT to register patient’s 
screening (date of call/notification will be automatically captured) and ensure timely 
availability of trial medication.

The patient will receive a trial identification card.

Patient and parent(s)/legal guardian will be instructed on procedures to be followed 
until the next study visit.

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), the HRCT can be performed for the 
purposes of participation in the trial provided the patient meets eligibility criteria that 
can be assessed at that timepoint.


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
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.
Visit 1 (Screening)
Observations and procedures:

If informed consent was not collected at a separate visit, obtaining informed consent 
(and assent where applicable) and the above listed procedures will be done prior to 
any further procedure at this visit.

If not done at a separate visit, site personnel will perform a screening call in IRT to 
register patient’s screening (date of call/notification will be automatically captured)
and ensure timely availability of trial medication.

Demographics will be recorded.

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.

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.

SpO2 measurement will be conducted on room air at rest.

FVC measurement will be conducted with the spirometer provided by the sponsor, 
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 (for 
details refer to Section 5.2.3 and instructions given in the ISF). Prior to blood draw a 
pre-assessment of all in-/exclusion criteria is highly recommended to avoid 
unnecessary blood draws.

HRCT will be done (if needed) and sent to central review by site personnel (if not 
done before).

Biopsy will be sent to central review by site personnel (if needed and not done 
before).

An interim check of in-/exclusion criteria will be done.

If the patient qualifies to enter the screening period, Visit 2 will be scheduled; patient 
and parent(s)/legal guardian will be instructed on procedures to be followed until the 
next visit.


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6.2.2
Treatment period
The following has to be ensured during trial visits according to the study Flow Chart:

The PedsQL™questionnaire must be always administered prior to any other 
procedures, and according to instructions given (see Section 5.6.1 and Appendix 
10.7).

Blood draw for laboratory tests must be performed prior to administration of trial 
medication (applicable to Visit 2 and Visit 6 only; for the timing of blood draws to be 
conducted at Visit 3 and Visit 7 please refer to the Flow Chart for PK blood 
sampling).

FVC measurements at all visits should be performed approximately at the same time 
of the day to reference time point at Visit 2.

Order of pulmonary function tests at Visit 2 must be:
1. FVC measurement with the spirometer provided, followed by patient’s rest
2. DLCO measurement with site’s own equipment.
Visit 2 (baseline)
For the conduct of Visit 2 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 creatinine measurements, have been provided and are available at 
the site.
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 randomization. The 
screening phase (from informed consent until Visit 2) must be no longer than 12 weeks.
Observations and procedures: 

PedsQL™ questionnaire will be administered prior to any other procedures and 
checked for completeness (see Section 5.6.1 and Appendix 10.7).

Adverse events, any ILD exacerbations, respiratory-related hospitalizations 
 
, and 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 timely entered 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.

SpO2 measurement will be conducted on room air at rest.

FVC measurement will be conducted according to procedures defined (see ISF for 
details).


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
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).

The 6-minute walk test including Borg CR-10 scale® and continuous pulse oximetry 
(SpO2) will be conducted per instructions given in Section 5.1.6.

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, randomization will be performed by using the IRT 
system.

The assigned trial medication will be administered at the site. Medication wallets will 
be dispensed, patients and parent(s)/legal guardian will be properly instructed about 
how and when the study medication should be taken until the next visit. The 
parent(s)/legal guardian (and the patient, where applicable based on the patient’s age) 
will be properly instructed to contact the site in case of adverse events (details given 
in the informed consent, and assent where applicable).

A PK diary card will be dispensed; the patient and 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 and parent(s)/legal guardian will be 
instructed on procedures to be followed until the next visit.

An MRI of epiphyseal growth plates will be conducted* in all patients who qualified 
for randomisation 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* in all patients who qualified for randomisation
according to protocol requirements (see Section 5.2.6), and evaluated at site.

Dental imaging will be conducted* in all patients who qualified for randomisation
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.
*If it’s not possible to conduct this procedure on the day of the visit, the procedure can be 
done in the 2 weeks immediately after the visit (please refer to the image acquisition 
guideline available in the ISF for details).
If by the end of Visit 2 the patient does not qualify for randomization, screening failure will 
be notified via IRT. Patient rescreening at a later date is possible. At due time a new informed 
consent (and assent where applicable) will be collected; site personnel will perform a re-
screening call/notification in IRT to register patient’s re-screening; the patient will be 
assigned a new patient number which will be linked to the original patient number, and 


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complete all study procedures according to Flow Chart. Re-screening of a previously screen 
failed patient will be permitted once.
Results of laboratory examination of samples collected at Visit 2 will become available only 
after Visit 2. Since laboratory results from Visit 2 cannot be used to assess patient’s 
eligibility, laboratory results from Visit 1 will be used instead. In case laboratory results of 
Visit 2 meet any exclusion criterion, the investigator must discuss the case with the sponsor, 
and obtain directions whether or not the patient should discontinue trial medication. The 
patient’s conditions and the decision taken should be properly documented, reason for 
continuation should be justified in writing by the investigator.
Visit 3 and Visit 7 (visits with extensive PK)
For the conduct of Visit 3 and Visit 7 extensive PK the following prerequisites must be met:

The patient has taken the trial medication in the three days preceding the visit as 
instructed.
If PK sampling needs to be repeated (see Flow Chart for PK blood sampling and Section 
5.3.1 for details), PK sampling will be repeated close before the end of treatment visit, to 
allow the maximum possible interval from the previous PK sampling.
Observations and procedures: 

The site personnel will check the PK diary card and confirm that the trial medication 
has been taken in the three days preceding the visit. If this is not confirmed, the visit 
will be rescheduled.

Criteria for dose reduction / interruption will be checked, if any.

The pre-dose PK sample will be taken immediately before drug administration, study 
medication will be administered, and post-dose PK samples will be taken at 
timepoints defined (see Flow Chart for PK blood sampling for details). Date and exact 
clock time of drug administration and blood sampling must be recorded in the eCRF. 

After administration of trial medication, the patient’s acceptability questionnaire will 
be administered (Visit 3 only).

Compliance will be checked and drug accountability will be completed (Visit 3 only; 
at Visit 7 drug accountability is to be completed only in case of dose reduction / 
increase).

Adverse events, any ILD exacerbations, respiratory-related hospitalizations 
 
, and concomitant therapy since last 
visit will be reviewed and recorded.

Physical examination including vital signs and weight (the latter Visit 3 only) will be 
performed; data will be recorded in source documents and transferred as instructed.

SpO2 measurement will be conducted on room air at rest.

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.


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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) (Visit 3 only).

The next visit will be scheduled; patient and parent(s)/legal guardian will be 
instructed on procedures to be followed until the next visit.
Visits 4, 5, 6, 8, 9, X (treatment period)
Observations and procedures: 

PedsQL™ questionnaire will be administered prior to any other procedures and 
checked for completeness (Visit 6 and Visit 9 only).

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 (females only, and not to 
be done at Visit 4) and confirm that since the last scheduled visit at the site the 
pregnancy test has been repeated every 4-6 weeks until the current visit. If not 
confirmed, the investigator will re-instruct the patient and 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.

Adverse events, any ILD exacerbations, respiratory-related hospitalizations 
 
 and 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 4; 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 (Visit 6, Visit 9 and every 24 weeks after the 
first year only).

SpO2 measurement will be conducted on room air at rest.

FVC measurement will be conducted according to procedures defined (see ISF for 
details).

The 6-minute walk test including Borg CR-10 scale® and continuous pulse oximetry 
(SpO2) will be conducted (Visit 6 and Visit 9 only).

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).

Visit 6 only: The first dose of the open label trial medication will be administered at 
the site.

Visit 6 only: The patient’s acceptability questionnaire will be administered.


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
Visit 6 only: a PK diary card will be dispensed; the patient and parent(s)/legal 
guardian will be instructed on how it should be completed in the 3 days before the 
next visit. If PK sampling needs to be repeated (see Flow Chart for PK blood 
sampling and Section 5.3.1 for details), the PK diary card will be dispensed during the 
visit before PK sampling, and the patient will be instructed as needed.

Urine dipstick pregnancy tests and a pregnancy test diary card will be dispensed
(females only); the patient and parent(s)/legal guardian will be instructed on how the 
test should be conducted, and the diary should be completed, until the next visit.

The next visit will be scheduled; patient and parent(s)/legal guardian will be 
instructed on procedures to be followed until the next visit. In preparation to Visit 6 
the patient and parent(s)/legal guardian will be instructed that on the day of this visit 
the morning dose of trial medication should not be taken before going to the site, 
because the morning dose will be taken during 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 - at 12 weeks, 24 weeks, 
36 weeks, 52 weeks and 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.

Follow-up dental examination will be conducted* in all patients at 12 weeks, 24 
weeks, 36 weeks, 52 weeks and every 24 weeks thereafter until the end of the study.

Follow-up dental imaging will be conducted* in all patients at 24 weeks, 52 weeks 
and every 48 weeks thereafter until the end of the study. Panoramic x-ray will be sent 
to central evaluation by paediatric dentistry expert on a timely manner.
*If it’s not possible to conduct this procedure on the day of the visit, the procedure can be 
done in the week immediately before or after the visit (please refer to the image
acquisition guideline available in the ISF for details).
End of Treatment Visit
Patients who discontinue trial treatment prematurely will undergo the End of Treatment 
(EoT) visit as soon as possible, and complete procedures defined (see Flow Chart and Section 
3.3.4). The first visit after the EoT visit will be skipped if the EoT visit occurs within 4 weeks 
prior to the scheduled visit.
Patients who did not discontinue trial treatment prematurely should undergo the EoT visit as 
soon as the timing of final DBL (DBL 2) and EoT visit has been communicated (see Section 
3.1 for details). If a regular study visit is scheduled in the period when the EoT visit should be 
conducted, all procedures required at this regular study visit and the additional procedures, if 
any, required at the EoT visit will be conducted during the same visit.
If the initiation of the open label extension trial is supported by the benefit-risk assessment 
from DBL 1, patients who completed the treatment period according to protocol will be 
offered participation in a separate open label extension trial. When the End of Treatment 
Visit is planned, the Investigator or delegated personnel should discuss with the patient and 


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the patient’s parent(s)/caregiver about recruitment into the open label extension trial. The 
discussion should be documented and the information will be collected via eCRF. A separate 
informed consent/assent for the participation in the open label extension trial will be collected 
as part on the open label extension trial procedures.
If the initiation of the open label extension trial is not supported, patients will complete the 
EoT visit and be asked to attend a follow-up visit (see Section 6.2.3 for details).
At the EoT visit the site personnel will perform a call in IRT to register patient’s end of 
treatment. Returned wallets will be collected as instructed (see ISF for details).
Dose reduction visit / dose increase visit
If a patient experiences a drug related adverse event, the dose can be reduced and the dose 
can be re-increased after recovery as described in Section 4.1.2. 
If the dose change does not occur in concomitance to a scheduled visit, the patient will attend 
an unscheduled visit at the site. 
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, any ILD exacerbations, respiratory-related hospitalizations 
 
 and 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.

New medication wallets will be assigned by using the IRT system and dispensed, 
returned wallets will be collected as instructed (see ISF for details).
Intermediate ‘a-Visits’
During the treatment period intermediate lab tests (“a”-Visits) for safety monitoring may be 
conducted, 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 will give the parent(s)/legal guardian (or the patient, depending 
on the age), 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.


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Intermediate pregnancy tests
During the treatment period and the follow-up period a pregnancy test must be conducted in 
all female patients every 4-6 weeks.
Pregnancy test will be conducted on blood collected at every visit until end of treatment.
Urine dipstick pregnancy test kits will be provided locally for use between visits when visit 
intervals are >6 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.
6.2.3
Follow-up period and trial completion
Follow-up Visit
A Follow-up Visit should be conducted 28 days (+3 days) after the end of treatment in all 
patients who are not enrolled into the separate open label extension trial. 
Observations and procedures: 

Adverse events, any ILD exacerbations, respiratory-related hospitalizations, and 
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 follow-up in case of clinically relevant 
changes at EoT, unless the patient is enrolled into the open label extension trial.

Pregnancy test on urines will be conducted in female patients only. Test results will 
be documented in the patient’s records.

Patient’s participation will be concluded for patients with withdrawn consent (and/or 
assent as applicable) and do not attend future visits.
Trial completion
The trial completion CRF page must be filled-in when the patient has terminated the trial. 
The end of the trial for the individual patient is:

For patients who have completed the study visits as scheduled and are enrolled into 
the separate open label extension trial, end of trial is at EoT.

For patients who have completed the study visits as scheduled and are NOT enrolled 
into the separate open label extension trial, end of trial is at the follow-up visit.

For patients who have NOT completed the study visits as scheduled and withdraw 
consent:
o
If consent withdrawal occurs at time of trial medication discontinuation, end of 
trial is at EoT visit followed by the follow-up visit.
o
If consent withdrawal occurs after EoT was already completed, then the patient 
should have a final visit based on their scheduled study visit.


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After completion of the trial, patients who are enrolled into the open label extension trial will 
have access to treatment with nintedanib.
Patients who prematurely discontinued trial medication
In case a patient has permanently discontinued trial medication, for whatever reason, at the 
End of Treatment visit the patient will be encouraged to attend all future visits (except ‘a-
Visits’) up to the end of trial as originally planned.
During these visits the patient will undergo the following observations and procedures:

PedsQL™ questionnaire will be administered prior to any other procedures and 
checked for completeness (Visit 6 and Visit 9 only).

Adverse events, any ILD exacerbations, respiratory-related hospitalizations 
 
 and concomitant therapy since last 
visit will be reviewed and recorded.

Physical examination including vital signs, weight, height, and leg length will be 
performed (height and leg length not planned at Visit 4; 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.

SpO2 measurement will be conducted on oom air at rest.

FVC measurement will be conducted according to procedures defined (see ISF for 
details).

The 6-minute walk test including Borg CR-10 scale® and continuous pulse oximetry 
(SpO2) will be conducted (Visit 6 and Visit 9 only).

The next visit will be scheduled; patient and parent(s)/legal guardian will be 
instructed on procedures to be followed until the next 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 - at 12 weeks, 24 weeks, 
36 weeks, 52 weeks and 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.

Follow-up dental examination will be conducted* in all patients at 12 weeks, 24 
weeks, 36 weeks, 52 weeks and every 24 weeks thereafter until the end of the study.

Follow-up dental imaging will be conducted* in all patients at 24 weeks, 52 weeks 
and every 48 weeks thereafter until the end of the study. Panoramic x-ray will be sent 
to central evaluation by paediatric dentistry expert on a timely manner.
*If it’s not possible to conduct this procedure on the day of the visit, the procedure can be 
done in the week immediately before or after the visit (please refer to the image
acquisition guideline available in the ISF for details).
These visits will be regarded as part of the trial despite the patient having discontinued trial 
medication.


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The need for coming to future visits in case of prematurely discontinuation of trial medication 
will be explained to patients and parent(s)/legal guardian prior to start of trial participation.
Vital status information
In case of premature discontinuation of trial medication, if the patient does not attend future 
visits as planned, every attempt will be made to get information on vital status at 24 weeks 
after randomization, i.e. at the time of data cut-off for the primary analysis, at 52 weeks and 
at the end of the trial.
Permission to further contacts by site personnel, e.g. by telephone calls, to allow collection of 
the vital status must be given in the informed consent.
Collection of vital status will be performed in accordance with national ethical and regulatory 
guidelines.
If death occurs, the investigator will review the circumstances, including the relevant medical 
records, to ascertain the most likely primary and secondary causes of death. The cause of 
death will be adjudicated by the AC.


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7.
STATISTICAL METHODS AND DETERMINATION OF 
SAMPLE SIZE
The main objective will be assessed by calculating descriptive statistics for safety endpoints 
and by exploratory PK analyses. The PK, safety and efficacy endpoints as well as other 
assessments as stated in Section 5, will be compared between the treatment groups using 
descriptive statistics.
7.1
NULL AND ALTERNATIVE HYPOTHESES
No confirmatory testing is performed and hence no null and alternative hypotheses are 
defined. A justification of the sample size is provided in Section 7.5. 
Any confidence intervals computed are to be interpreted in the perspective of the exploratory 
character of the study; i.e., confidence intervals are considered as interval estimates for 
effects.
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 are randomised to a treatment group 
and receive at least one dose of study medication.

Per Protocol Set (PPS):
The Per Protocol Set (PPS) will consist of patients from TS considering exclusion 
from the set based on important protocol deviations.

Pharmacokinetic Parameter Analysis Set (PKS):
The Pharmacokinetic Parameter Analysis Set (PKS) includes all patients in the 
Treated Set (TS) who provide at least one PK endpoint that was not excluded due to a 
protocol deviation relevant to the evaluation of PK or due to PK non-evaluability (as 
specified in the following subsection ‘Pharmacokinetics’). Thus, a patient will be 
included in the PKS, even if he/she contributes only one PK parameter value for one 
period to the statistical assessment.
Descriptive and model based analyses of PK parameters will be based on the PKS. All other 
analyses will be based on the TS. 
Pharmacokinetics:
The pharmacokinetic parameters listed in Section 2.1 and Section 2.2 for nintedanib will be 
calculated using Phoenix WinNonlinTM software (version 6.3 or higher, 
 
) or SAS® Version 9.4 (or later version) by means of noncompartmental 
analysis and according to the relevant SOP of the sponsor.


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Plasma concentration data and parameters of a subject will be included in the PK analyses, if 
they are not flagged for exclusion due to a protocol deviation relevant to the evaluation of PK 
(to be decided no later than in the Blinded Report Planning Meeting) or due to PK non-
evaluability (as revealed during data analysis, based on the criteria specified below). 
Exclusion of a subject’s data will be documented in the CTR.
Patients who are considered as not evaluable will be listed with their individual plasma 
concentrations and individual pharmacokinetic parameters. However they will not be 
included in descriptive statistics for plasma concentrations, pharmacokinetic parameters or 
other statistical assessment apart from safety evaluation.
Plasma concentrations will be plotted graphically versus time for all patients as listed in the
drug plasma concentration-time tables. Only concentrations within the validated 
concentration range and actual sampling-times will be used for the calculation of 
pharmacokinetic parameters. For the presentation of the mean profiles, the arithmetic mean 
and the planned blood sampling times will be used.
Handling and derivation of pharmacokinetic parameters will be done according to BI 
standards.
The following descriptive statistics will be calculated for analyte concentrations as well as for
all pharmacokinetic parameters: N, arithmetic mean, standard deviation, minimum, median,
maximum, arithmetic coefficient of variation, geometric mean and geometric coefficient of
variation. The data format for descriptive statistics of concentrations will be identical with the
data format of the respective concentrations (i.e. three significant digits). The descriptive
statistics of pharmacokinetic parameters will be calculated using the individual values with
the number of decimal places as provided by the evaluation program. Then the individual
values as well as the descriptive statistics will be reported with three significant digits in the
clinical trial report.
Adherence to the protocol will be assessed by the trial team. Important protocol deviation
(IPD) categories will be suggested in the integrated Quality and Risk Management Plan 
(IQRMP). IPDs will be identified no later than in the Report Planning Meeting, and the IPD 
categories will be updated as needed.
All analyses will be based on the actual treatment group. Details will be specified in the 
TSAP.
Patients without any post-randomization data will be handled as missing for the respective 
endpoints and assessments (see Section 7.3).
Handling of anticipated problems (e.g. planned data transformations based on the expected 
distributional characteristics or convergence of the mixed models) will be addressed in the 
TSAP.


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7.2.2
Primary endpoint analyses
For the primary PK analysis, the area under the plasma concentration-time curve at steady 
state (AUCτ,ss) will be calculated by non-compartmental as well as compartmental analysis
and descriptive statistics will be provided as detailed in Section 7.2.1.
For patients receiving nintedanib in Part A, PK profiles on week 2 and week 26 are planned 
to be collected. For the primary endpoint AUCτ,ss the AUCτ,ss at week 2 will be used. If the 
week 2 value is missing, then it will be replaced by available AUCτ,ss at week 26. For 
patients receiving placebo in Part A and nintedanib in Part B, AUCτ,ss evaluated based on 
PK profiles at week 26 will be used (which corresponds to week 2 on active treatment).
Further details on the PK analysis will be specified in the TSAP.
The primary safety endpoint listed in Section 2.1.2 will be derived according to BI standards. 
For the primary analysis, only treatment emergent AEs during the double-blind period until 
week 24 will be included. The analysis will be based on the TS and will be descriptive in 
nature.
Subgroup analyses will be specified in the TSAP.
7.2.3
Secondary endpoint analyses
Analysis of secondary endpoints listed in Section 2.1.3 will be descriptive in nature using a 
mixed model with repeated measurements (MMRM) for continuous endpoints. Time-to-event 
endpoints will be displayed descriptively using the Kaplan-Meier method. Categorical 
endpoints, safety and tolerability will be displayed descriptively in frequency tables. Further 
details will be provided in the TSAP.
7.2.5
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 
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’.


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As this study consists of a double-blind, placebo-controlled part (Part A) and an open-label 
part (Part B), two treatment periods will be used for analysis and definition of ‘treatment-
emergent’:
1. Double-blind period: Only adverse events assigned to the on-treatment period with 
onset during the double-blind period will be considered for the analysis.
2. Whole-trial period: All adverse events assigned to the on-treatment period will be 
considered for the analysis.
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. Treatment 
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.
7.2.7
Interim Analyses
No interim analysis is planned, but a SMC will be in place with tasks as described in Section 
8.7.
Furthermore, the study will include two database locks (DBL 1 and DBL 2). The first DBL 
will be announced once 30 patients (at least 20 adolescents aged 12-17 years, and if feasible 
at least 10 children aged 6-11 years) have completed PK sampling at 26 weeks, or 
prematurely discontinued the trial (last-patient-last-visit-primary-endpoint). At this timepoint 
patient recruitment will close. Based on the data from DBL 1 (or updated DBL 1 data once 
the number of patients with sufficient PK data has been reached), the primary analysis and a 
benefit-risk assessment will be done and the clinical trial report for the primary analysis will 


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be written. If PK data collected for the primary analysis are not sufficient, then further PK 
data will be collected as explained in Section 3.1.
The timing of final DBL (DBL 2) and EoT visit will be communicated after confirming 
adequacy of PK data from DBL 1 (or updated DBL 1 data). Please see Section 3.1 for further 
details.
Moreover, the primary analysis may be conducted while the data collection for selected other 
analyses is still ongoing.
7.3
HANDLING OF MISSING DATA
In general, missing data will not be imputed.
Missing or incomplete AE onset and end dates are imputed according to BI standards.
The mixed effect model will handle missing data based on a likelihood method under the 
"missing at random assumption".
In the analysis of time-to-event endpoints, missing or incomplete data will be handled using
standard survival analysis techniques (i.e. censoring).
In the analyses of the binary endpoints, multiple imputation will be used to handle missing 
data at week 24. For week 52 and later, data will not be imputed and only observed values 
will be used. 
For pharmacokinetics:
Handling of missing PK data will be performed according to BI standards. For the non-
compartmental analysis, concentration data identified with NOS (no sample), NOR (no valid 
result), NOA (not analysed) will generally not be considered. Concentration values in the lag 
phase identified as BLQ or NOP will be set to zero. All other BLQ (below the limit of 
quantification), and NOP (no peak detectable) values of the profile will be ignored. The lag 
phase is defined as the period between time zero and the first time point with a concentration 
above the quantification limit.
7.4
RANDOMISATION
Patients will be randomised to each treatment group with an approximate ratio of 2:1
(nintedanib:placebo) stratified by age group (6 - <12 years; 12 - <18 years). BI will arrange 
for the randomisation and the packaging and labelling of trial medication. The randomisation 
list will be generated using a validated system, which involves a pseudo-random number 
generator so that the resulting treatment will be both reproducible and non-predictable. The 
block size will be documented in the CTR. Access to the codes will be controlled and 
documented.
7.5
DETERMINATION OF SAMPLE SIZE
For the primary evaluation of PK including the assessment on whether nintedanib exposure at 
steady-state (AUCτ,ss) in paediatric patients is comparable to adult exposure, the clearance 


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parameter needs to be estimated with adequate precision. Assuming a coefficient of variation 
(CV) of 70.8% (based on geometric CV [gCV] of apparent clearance at steady-state [CL/Fss] 
after extravascular administration observed in the PK meta-analysis [U11-1639-01]), at least 
20 actively treated patients with available PK measurements per age group (6 - <12 years; 12 
- <18 years) would be needed to achieve at least 80% probability (loosely referred to as 
power in this context [R12-0884]) of having the 95% CI of nintedanib CL/Fss and with this 
AUCτ,ss within 60% and 140% of the geometric mean estimate. This calculation was 
performed as described by Wang et al. [R12-0884] using R Version 3.5.1.
Table 7.5: 1 provides an overview of the achievable probability of having the 95% CI of 
nintedanib CL/Fss and with this AUCτ,ss within 60% and 140% of the geometric mean 
estimate.


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Table 7.5: 1 Probability that can be expected of having the 95% CI of nintedanib CL/Fss and 
with this AUCτ,ss within 60% and 140% of the geometric mean estimate.
gCV [%]
Sample Size
Probability [%]
60
16
80.60
60
18
91.20
60
20
96.82
60
22
99.10
60
24
99.81
70.8
16
52.82
70.8
18
68.03
70.8
20
81.03
70.8
22
90.32
70.8
24
95.82
80
16
32.78
80
18
45.71
80
20
59.64
80
22
72.81
80
24
83.63
Based on the inclusion criteria of the proposed study and preliminary feasibility assessment, 
it is anticipated that the study will only be powered for patients with ≥12 years of age. PK 
parameters in children <12 years will be collected and analysed but are expected to be limited 
due to expected small number of patients falling in that age range.
To further optimise PK assessment from the study population, on-treatment PK sampling is 
planned in those assigned to placebo after switching to active treatment. By this, 30 
randomized paediatric patients have the possibility to contribute for the PK assessment at the 
time of primary analysis. This increases the sample size for the PK analysis.
The target sample size of a minimum of 30 patients is based on the sample size estimation for 
the evaluation of the primary endpoint of PK and trial feasibility evaluation. Although the 
planned basket approach makes it feasible to evaluate this extremely rare patient population, 
one of the limitations of this approach is the heterogeneity of the study populations, 
especially in evaluating efficacy outcomes of potential interest (e.g. lung function). Due to 
the high unmet medical need, lack of therapeutic options and the potential for more robust 
efficacy evaluation, patient recruitment into the treatment phase will remain open until 30 
patients (at least 20 adolescents aged 12-17 years, and if feasible at least 10 children aged 6-
11 years) have completed PK sampling at 26 weeks, or prematurely discontinued the trial. 
This will allow for any eligible patient identified beyond the target (i.e. 30 subjects 
randomized including at least 20 adolescents aged 12-17 years) to have access to study drug.  
Although the duration of the blinded treatment period (Part A) will be variable in some of 
these patients, all PK and clinical data collected will be used in the primary analysis to allow 
for more robust estimate of exposure and potential treatment effect.


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8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY, AND
ADMINISTRATIVE STRUCTURE
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 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
patient’s legally accepted representative (and written informed assent must be obtained from 
the patient, where applicable) according to ICH-GCP and to the regulatory and legal 
requirements of the participating country. Each signature must be personally dated by each 
signatory and the informed consent (and assent where applicable) and any additional parental
information form (and patient information form where applicable) retained by the 
investigator as part of the trial records. A signed copy of the informed consent (and assent 
where applicable) and any additional parental information (and patient information where 
applicable) must be given to the patient’s legally accepted representative (and the patient, 
where applicable).
The patient and the patient’s legally accepted representative must be given sufficient time to 
consider participation in the trial. The investigator or delegate obtains written consent of the 
patient’s legally accepted representative own free will with the informed consent form after 
confirming that the representative understands the contents. Moreover, where applicable, the 
investigator or delegate obtains written assent of the patient’s own free will with the informed 


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assent form after confirming that the patient understands the contents. The investigator or 
 
delegate must sign (or place a seal on) and date the informed consent form (and the informed 
assent form where 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 (and the 
informed assent where applicable).
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 (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 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 (and assent where applicable) documentation of this clinical trial.
8.3
RECORDS
CRFs for individual patients will be provided by the sponsor. See Section 4.1.5.2 for rules 
about emergency code breaks. 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 trail).
Data reported on the CRF 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 


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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 CRF

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, PK analyses, 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. 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 eCRF all data need to be derived from source documents, which need to be available on-
site, for example:

Patient identification: gender, year of birth (in accordance with local laws and 
regulations)

Patient participation in the trial (substance, trial number, patient number, date patient
and 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

Medical history (including trial indication and concomitant diseases)

Medication history

Adverse 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 


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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.
* For adverse events, an end date may not always be available (e.g. due to hospital discharge 
and later recovery, or change in treating physician), but should be recorded in the source if 
known.
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
(including PedsQL™ and 6MWT)

laboratory print-outs

biopsy slides including any reading by the pathology expert

originals or copies of HRCT scans including any reading by the thoracic radiology 
expert

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

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 CRF 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 CRFs and informed consents (and assents where 
applicable). The accuracy of the data will be verified by direct comparison with the source 
documents described in Section 8.3.1 The sponsor will also monitor compliance with the 
protocol and GCP.
In the event of force majeure or other disrupting circumstances (e.g. pandemic, 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 sites:
The trial sites 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:


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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, storage and 
future use of biological samples and clinical data, in particular

Sample and data usage has to be in accordance with the informed consent

The BI-internal facilities storing biological samples from clinical trial participants as 
well as the external banking facility are qualified for the storage of biological samples 
collected in clinical trials

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

Samples and/or data may be transferred to third parties and other countries as 
specified in the 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 assent (where applicable, and) has informed consent signed by parent(s) / legal 
guardian.
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 


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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 
(HA) 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 six 
months 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 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. Relevant 
documentation on all participating (Principal) Investigators and other important study 
personnel, including their curricula vitae, will be filed in Investigator Site File (ISF).
A blinded external expert in thoracic radiology will review HRCT scans and confirm 
evidence of fibrosing ILD to the Investigator. Tasks and responsibilities are defined in a 
contract.
A blinded external pathology expert will review biopsies 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 the external expert and images will be provided to the SMC for the 
evaluation of potential effects on bone development. Tasks and responsibilities are defined in 
a contract.
A blinded external expert in paediatric dentistry will review panoramic x-rays. Review by the
external expert and images will be provided to the SMC for the evaluation of potential effects 
on teeth. Tasks and responsibilities are defined in a contract.
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 


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for all patients evaluated for study participation at Visit 1. Members of the committee will be 
blinded to patient screening outcome as well as patient treatment allocation.  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. 
A SMC composed of external experts independent from the trial and selected BI non-trial 
team members will be established to review individual and aggregated PK 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 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.
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).
A Steering Committee will provide scientific advice on the clinical development program of 
nintedanib in the paediatric population. Tasks and responsibilities are defined in a contract.
Relevant documentation on the participating (Principal) Investigators (e.g. their curricula 
vitae) will be filed in the ISF. The investigators will have access to the BI clinical trial portal 
(Clinergize) to facilitate document exchange and maintain electronic ISF. 
BI has appointed a Clinical Trial Leader (CT 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.
The organisation of the trial in the participating countries 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) with which the 
responsibilities and tasks will have been agreed and a written contract filed before initiation 
of the clinical trial.
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.


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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 and Central 
Laboratory / Spirometry / Imaging Manual, available in the ISF.


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9.
REFERENCES
9.1
PUBLISHED REFERENCES
P04-08733
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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.
P06-05020
King TE Jr, Tooze JA, Schwarz MI, Brown KR, Cherniack RM. 
Predicting survival in idiopathic pulmonary fibrosis: scoring system and 
survival model. Am. J Respir Crit Care Med. 2001. 164(17): 1171-1181.
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.
P11-07084
Raghu G, Collard HR, Egan JJ, Martinez FJ, Behr J, Brown KK, et al. An 
officialATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: 
evidence-based guidelines for diagnosis and management. Am J Respir 
Crit Care Med. 2011. 183(6): 788-824.
P12-09611
du Bois RM, Weycker D, Albera C, Bradford WZ, Costabel U, Kartashov 
A, et al. Forced vital capacity in patients with idiopathic pulmonary 
fibrosis: test properties and minimal clinically important difference. Am J 
Respir Crit Care Med. 2011. 184(12): 1382-1389.
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.
P14-07514
Richeldi L, et al, INPULSIS Trial Investigators. Efficacy and safety of 
nintedanib in idiopathic pulmonary fibrosis. New England Journal of 
Medicine, published on May 18, 2014, doi: 10.1056/NEJMoa1402584. N 
Engl J Med. 2014. 370(22): 2071-2082.
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.


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behalf of the ERS Global Lung Function Initiative. Multi-ethnic reference 
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Lynch DA, Godwin JD, Safrin S, Starko KM, Hormel P, Brown KK, et al. 
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Incidence and classification of pediatric diffuse parenchymal lung diseases 
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Kim A, Dombi E, Solomon J, Fox E, Balis FM, Widemann BC. 
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resonance imaging for monitoring skeletal toxicity in children treated on 
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9.2
UNPUBLISHED REFERENCES
U07-1710
 Internal report. 07B002. 28 
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.
U11-1639-01
 Metaanalysis of noncompartmental pharmacokinetic 
parameters, influence of covariates, and exploratory PK/AE investigations 
across BIBF 1120 monotherapy Phase I studies in oncology patients. 
Study numbers 1199.1, 1199_PK Metaa. Cancer Pat. Mono.,1199.19, 
1199.3, 1199.2. 10 June 2011.
U13-1478-01
 Relative 
bioavailability of a single oral dose of nintedanib given alone and in 


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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.
c01783972-16
Investigator's Brochure Nintedanib (BIBF 1120), Indications: Idiopathic 
Pulmonary Fibrosis, Systemic Sclerosis, Progressive Fibrosing Interstitial 
Lung Disease. Version 18, 16 December 2020.


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10.
APPENDICES
10.1
FAN SEVERITY SCORE
The severity-of-illness score assigned by the investigator at Visit 2 will be based on 
information in the patient records at the time of initial evaluation [R09-5337]. Refer to Table 
10.1: 1 for details.
Table 10.1: 1
Severity-of-illness score


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10.2
CREATININE CLEARANCE
Calculation of creatinine clearance according to Schwartz Formula [R10-0828]
Conventional:

in adolescent males k=0.70:
GFR (mL/min./1.73m2) = height (cm) x 0.70 / serum creatinine (mg/dL)

in adolescent females k=0.55:
GFR (mL/min./1.73m2) = height (cm) x 0.55 / serum creatinine (mg/dL)
SI:

in adolescent males k=0.70:
GFR (mL/min./1.73m2) = height (cm) x 0.70 / (serum creatinine (µmol/L) x 0.01131)

in adolescent females k=0.55:
GFR (mL/min./1.73m2) = height (cm) x 0.55 / (serum creatinine (µmol/L) x 0.01131)
Calculation of creatinine clearance according to Schwartz Formula [R11-4789]
Conventional:

in children 2-12 years of age k=0.41:
GFR (mL/min/1.73m2) = height (cm) x 0.41 / serum creatinine (mg/dL)
SI:

in children 2-12 years of age k=0.41:
GFR (mL/min/1.73m2) = height (cm) x 0.41 / (serum creatinine (µmol/L) x 0.01131)


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10.3
EQUATIONS FOR DLCO ADJUSTMENT FOR HAEMOGLOBIN
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)

In children <15 years of age and females
DLCO predicted corrected for Hb = DLCO predicted x (1.7Hb)/(9.38+Hb)


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10.4
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 10.4: 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 10.4: 2
Predicted equations for Blood Pressure: white boys aged 1-10 years 
(from [P04-08733])


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Table 10.4: 3
Predicted equations for Blood Pressure: white boys aged 11-17 years 
(from [P04-08733])


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Table 10.4: 4
Predicted equations for Blood Pressure: white girls aged 1- 10 years 
(from [P04-08733])


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Table 10.4: 5
Predicted equations for Blood Pressure: white girls aged 11- 17 years 
(from [P04-08733])


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10.5
SIX-MINUTE WALK TEST
The methodology of the six-minute walk test is based on the ATS/ERS Technical Standards 
on the 6-minute walk test [R17-3628]. Instructions will be provided in the ISF.


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10.6
BORG CR-10 SCALE
Instructions will be provided in the ISF.


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10.7
PEDSQL


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PedsQL™ Administration GuidelinesSM
The following guidelines are intended for use by individuals trained in the administration of 
standardized questionnaires.  The PedsQL™ administrator is crucial in developing rapport 
with the respondents, emphasizing the importance of the questionnaire, addressing concerns, 
and ensuring that the PedsQL™ is completed accurately and confidentially.  
General Protocol
1. Create a procedure for assigning identification numbers that will allow for parent/child 
comparisons as well as comparisons of baseline/follow-up data.
2. If feasible, the PedsQL™should be completed before the respondents complete any other 
health data forms and before they see their physician or healthcare provider.
3. The parent/child should first complete the PedsQL™ Generic Core Scales and then 
complete any additional PedsQL™Module.
4. Parents, Children (8-12) and Teens (13-18) may self-administer the PedsQL™ after 
introductory instructions from the administrator.  If the administrator determines that the 
child or teen is unable to self-administer the PedsQL(e.g., due to illness, fatigue, 
reading difficulties), the PedsQLshould be read aloud to the child or teen.  For the 
Young Child (5-7), the PedsQL™ should be administered by reading the instructions and 
each item to the young child word for word.  At the beginning of each subscale repeat the 
recall interval instructions (one month or 7 days) to remind the young child to respond 
only for that specific recall interval.  Use the separate page with the three faces response 
choices to help the young child understand how to answer.  When reading items aloud to 
a child, intonation should be kept neutral to avoid suggesting an answer.
5. If a child has difficulty understanding the age-appropriate PedsQL, the preceding age 
group version may be administered to the child (e.g., administering the Young Child (5-7) 
Self-Report version with the three faces response choices to an 8 year old).  However, if a 
child presents with severe cognitive impairments (as determined by the administrator), the
PedsQLmay not be appropriate for that child.  In such cases, only the Parent-Proxy 
Report should be administered to the child’s parent.
6. The parent and child must complete the questionnaires independently of one another. 
Discourage the parent, child, or other family members from consulting with one another 
during the completion of the questionnaire.  Let them know that they can feel free to 
discuss their answers following completion of the questionnaires, but that it is important 
to get both the parent’s and the child’s individual perspectives.  If you are administering 
the questionnaire to the child, the child should be facing away from the parent.
7. If the child or parent has a question about what an item means or how they should answer 
it, do not interpret the question for them.  Repeat the item to them verbatim.  Ask them to 
answer the item according to what they think the question means.  If they have trouble 
deciding on an answer, ask them to choose the response that comes closest to how they 
feel. The child and/or the parent has the option of not answering a question if they truly 
do not understand the question. 
8. If a parent/child asks you to interpret the responses, tell her/him that you are not trained to 
interpret or provide a score for the answers given.  If the PedsQL™ is being used for a 


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clinical study, let the parent/child know that their answers will be combined with other 
participants’ answers and analysed as a group rather than as individual respondents.
9.   Document all reasons for refusals and non-completions of the PedsQL™.
Administering the PedsQL™
1. The following scripts have been developed as a guide to introduce the PedsQL™ to the 
child and his/her parent(s).  Modify the language to a style that is most appropriate for 
you and the respondent.
For the child:
The PedsQL™ asks you questions about how you feel and what you think about your 
health.  It is not a test, and there are no right or wrong answers.  It takes about 5 
minutes to complete.   If you have any questions, please let me know.
For the parent:
The PedsQL™ is a questionnaire that assesses health-related quality of life in 
children and adolescents.  It contains questions about your child’s physical, 
emotional, social, and school functioning in the past one month (or for the Acute 
version, in the past 7 days).  
The PedsQL™ is brief and typically takes less than 5 minutes to complete.  It is not a 
test, and there are no right or wrong answers.  Please be sure to read the instructions 
carefully and choose the response that is the closest to how you truly feel.  Please do 
not compare your answers with your child's responses.  We are interested in your and 
your child’s individual perspectives.  However, feel free to discuss the questionnaire 
with your child after you have both completed it and returned it to me.  If you have 
any questions, please let me know.
2. Provide the respondent with a pen or pencil and a solid writing surface.  If a table is not 
available, the participant should be provided with an item such as a clipboard.  Remain 
nearby should questions or concerns arise.
3. When the parent/child returns the PedsQL™, look it over and check to see that all 
answers have been completed.  Verify that no item has more than one response.  If any 
responses are incomplete, illegible, or there are multiple responses for an item, please ask 
the parent or child to indicate their response.  
4. Ask the participants if they had any difficulties completing the questionnaire or if they 
have any other comments regarding the questionnaire.  Document any important 
feedback.
5. Thank the parent and child for taking the time to complete the questionnaire.  If the study 
design involves following up with these respondents, let them know that they may be 
asked to complete the PedsQL™ again at another time.  Indicate when they can expect to 
be contacted again if known.
Copyright 1998 JW Varni, PhD. All rights reserved.


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10.8
ACCEPTABILITY QUESTIONNAIRES
The assessment of acceptability of the investigational product based on the size and number 
of capsules will be performed by the patient using the acceptability questionnaire for the 
patient. If the patient is considered not old enough per investigator judgment, the 
parent/caregiver can assist with completion of the questionnaire.
Section to be completed before administration of the questionnaire
PATIENT NO.: …………
DATE OF COMPLETION:  DD-MMM-YYYY
SIZE OF CAPSULES TAKEN DAILY:             150 MG, OR            100 MG, OR             25 MG
For 25 MG capsules ONLY
NUMBER OF CAPSULES TAKEN:  IN THE MORNING ___________      
NUMBER OF CAPSULES TAKEN: IN THE EVENING  ___________


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Acceptability questionnaire for the patient
We would like to learn about your impression of the study capsules.
Please take some time to answer the following questions. 
For each question, please choose only the best applicable response.
QUESTION 1: HOW DOES IT FEEL WHEN YOU TAKE CAPSULES?
   Very bad 
Bad
         Ok           Good    Very good
QUESTION 2: WAS TAKING THE STUDY CAPSULES (CHOOSE ONE OPTION):

Very easy

Easy

Neither easy nor difficult

Somewhat difficult 

Very difficult  
QUESTION 3: HOW IS THE SIZE OF THE CAPSULE?
OK (= acceptable)
Large
Very large
QUESTION 4: HOW EASY WAS TO SWALLOW THE GIVEN NUMBER OF CAPSULES? (CAPSULES 
SHOULD BE TAKEN WITH A GLASS OF WATER)
I had no problem swallowing them (= acceptable)
I swallowed them, but it was difficult
I couldn’t swallow them sometimes
QUESTION 5: COULD YOU TAKE THIS MEDICATION FOR A LONGER TIME PERIOD?
yes
no
Acceptability Questionnaire (Patient)
Version 1.0 22 May 2019


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Treatment acceptability questionnaire for the investigator or investigational site staff
Instructions:
For each question, please choose the response that most closely corresponds to this patient at 
the given time-point. Please consult the patient and his/her parents/caregiver if needed to 
answer the following questions:
QUESTION 1: WHAT IS YOUR IMPRESSION ABOUT THE PATIENT’S ACCEPTABILITY OF 
STUDY MEDICATION INTAKE? (CHOOSE ONE OPTION)

Good

Satisfactory

Mediocre

Bad

Not assessable
QUESTION 2: STUDY MEDICATION INTAKE WAS POSSIBLE (CHOOSE ONE OPTION):

Possible all the time

Very often possible

Occasionally not possible

Often not possible

Not assessable
QUESTION 3:  IF THE DRUG WAS NOT TAKEN, WAS THIS DUE TO:
(CHECK ALL ANSWERS THAT YOU CONSIDER APPLICABLE FOR THIS PATIENT AT THIS POINT 
IN TIME)
Lack of general well-being
Difficulties to swallow the medication because of the capsule size
Have forgotten the intake
Other
Please specify _______________________________
Acceptability Questionnaire (Investigator)
Version 1.0 22 May 2019


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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
STANDARD PROCEDURE
POSSIBLE MODIFICATION
Face-to-face patient visit 
performed by an adequate site 
staff under the responsibility of 
a physician on site.

for Visit 3 Visit 4 and Visit 5: 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 the following visits, visits may be converted to home 
visits, or combined home and remote visits.
If physical exam, vital signs, height, weight cannot be 
conducted at least every 16 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.
Home visit performed (with portable stadiometer, tape, scale, 
ECG machine, pulsoximeter to measure SpO2) by the 
(sub)investigator or delegated and trained personnel to complete
at least: 
•
Physical examination and vital signs 
•
Height sitting and standing
•
Leg length
•
Weight
•
ECG
•
SpO2
•
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 bone MRI/x-ray and panoramic x-
ray to site (when needed)
•
Collect medication for IMP compliance
•
Assessments listed under “Investigator Call,” if not done by 
separate call
Investigator Call: the following assessments could be 
completed by the (sub)investigator via phone or telemedicine, if 
not done during the home visit:


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STANDARD PROCEDURE
POSSIBLE MODIFICATION
•
ILD exacerbations
•
Hospitalizations
•
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 the 
investigational site:
•
FVC
•
6MWT
•
PK sampling
PK sampling will be conducted at the next scheduled visit at the 
site, as far as the study medication was regularly taken in the 10 
days before PK sampling, and intake in the 3 days before PK 
sampling was documented in the PK diary card.
FVC, 6MWT 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 the 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

Testing must occur every 4-6 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.


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STANDARD PROCEDURE
POSSIBLE MODIFICATION
If pregnancy tests cannot be conducted every 4-6 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. Medical decision has to be documented in 
patient’s source notes.
Dispensation of study 
medication 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’s parent(s)/legal guardian (or the patient if 
applicable) must consent to provide contact details for 
shipping purposes 

The patient’s parent(s)/legal guardian (or the patient if 
applicable) 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 AMENDMENTS
11.1
GLOBAL AMENDMENT 1
Date of amendment
19 Jun 2020
EudraCT number
EU number
2018-004530-14
BI Trial number
1199-0337 (InPedILD™)
BI Investigational Medicinal 
Product(s)
Ofev®, nintedanib
Title of protocol
A double blind, randomised, placebo-controlled 
trial to evaluate the dose-exposure and safety of 
nintedanib per os on top of standard of care for 24 
weeks, followed by open label treatment with 
nintedanib of variable duration, in children and 
adolescents (6 to 17 year-old) with clinically 
significant fibrosing Interstitial Lung Disease
Global Amendment due to urgent safety reasons
Global Amendment
Section to be changed
4.1.5.1 Blinding
Description of change
“non-trial” added before “personnel from the 
sponsor involved in the PK analyses will be 
unblinded”;
“after the 30th patient (either nintedanib or 
placebo) has completed planned PK assessment in 
Part A” removed at the end of the statement “In 
order to enable early analysis of PK, selected non-
trial personnel from the sponsor involved in the 
PK analyses will be unblinded.”;
“will be conducted on a continuous basis and” 
added into the sentence “The planned preliminary 
analyses will focus purely on PK (no efficacy or 
safety outcomes will be analysed at that time)”, 
and “Available PK data will be provided to the 
SMC for consideration when evaluating the safety 
of the trial.” added after the sentence;
“Final PK analyses and (“Fast-track”) PK/PD 
analyses will be reported once after availability of 
data from DBL 1.” removed after “No formal 
interim report will be generated.”;
“upon request” removed after “The SMC will 
review unblinded data”;
“upon request by SMC” removed after “The 
independent statistician of the SMC will receive 
the randomization code to allow the required 
analyses on unblinded data”.


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Rationale for change
FDA recommended to conduct an interim PK 
evaluation at Week 2 post-dose to ensure that the 
systemic exposure of nintedanib with the proposed 
weight-based dosing regimen in patients 6 to 17 
years of age is comparable to adults, so the study
procedures have been updated to meet this 
requirement.
The specification “non-trial” will make clear that 
the personnel from the sponsor involved in the PK 
analyses is independent from the study team.
Section to be changed
8.7 Administrative structure of the trial
Description of change
“members of the BI trial team and trial 
independent members” replaced by “external 
experts independent from the trial and selected BI 
non-trial team members”;
“PK and” added to the sentence “A SMC 
composed of … will be established to review 
individual and aggregated PK 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”.
Rationale for change
To clarify the independence of SMC members 
from trial team, and specify that the SMC will 
review PK data in addition to safety data.
Section to be changed
1.4.2 Risks
Description of change
Added “review individual and aggregated PK and 
safety data at regular intervals,”, “about the 
appropriateness of further enrolment and 
continuation/modification/premature interruption 
of the study”, and “dose modification and/or
additional assessments (e.g.” to the sentence “The 
SMC will review individual and aggregated PK
and safety data at regular intervals, advise the 
study team about the appropriateness of further 
enrolment and 
continuation/modification/premature interruption 
of the study, and might recommend dose 
modification and/or additional assessments (e.g. 
intermediate checks in those patients who 
switched from placebo to nintedanib at the end of 
the initial 24 weeks of treatment).”
Rationale for change
To specify actions expected from SMC to mitigate 
the risk.


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Section to be changed
4.2.2.1 Restrictions regarding concomitant 
treatment
Description of change
Added Table 4.2.2.1: 1 Restrictions regarding use 
of potent P-gp and CYP3A4 inhibitors and 
inducers.
Rationale for change
FDA recommended to exclude P-gp and CYP3A4 
inducers per nintedanib prescribing information, 
so the restriction regarding use of potent P-gp and 
CYP3A4 inhibitors and inducers has been added
to address the concerns raised, and minimize 
potential impact of these co-medications on the 
primary PK endpoint.
Section to be changed
3.3.3 Exclusion criteria
Description of change
Added into criterion 13 the exclusion of patients 
with documented allergy to soya
Rationale for change
The Office for Registration of Medicinal Products, 
Medical Devices and Biocidal Products in Poland 
recommended to exclude patients with 
documented allergy to soya per contraindications 
reported in the Investigator’s Brochure.
Section to be changed
1.2 Drug profile, 1.3.1 Similarities and differences 
in the condition between populations and 
pharmacological rationale, 1.4.1 Benefits, 4.1.2 
Selection of doses in the trial and dose 
modifications, 9.2 Unpublished references
Description of change
Updated reference to the current Investigator’s 
Brochure (IB) Nintedanib in Idiopathic Pulmonary 
Fibrosis, Systemic Sclerosis, Progressive 
Fibrosing Interstitial Lung Disease.
Rationale for change
Updated version of the referenced documents has 
become available.
Section to be changed
1.2 Drug profile
Description of change
Added results from the study in adults with PF-
ILD.
Rationale for change
Results from the study in adults with PF-ILD have 
become available.
Section to be changed
1.2 Drug profile, 1.3 Rationale for performing the 
trial, 1.4.1 Benefits, 9.1 Published references
Description of change
Added references to the recently published results 
from the study in adults with PF-ILD.
Rationale for change
Results from the study in adults with PF-ILD have 
become available.
Section to be changed
1.4.1 Benefits
Description of change
Section updated to state that nintedanib for SSc-
ILD application has been approved in Europe, US
and other countries; an application for an 
indication for nintedanib in adults with chronic 


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fibrosing interstitial lung diseases with a 
progressive phenotype is approved in the US and 
other countries, and received a positive opinion in 
Europe; results of the INBUILD® trial are 
available.
Rationale for change
Regulatory status has changed, and results from 
the study in adults with PF-ILD have become 
available.
Section to be changed
3.1 Overall Trial Design and Plan
Description of change
“Monitory” amended to “Monitoring”, and 
statement about implementation of a protocol 
amendment if additional PK data are needed
replaced by detailed information about the process 
to be followed and PK samples to be collected if 
additional PK data are needed.
Rationale for change
To amend a typo, and avoid a further protocol 
amendment.
Section to be changed
7.2.2 Primary endpoint analyses
Description of change
Added details about the analysis of the primary 
endpoint AUCτ,ss, and that further details on the 
PK analysis will be specified in the TSAP.
Rationale for change
Clarify how PK data will be used in the primary 
PK analysis.
Section to be changed
7.2.7 Interim Analyses
Description of change
Added information about update of primary 
analysis in case PK data are not sufficient and 
further PK data are collected.
Rationale for change
Clarify that if PK data collected for the primary 
analysis are not sufficient, then further PK data 
will be collected, the primary analysis will be 
updated and reported in the revision of the clinical 
trial report based on data from DBL 2.
Section to be changed
2.1.3 Secondary endpoints
Description of change
Added that the secondary endpoint “Change in 
height, sitting height, leg length from baseline at 
week 24, and week 52*” is also assessed at week 
76*, and week 100*, but these time points will not 
be available for all patients.
Rationale for change
Clarify procedures and remove inconsistency with 
protocol synopsis.
Section to be changed
Description of change
Rationale for change
Section to be changed


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Description of change
Rationale for change
Share the information available at the time of the 
current amendment. 
Section to be changed
5.2.7.2.2 AE reporting to the sponsor and 
timelines
Description of change
“via fax” removed and “country specific contact 
details” replaced by “country specific reporting 
process”.
Rationale for change
Adhere to changed corporate procedure and 
foresee submission of SAE forms by other means 
than fax.
Section to be changed
5.6.1 Assessment of quality of life via PedsQL™
Description of change
“and site staff” removed after “The PedsQL™ 
should be completed in a quiet area/room before 
the respondents complete any other health data 
forms and before they see the investigator”
Rationale for change
The patient will see the site staff before 
completion of the questionnaire as the site staff 
will administer the questionnaire.
Section to be changed
5.6.6 Assessment of HRCT
Description of change
“will” replaced by “might” in the sentence “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”.
Rationale for change
Clarify that these analyses might also not be 
performed, if not possible to perform.
Section to be changed
5.6.6 Assessment of HRCT
Description of change
With regards to HRCTs added “screening” and 
specified that the same acquisition protocol 
specifications should be followed when possible 
for screening HRCTs.
Rationale for change
Clarify that in some circumstances (e.g., historical 
HRCTs or when the devices used at a site is 
different from the standard referred to by the 
acquisition protocol) it might not be possible to 
follow the acquisition specifications defined by 
protocol.
Section to be changed
5.6.6 Assessment of HRCT, 
 
Description of change
Maximum duration of storage specified for HRCT 
scans updated to “30 years”,
 


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Rationale for change
Provide updated information aligned with current 
standard procedures for data storage.
Section to be changed
Flow Chart
Description of change
Weeks under x visit changed from “64 plus 
Q12w” to “52 plus Q12w”.
Days under x visit changed from “449 plus Q84d 
±7” to 365 plus Q84d±7”.
Rationale for change
To ensure consistency with flowchart footnote 16: 
“Imaging follow-up will be conducted … at 12 
weeks, 24 weeks, 36 weeks, 52 weeks and every 
24 weeks thereafter ... 
Dental examination (clinical) …. Follow-up will 
be conducted in all patients at 12 weeks, 24 weeks, 
36 weeks, 52 weeks and every 24 weeks thereafter 
…
Dental imaging (panoramic x-ray) …. Follow-up 
will be conducted in all patients at 24 weeks, 52 
weeks and every 48 weeks thereafter …”.
Section to be changed
6.2.2 Treatment period: Visits 4, 5, 6, 8, 9, X 
(treatment period); 6.2.3 Follow-up period and 
trial completion
Description of change
Frequency of bone imaging follow-up changed 
from “every 3 months, and every 6 months after 
the first year” to “at 12 weeks, 24 weeks, 36 
weeks, 52 weeks and every 24 weeks 
thereafter …”.
Frequency of dental examination follow-up 
(clinical) changed from “every 3 months, and 
every 6 months after the first year” to “at 12 
weeks, 24 weeks, 36 weeks, 52 weeks, and every 
24 weeks thereafter …”.
Frequency of dental imaging follow-up changed 
from “every 6 months, and every 12 months after 
the first year” to “at 24 weeks, 52 weeks, and 
every 48 weeks thereafter …”.
Rationale for change
Clarify schedule of trial procedures and ensure 
consistency with Flow Chart footnote.


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Section to be changed
6.2.2 Treatment period
Description of change
“A scheduled visit (V3-Vx)” replaced by “The 
first visit after the EoT visit” as subject of the 
sentence “will be skipped if the EoT visit occurs 
within 4 weeks prior to the scheduled visit.”
Rationale for change
Clarify trial procedures and ensure consistency 
within Flow Chart footnote (**).
Section to be changed
Flow Chart footnote 16, 5.2.5 Assessment of 
pathological findings of epiphyseal growth plate, 
5.2.6 Assessment of pathological findings on 
dental examination or imaging, 6.2.2 Treatment 
period
Description of change
“who qualified for randomisation” added after 
“will be conducted in all patients” for MRI/x-ray, 
dental examination, and dental imaging.
Rationale for change
Specify that these procedures will only be done if 
patient qualified for randomization, to avoid 
unnecessary procedures.
Section to be changed
6.2.2 Treatment period: Visit 2 (baseline)
Description of change
About the conduct of MRI/x-ray, dental 
examination, dental imaging at Visit 2, replaced 
“immediately before or after” with “immediately
after” in the sentence “If it’s not possible to 
conduct this procedure on the day of the visit, the 
procedure can be done in the weeks immediately
after the visit”.
At the end of the sentence added a reference to the 
HRCT acquisition protocol available in the ISF for 
details.
Rationale for change
Amend the information as these procedures should 
not be done before Visit 2, and refer the 
investigator to the Image Acquisition Guideline
for details.
Section to be changed
6.2.2 Treatment period: Visits 4, 5, 6, 8, 9, X 
(treatment period); 6.2.3 Follow-up period and 
trial completion
Description of change
About the conduct of MRI/x-ray, dental 
examination, dental imaging at Visits 4, 5, 6, 8, 9, 
X and in patients who prematurely discontinued 
trial medication, at the end of the sentence “If it’s 
not possible to conduct this procedure on the day 
of the visit, the procedure can be done in the 
weeks immediately after the visit” added a 
reference to the HRCT acquisition protocol 
available in the ISF for details.
Rationale for change
Refer the investigator to the Image Acquisition 
Guideline for details.


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Section to be changed
Title page
Description of change
Trial acronym added in brackets after the BI Trial 
No.
Rationale for change
Specify trial acronym.
Section to be changed
8.7 Administrative structure of the trial
Description of change
Purpose of the Disease Review Committee (DRC) 
amended from “To determine what percent of 
screen patients met protocol criteria for inclusion” 
to “To determine how well the protocol inclusion 
criteria were able to identify the intended 
population”.
Word “for” added to “… central reading for all 
patients evaluated for study participation at Visit 
1”.
Rationale for change
Amend incorrect information ensuring consistency 
with the DRC Charter, and clarify the following 
sentence.
Section to be changed
8.3.1 Source documents
Description of change
Missing words and commas added to the 
following sentences: “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.”


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Rationale for change
Add text which was missing due to a technical 
issue.
Section to be changed
6.2.1 screening
Description of change
Removed “)”
Rationale for change
Typo
11.2
GLOBAL AMENDMENT 2
Date of amendment
14 Jun 2021
EudraCT number
EU number
2018-004530-14
BI Trial number
1199-0337 (InPedILD™)
BI Investigational Medicinal 
Product(s)
Ofev®, nintedanib
Title of protocol
A double blind, randomised, placebo-controlled 
trial to evaluate the dose-exposure and safety of 
nintedanib per os on top of standard of care for 24 
weeks, followed by open label treatment with 
nintedanib of variable duration, in children and 
adolescents (6 to 17 year-old) with clinically 
significant fibrosing Interstitial Lung Disease
Global Amendment due to urgent safety reasons
Global Amendment
Section to be changed
Flow Chart, Flow Chart footnote 12, 6.1 Visit 
Schedule, 6.2.2 Treatment period
Description of change
In Flow Chart added to Visit 6 the procedure of 
IMP administration during the visit.
In Flow Chart footnote 12 changed sentence to 
state that Part B will start once the first open label 
dose has been taken in the morning during the 
visit.
In Section 6.1 specified that also the morning dose 
at Visit 2 and Visit 6 should be taken at the site.
In section 6.2.2 specified that blood draw prior to 
administration of trial medication is applicable to 
Visit 2 and Visit 6 only, and that for the timing of 
blood draws to be conducted at Visit 3 and Visit 7 
the Flow Chart for PK blood sampling should be 
referred to.
Also specified that at Visit 6 the first dose of the 
open label trial medication will be administered at 
the site, then the patient’s acceptability 
questionnaire will be administered. In preparation 
to Visit 6 the patient and parent(s)/legal guardian 
will be instructed that on the day of this visit the 


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morning dose of trial medication should not be 
taken before going to the site, because the morning 
dose will be taken during the visit.
Rationale for change
At Visit 6 the study medication should be taken at 
site to ensure monitoring of possible immediate 
adverse reactions in those patients who received 
placebo during Part A and will receive their first 
dose of active medication at Visit 6.
Section to be changed
Flow Chart, Flow Chart footnote 9, Table 1.4.2:1, 
5.2.3 Safety laboratory parameters, 6.2.2 
Treatment period, 6.2.3 Follow-up period and trial 
completion
Description of change
Removed from Follow-up Visit the procedure to 
review the pregnancy test diary card and dispense 
the diary card together with urine dipstick 
pregnancy test.
Specified that pregnancy testing will be conducted 
on blood at visits until end of treatment, and that at 
the Follow-up Visit the pregnancy test will be 
conducted on urines (if acceptable). 
Specified that test results will be documented in 
the patient’s records. In case of positive results, 
procedures defined in Section 5.2.7.2.3 should be 
followed.
Amended the sentence in section 6.2.2 with 
addition of bold words and removal of 
strikethrough words: “Urine dipstick pregnancy 
tests and aA pregnancy test diary card will be 
dispensed (females only); the patient and 
parent(s)/legal guardian will be instructed on how 
the test should be conducted, and the diary
should be completed, untilin the three days before
the next visit.”
Rationale for change
At the Follow-up Visit the pregnancy test will be 
conducted on urines to make test results available 
immediately.
Amend incorrect information given in Section 
6.2.2.
Section to be changed
Flow Chart footnote 6, 6.2.3 Follow-up period and 
trial completion
Description of change
Specified that in case of clinically relevant 
changes of laboratory tests at EoT, lab tests will be 
repeated at follow-up unless the patient is enrolled 
into the open label extension trial.
Rationale for change
Clarify that laboratory tests with clinically 
relevant changes at EoT will be repeated only in 


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patients who do not roll-over to the open label 
extension trial.
Section to be changed
Flow Chart footnotes
Description of change
Added a sentence to state that the interval between 
Visit 1 and Visit 2 could be >28 days.
Rationale for change
In some circumstances 28 days between Visit 1 
and Visit 2 might not be sufficient to complete 
screening procedures.
Section to be changed
Flow Chart footnote 2, 5.2.5 Assessment of 
pathological findings of epiphyseal growth plate, 
5.2.6 Assessment of pathological findings on 
dental examination or imaging, 5.6.6. Assessment 
of HRCT, 
 6.2.1 
screening, 6.2.2 treatment period, 6.2.3 Follow-up 
period and trial completion,
 
 
Description of change
“(HRCT) acquisition protocol” replaced by 
“image acquisition guideline”.
Rationale for change
Ensure consistency with the image acquisition 
guideline filed in ISF.
Section to be changed
Flow Chart footnote 16


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Description of change
Specify that the time window for the baseline bone 
imaging, dental examination, dental imaging is 2 
weeks after Visit 2, and that the time window for 
the follow-up bone imaging, dental examination, 
dental imaging is 1 week before or after the visit.
Replaced “examination” with “dental imaging”.
Rationale for change
Provide also in the Flow Chart footnote the 
information that these assessments could be made 
on a day close to the visit.
To make clear that the sentence refers to dental 
imaging.
Section to be changed
Flow Chart for PK blood sampling, 5.3.1 
Assessment of pharmacokinetics, 6.2.2 Treatment 
period
Description of change
Added to the Flow Chart for PK blood sampling
and Section 5.3.1 a sentence to state that in rare 
circumstances PK sampling might need to be 
repeated (blood samples not taken at required 
timepoint, wrong medication taken in the days 
before PK sampling or on the day of PK sampling, 
destroyed/lost sample during shipment). In such 
cases PK sampling will be repeated close before 
the end of treatment visit, to allow the maximum 
possible interval from the previous PK sampling.
Specified in Section 6.2.2 that PK sampling may 
occur, and PK diary card may be dispensed, at a 
different visit in case PK sampling needs to be 
repeated.
Rationale for change
As assessment of pharmacokinetics (PK: AUCτ,ss 
based on sampling at steady state (at week 2 and 
week 26)) is (next to assessment of safety) the 
main objective of the trial and the included patient 
population is small, every effort should be 
conducted to obtain all required samples for an 
appropriate and comparable PK analyses. This 
includes the exceptional possibility to repeat PK 
sampling if initial samples cannot be used.
Section to be changed
Abbreviations
Description of change
Added abbreviations.
Rationale for change
New words have been introduced with the current 
amendment.
Section to be changed
1.2 Drug Profile
Description of change
Removed sentence “This is the period after the last 
dose with measurable drug levels and/or 
pharmacodynamic effects still likely to be 
present.” after “The Residual Effect Period (REP) 


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of nintedanib for the paediatric programme is 28 
days.”
Rationale for change
Remove incorrect information, as the period after 
the last dose with measurable drug levels and/or 
pharmacodynamic effects still likely to be present 
is shorter than 28 days.
Section to be changed
1.3 Rationale for performing the trial
Description of change
Changed order of diseases mentioned.
Rationale for change
Add clarity.
Section to be changed
1.3.1 Similarities and differences in the condition 
between populations and pharmacological 
rationale
Description of change
Added “chronic” before “HP”.
Replaced “severe forms” with “progressive form” 
with regards to IPF.
Rationale for change
Be more accurate.
Section to be changed
1.4. Benefits
Description of change
Provided updated information about registration 
status.
Rationale for change
Registration obtained in further countries.
Section to be changed
1.4.2 Risks
Description of change
Removed “safety” from the sentence “Currently 
there is no experience with nintedanib in the 
paediatric population”.
Rationale for change
Make clear that there’s also no experience on 
efficacy in this population.
Section to be changed
1.4.2 Risks
Description of change
Added narrative text to describe reported adverse 
reactions associated with the use of nintedanib in 
adults and risks specific for the paediatric 
population based on preclinical animal studies; 
added heading to table.
Rationale for change
Provide additional information about reported 
adverse reactions and risks specific for the 
paediatric population based on preclinical animal 
studies.
Section to be changed
Table 1.4.2:1 Overview of trial related risks, 
Section 5.2.7.1.4 Adverse events of special 
interest
Description of change
Added pathological findings identified on bone
imaging to the list of adverse events of special 
interest, and added expedited reporting of 
pathological findings identified on bone imaging 
to Table 1.4.2:1.
Rationale for change
Ensure expedited reporting from site to 
pharmacovigilance and timely reporting to SMC.


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Section to be changed
Table 1.4.2:1 Overview of trial related risks, 
Section 5.2.7.1.4 Adverse events of special 
interest
Description of change
Added stunted growth identified on dental 
imaging to the list of adverse events of special 
interest, and added expedited reporting of stunted 
growth identified on dental imaging to Table 
1.4.2:1.
Rationale for change
Ensure expedited reporting from site to 
pharmacovigilance and timely reporting to SMC.
Section to be changed
Flow Chart footnotes, 1.4.2 Risks, Table 1.4.2:1 
Overview of trial related risks, 4.1.4 Drug 
assignment and administration of doses for each 
patient, 6.1 Visit schedule, 8.3.2 Direct access to 
source data and documents, Appendix 10.9 Visit 
modification in exceptional circumstances
Description of change
Added risks associated to the conduct of the study 
during the COVID-19 pandemic. Added 
mitigation measures and protocol modifications 
that can be implemented at a site.
Rationale for change
The COVID-19 pandemic has added risks 
associated with patient’s visits at the site; 
mitigation measures and possible protocol 
modifications have been defined.
Section to be changed
8.3.2 Direct access to source data and documents
Description of change
Added sentence about remote and centralized 
monitoring.
Rationale for change
In case site access is restricted, some activities on 
site such as on-site source data review and source 
data verification may be performed remotely or 
replaced by centralized monitoring.
Section to be changed
4.2.2.1 Restrictions regarding concomitant 
treatment
Description of change
Added that there are no restrictions for trial 
participants to receive vaccination for COVID-19 
during or after study treatment period.
Rationale for change
Clarify that vaccination for COVID-19 is allowed.
Section to be changed
Description of change


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Rationale for change
Section to be changed
3.1 Overall trial design and plan, 3.2 Discussion of 
trial design, including the choice of control group, 
7.2.7 Interim analyses, 7.5 Determination of the 
sample size
Description of change
Added words in bold: “The first DBL will be 
announced once 30 patients (at least 20 
adolescents aged 12-17 years, and if feasible at 
least 10 children aged 6-11 years) have 
completed PK sampling at 26 weeks, or 
prematurely discontinued the trial…”.
Rationale for change
Specify that the study will also try to complete PK 
sampling in 10 children aged 6-11 years.
Section to be changed
3.1 Overall trial design and plan, 3.2 Discussion of 
trial design, including the choice of control group,
7.2.7 Interim Analyses
Description of change
In Section 3.1 added words in bold
“Based on the data from DBL 1 (or updated DBL
1 data once the number of patients with 
sufficient PK data has been reached), the 
primary analysis/updated primary analyses and a 
benefit-risk assessment will be done and the 
clinical trial report for the primary analysis will be 
written. The timing of final DBL (DBL 2) and 
EoT visit will be communicated after confirming 
adequacy of PK data from DBL 1 (or updated 
DBL 1).” and “In the rare case that additional PK 
data is deemed necessary to complete the primary 
PK assessment, data from DBL 1 will be 
updated and the administrative DBL 2 will be 
postponed”.
In Section 3.2 added words in bold: “All PK and 
clinical data available at DBL 1 (or updated DBL 
1) will be used in the primary analysis to allow for 
more robust estimates of exposure and potential 
treatment effect.”


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In Section 7.2.7 Interim Analyses the following 
words have ben removed: “the primary analysis 
will be updated and reported in the revision of the 
clinical trial report based on data from DBL 2”.
Rationale for change
Clarify that, in case after DBL1 further PK data 
are needed, a data snapshot will be taken once 
further PK data have been collected, and data 
based on DBL 1 will be updated.
Section to be changed
3.2 Discussion of trial design, including the choice 
of control group and 7.5 Determination of the 
sample size
Description of change
Added words in bold “study enrolment into the 
treatment phase will remain open until …” in 
Section 3.2, and “patient recruitment into the 
treatment phase will remain open until …” in 
Section 7.5.
Rationale for change
Make clear that enrolment into the treatment phase 
will be closed once the defined milestone is met.
Section to be changed
4.1.2 Selection of doses in the trial and dose 
modifications
Description of change
Added “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.”
Rationale for change
Specify procedures to be followed in case of in 
case of patient’s weight decrease below 13.5 kg.
Section to be changed
4.1.2 Selection of doses in the trial and dose 
modifications
Description of change
Added: “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.”
Rationale for change
Provide instructions about requirements in case 
these AESIs are reported: treatment interruption, 
evaluation by SMC and recommendation from the
SMC before treatment can be resumed.
Section to be changed
Table 4.1.2: 2 Allowed treatment reduction / 
interruption periods
Description of change
Added “other events” as possible cause for 
treatment interruption.
Rationale for change
Treatment interruption might be caused by events 
other than AEs.
Section to be changed
Table 4.1.2:2 Allowed treatment reduction / 
interruption periods


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Description of change
Changed text to clarify that IMP interruption 
should be max 4 weeks, while re-escalation to the 
dose assigned per Table 4.1.2: 1 may occur any 
time per investigator judgement.
Rationale for change
Clarify that IMP interruption should be max 4 
weeks, while re-escalation to the dose assigned per 
Table 4.1.2: 1 may occur any time per investigator 
judgement.
Section to be changed
Table 4.1.2: 5 Recommendations for managing 
liver enzyme elevations
Description of change
The wording regarding withdrawal and 
interruption of trial medication has been revised.
Rationale for change
Clarify the information given.
Section to be changed
4.1.4 Drug assignment and administration of doses 
for each patient
Description of change
Added words in bold: “One reserve wallet will be 
dispensed at Visit 2 and at Visit 6, and replaced 
as needed (e.g. in case of dose change requiring 
unit strength change, or use-by-date before the 
date planned for the next clinic visit) thereafter. At 
Visit 6 any remaining wallet, including reserve, 
dispensed to the patient while the patient was 
taking part in the double-blind part of the 
study will be collected, and open label wallets 
will be dispensed.”
Rationale for change
Specify that at Visit 6 a new reserve wallet will be 
dispensed to the patient, and any remaining wallet 
from the double-part of the study will be collected 
from the patient.
Section to be changed
4.1.4 Drug assignment and administration of doses 
for each patient
Description of change
Added “To obtain kits with smaller capsules, an 
unscheduled visit should be registered in IRT. 
Once smaller capsules have been assigned, IRT 
will not allow to switch back to bigger capsules.”
Rationale for change
Provide instructions about how to obtain smaller 
capsules in case the patient is not able to swallow 
big capsules.
Section to be changed
4.1.4 Drug assignment and administration of doses 
for each patient
Description of change
Added “If contact with the content of the capsule 
occurs, hands should be washed immediately and 
thoroughly.”
Rationale for change
Add recommendation implemented in the updated
version of the IB.
Section to be changed
4.1.5.1 Blinding


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Description of change
Removed “and Blinded Report Planning Meeting 
minutes”.
Rationale for change
Procedures have changed.
Section to be changed
4.1.5.1 Blinding
Description of change
Added “No individual unblinding information will 
be shared, however it could be communicated to 
the trial team how many patients with evaluable 
PK data are missing to reach the target.”
Rationale for change
Specify that the trial team could be informed about 
how many patients with evaluable PK data are 
missing to reach the target.
Section to be changed
4.1.5.2 Unblinding and breaking the code
Description of change
Added that in case the automated unblinding 
option via the IRT system is malfunctioning, the 
treatment allocation can be obtained contacting the 
IRT service provider, per instructions provided in 
the ISF.
Rationale for change
Clarify how to obtain unblinded information in 
case the IRT system is malfunctioning.
Section to be changed
Flow Chart, 5.1.2 Assessment of SpO2, 6.2.1 
Screening
Description of change
Specification that earlobe or forehead probes 
should be used has been removed. In Section 5.1.2 
it has been specified that forehead probe is 
recommended, but if not available earlobe and 
finger probe are also allowed, as far as they are 
used consistently in the same patient.
Rationale for change
Earlobe or forehead probes suitable for the 
pediatric population are not available in all 
countries. Expert in ChILD confirmed that any 
probe can be used, if used consistently.
Section to be changed
Flow Chart, 5.1.2 Assessment of SpO2, 6.2.2 
Treatment period
Description of change
In the Flow Chart and Section 6.2.2 specified that 
continuous pulsoximetry (SpO2) will be conducted 
during the 6MWT.
In Section 5.1.2 specified that “SpO2 with exertion 
will be measured during the 6MWT. See Section 
5.1.6 for details.”
Rationale for change
Specify that also SpO2 with exertion will be 
measured, and that the 6MWT includes continuous
pulsoximetry (SpO2).
Section to be changed
5.2.6 Assessment of pathological findings on 
dental examination or imaging
Description of change
Added “Dental cone beam computed tomography 
can be conducted only in case panoramic x-rays 
cannot be performed, as far as it allows the same 


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assessments, it is conducted according to the 
image acquisition guideline, and the same device 
is used consistently in the same patient.”
Rationale for change
Specify that dental cone beam computed 
tomography is permitted under special conditions.
Section to be changed
Section to be changed
5.6.1 Assessment of quality of life via PedsQL™
Description of change
Added “If during the trial a patient changes age 
group, then the questionnaire appropriate for that 
age group should be administered.”
Rationale for change
Clarify which questionnaire should be 
administered in case the patient changed age group 
during the trial.
Section to be changed
6.2.2 Treatment period, Visit 2 (baseline)
Description of change
About possible patient re-screening specified that 
to register patient’s re-screening the site personnel 
should perform a re-screening call/notification in 
IRT; this way the patient will be assigned a new 
patient number linked to the original patient 
number.
Specified also that re-screening of a previously 
screen failed patient will be permitted once.
Rationale for change
Provide further information about re-screening 
procedures and guide the investigator through the 
actions needed to associate the patient number 
assigned at re-screening with the patient number 
assigned at initial screening.


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Section to be changed
Flow Chart footnotes, 6.2.2 Treatment period, End 
of Treatment visit
Description of change
Added: “Patients who did not discontinue trial 
treatment prematurely should undergo the EoT 
visit as soon as the timing of final DBL (DBL 2) 
and EoT visit has been communicated (see Section 
3.1 for details). If a regular study visit is scheduled 
in the period when the EoT visit should be 
conducted, all procedures required at this regular 
study visit and the additional procedures, if any, 
required at the EoT visit will be conducted during 
the same visit.”
Rationale for change
Ensure procedures required at scheduled visits are 
completed in case a regular study visit is 
scheduled in the period when the EoT visit should 
be conducted.
Section to be changed
6.2.2 Treatment period, End of Treatment visit
Description of change
Added a paragraph about offering participation in 
a separate open label extension trial.
Rationale for change
Guide the Investigator to complete this procedure 
at the proper time. Offering participation in a 
separate open label extension trial is mentioned in 
the protocol synopsis, but not in the list of 
procedures to be completed before the EoT visit.
Section to be changed
6.2.2 Treatment period, End of Treatment visit
Description of change
Added that at the EoT visit the site personnel will 
perform a call in IRT to register patient’s end of 
treatment, and that returned wallets will be 
collected.
Rationale for change
Remind the site staff about the call in IRT and 
about the collection of study medication required 
at the EoT visit.
Section to be changed
7.2.1 General considerations
Description of change
Amended the definition of PKS with addition of 
bold words and removal of strikethrough words:
Pharmacokinetic Parameter Analysis Set (PKS):
The Pharmacokinetic Parameter Analysis Set
(PKS) includes all patientssubjects in the Treated 
Set (TS) who provide at least one PK endpoint 
that was not excluded due to a protocol 
deviation relevant to the evaluation of PK or 
due to PK non-evaluability (as specified in the 
following subsection ‘Pharmacokinetics’). 
Thus, a patient will be included in the PKS, 
even if he/she contributes only one PK 
parameter value for one period to the statistical 
assessment. with at least one evaluable PK plasma 


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concentration (referring to PK plasma 
concentrations not excluded due to an important 
protocol violation relevant for PK evaluation).
Descriptive and model based analyses of PK 
parametersAnalyses for PK endpoints will be 
based on the PKS. All other analyses will be based 
on the TS.
Rationale for change
Clarify PKS.
Section to be changed
7.2.2 Primary endpoint analyses
Description of change
Amended the sentence with addition of bold words 
and removal of strikethrough words: “For the 
primary PK analysis, the area under the plasma 
concentration-time curve at steady state (AUCτ,ss) 
will be calculated by a non-compartmental as well 
as compartmental analysis approach and 
descriptive statistics will be provided as detailed in 
Section 7.2.1.”
Rationale for change
Specify that compartmental analysis will also be 
conducted.
Section to be changed
8.7 Administrative structure of the trial
Description of change
Amended the information about how the SMC will 
access safety readings and bone/dental images.
Rationale for change
The SMC will have no contact with the central 
readers; reports and images will be provided to the 
SMC via CRO.
Section to be changed
8.7 Administrative structure of the trial
Section to be changed
Added “A Steering Committee will provide 
scientific advice on the clinical development 
program of nintedanib in the paediatric population. 
Tasks and responsibilities are defined in a 
contract.”
Section to be changed
Specify that a Steering Committee will be 
consulted about the clinical development program 
of nintedanib in the paediatric population.
Section to be changed
8.7 Administrative structure of the trial
Description of change
Words “central images services” replaced with 
“… central imaging services  …”
Rationale for change
Amend a typo.
Section to be changed
9.2 Unpublished references
Description of change
Updated reference to the IB.
Rationale for change
A new IB version has been released since the last 
version of the protocol.
Section to be changed
10.2 Creatinine clearance
Description of change
Added SI units in Appendix 10.2.
Rationale for change
SI units have been added for countries using SI.


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c26450188
3.0
clinical-trial-protocol-version-03
A double blind, randomised, placebo-controlled trial to evaluate the dose-exposure
and safety of nintedanib per os on top of standard of care for 24 weeks, followed by
open label treatment with nintedanib of variable duration, in children and adolescents
(6 to 17 year-old) with clinically significant fibrosing Interstitial Lung Disease
Author-Clinical Trial Leader
14 Jun 2021 14:25 CEST
Author-Trial Statistician
14 Jun 2021 15:51 CEST
Approval-Clinical Pharmacokinetics
15 Jun 2021 08:24 CEST
Approval-Therapeutic Area
15 Jun 2021 08:36 CEST
Approval-Team Member Medicine
15 Jun 2021 08:59 CEST
Verification-Paper Signature
Completion
15 Jun 2021 14:04 CEST


Boehringer Ingelheim 
Page 2 of 2
Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c26450188
3.0

SAP_001.pdf: 
001-MCS-50-415_RD-01 (2.0) / Saved on: 06 Dec 2019
TITLE PAGE
TRIAL STATISTICAL ANALYSIS PLAN
c30253575-01
BI Trial No.:
1199-0337
Title:
A double blind, randomised, placebo-controlled trial to evaluate 
the dose-exposure and safety of nintedanib per os on top of 
standard of care for 24 weeks, followed by open label treatment 
with nintedanib of variable duration, in children and adolescents 
(6 to 17 year-old) with clinically significant fibrosing Interstitial 
Lung Disease
Investigational
Product(s):
Ofev®, nintedanib
Responsible trial 
statistician(s):
Phone: +
Date of statistical 
analysis plan:
09 MAR 2022 SIGNED
Version:
1
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2022 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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1.
TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
1.
TABLE OF CONTENTS......................................................................................2
LIST OF TABLES...................................................................................................................6
LIST OF FIGURES.................................................................................................................7
2.
LIST OF ABBREVIATIONS ..............................................................................8
3.
INTRODUCTION...............................................................................................10
4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY....................11
4.1
ADDITIONS / NEW ANALYSES.....................................................................11
4.2
CHANGES...........................................................................................................11
5.
ENDPOINT(S).....................................................................................................12
5.1
PRIMARY ENDPOINT(S) ................................................................................12
5.2
SECONDARY ENDPOINT(S) ..........................................................................12
5.2.1
Key secondary endpoint(s).................................................................................12
5.2.2
Secondary endpoint(s) ........................................................................................13
5.2.2.1
N (%) of patients with treatment-emergent pathological findings of epiphyseal 
growth plate on imaging at week 24, and week 52...............................................13
5.2.2.2
N (%) of patients with treatment-emergent pathological findings on dental 
examination or imaging at week 24, and week 52................................................13
5.2.2.3
N (%) of patients with treatment-emergent adverse events over the whole trial..14
5.2.2.4
Change in height, sitting height, leg length from baseline at week 24, and week 
52, week 76, and week 100...................................................................................14
5.2.2.5
Change in Forced Vital Capacity (FVC) % predicted from baseline at week 24, 
and week 52 ..........................................................................................................15
5.2.2.6
Absolute change from baseline in Pediatric Quality of Life Questionnaire 
(PedsQL) at week 24, and week 52 ......................................................................15
5.2.2.7
Change in oxygen saturation (SpO2) on room air at rest from baseline at week 
24, and week 52 ....................................................................................................15
5.2.2.8
Change in 6-min walk distance from baseline at week 24, and week 52 .............15
5.2.2.9
Patient acceptability based on the size of capsules at week 24.............................16
5.2.2.10
Patient acceptability based on the number of capsules at week 24.......................16
5.2.2.11
Time to first respiratory-related hospitalization over the whole trial ...................16
5.2.2.12
Time to first acute Interstitial Lung Disease (ILD) exacerbation or death over 
the whole trial .......................................................................................................17
5.2.2.13
Time to death over the whole trial ........................................................................18


Boehringer Ingelheim                                                                        
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5.4.1.1
Demographic data .................................................................................................21
5.4.3
Exposure ..............................................................................................................24
5.4.4
Liver enzyme and bilirubin elevations..............................................................26
5.4.4.1
Time-to-event analyses for liver enzyme elevations.............................................27
5.4.5
Vital signs.............................................................................................................28
6.
GENERAL ANALYSIS DEFINITIONS ..........................................................29
6.1
TREATMENT(S)................................................................................................29
6.2
IMPORTANT PROTOCOL DEVIATIONS....................................................31
6.3
SUBJECT SETS ANALYZED ..........................................................................31
6.5
POOLING OF CENTRES .................................................................................33
6.6
HANDLING OF MISSING DATA AND OUTLIERS....................................33
6.6.1
Primary endpoint................................................................................................33
6.6.2
Secondary and further endpoints......................................................................33
6.6.2.1
Change from baseline endpoints...........................................................................33
6.6.2.2 
Time-to-event endpoints .......................................................................................34
6.6.2.3 
Categorical endpoints............................................................................................34
6.6.2.4
Endpoints based on MRI/x-ray ............................................................................35
6.6.2.5
6-min walk test (6MWT) .....................................................................................35


Boehringer Ingelheim                                                                        
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6.6.3.3 
Exposure................................................................................................................36
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS ...................36
7.
PLANNED ANALYSIS......................................................................................43
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS.........43
7.4
PRIMARY ENDPOINT(S) ................................................................................45
7.4.1
Primary analysis of the primary endpoint(s) ...................................................45
7.4.1.1
PK endpoint...........................................................................................................45
7.4.1.2
Safety endpoint .....................................................................................................46
7.4.2.1
PK endpoint...........................................................................................................46
7.4.2.2
Safety endpoint .....................................................................................................46
7.5
SECONDARY ENDPOINT(S) ..........................................................................46
7.5.1
Key secondary endpoint(s).................................................................................46
7.5.2
(Other) Secondary endpoint(s) ..........................................................................47
7.5.2.1
Continuous (change from baseline) endpoints......................................................47
7.5.2.2
Time-to-event endpoints .......................................................................................48
7.5.2.3
Categorical endpoints, safety and tolerability endpoints ......................................48
7.8
SAFETY ANALYSIS..........................................................................................53
7.8.1
Adverse Events ....................................................................................................53
7.8.1.1 
Adjudicated adverse events...................................................................................55
7.8.1.2 
Exposure adjusted analysis of adverse events over the whole trial ......................55
7.8.1.3
Adverse events with additional information collection .......................................56


Boehringer Ingelheim                                                                        
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7.8.1.4
Pathological findings of epiphyseal growth plate on imaging, on dental 
examination or dental imaging..............................................................................57
7.8.2
Laboratory Data..................................................................................................57
7.8.2.1
Standard laboratory analyses ................................................................................57
7.8.2.2
Liver enzyme and bilirubin elevations..................................................................59
7.8.3
Vital signs.............................................................................................................59
7.8.4
ECG......................................................................................................................59
8.
REFERENCES....................................................................................................61
9.
ADDITIONAL SECTIONS ...............................................................................63
9.1
PEDSQL SCORING INSTRUCTIONS............................................................63
9.4
LIST OF POTENTIAL TERMS FOR HEPATIC INJURY 
DERIVATION.....................................................................................................78
10.
HISTORY TABLE..............................................................................................96


Boehringer Ingelheim                                                                        
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LIST OF TABLES
Table 5.2.2.11: 1
Censoring Rules for Time to first respiratory-related hospitalization 
over the whole trial...........................................................................................17
Table 5.2.2.12: 1
Censoring Rules for Time to first acute ILD exacerbation or death over 
the whole trial ...................................................................................................17
Table 5.2.2.13: 1
Censoring Rules for Time to death over the whole trial ..........................18
Table 6.3: 1
Patient sets analyzed.........................................................................................32
Table 6.7: 1
Time windowing rules for FVC, SpO2, missed school days, vital signs (syst. 
and diast. blood pressure, pulse rate) and laboratory tests (incl. LDH) ...........37
Table 6.7: 2
Time windowing rules for weight ....................................................................38
Table 6.7: 3
Time windowing rules for height and leg length..............................................39
Table 6.7: 4
Time windowing rules for dental examination and bone imaging ...................40
Table 6.7: 5
Time windowing rules for dental imaging .......................................................41
Table 6.7: 6
Time windowing rules for data from PedsQL questionnaire, 6MWT, Borg 
CR-10 scale®....................................................................................................41
Table 6.7: 7
Time windowing rules for data from acceptability questionnaire....................42
Table 7.8.2.1: 1 
Safety laboratory tests at regular site visits..............................................57
Table 7.8.2.1: 2 
Safety laboratory tests at intermediate ‘a’-visits......................................58
Table 10: 1
History table .....................................................................................................96


Boehringer Ingelheim                                                                        
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LIST OF FIGURES


Boehringer Ingelheim                                                                        
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2.
LIST OF ABBREVIATIONS
See Medicine Glossary:
http://glossary
Term
Definition / description
AE
Adverse event
AESI
Adverse event of Special Interest
ADS
Analysis Dataset
ALK
Alkaline Phosphatase
ALT
Alanine Aminotransferase
AST
Aspartate Aminotransferase
AUCτ,ss
Area under the Plasma Concentration-Time Curve at Steady State
AUCτ,ss_D
Dose normalized AUCτ,ss
BI
Boehringer Ingelheim
bid
bis in die
CDG
Customized Drug Groupings
cHP
Chronic Hypersensitivity Pneumonitis
CL/Fss
Apparent Clearance of the Analyte in the Plasma at Steady-State following 
extravascular multiple dose administration
Cmax
Maximum Concentration in Plasma
Cmax,ss
Maximum Measured Concentration of the Analyte in Plasma at Steady State
CT
Computed Tomography
CTD
Connective Tissue Disease
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
Δ
Delta, i.e. difference
DBL
Database Lock
DLCO
Diffusing Capacity of the Lung for Carbon Monoxide
DMARDs
Disease-Modifying Anti-Rheumatic Drugs
DRC
Disease Review Committee
DV domain
SDTM Protocol Deviations domain model
eCRF
electronic Case Report Form
EDMS
Electronic Document Management System


Boehringer Ingelheim                                                                        
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Term
Definition / description
EMA
European Medicines Agency
EOT
End of Treatment
FPI
First patient in (= first patient randomised)
FVC
Forced Vital Capacity
g
Gramm
Hb
Haemoglobin
HRCT
High-Resolution Computer Tomography
ICH
International Conference on Harmonisation
ILD
Interstitial Lung Disease
INR
International Normalized Ratio
iPD
Important Protocol Deviation
IRT
Interactive Response Technology
LDH
Lactate dehydrogenase
m
Meter
MACE
Major Adverse Cardiovascular Events
MAP
Meta-analytic predictive
MedDRA
Medical Dictionary for Regulatory Activities
mg
Milligramm
min
Minute
ml
Milliliter
MCMC
Markov Chain Monte Carlo
MMRM
Mixed effect Model Repeat Measurement
N
Number
PedsQL™
Pediatric Quality of Life Questionnaire™
P-gp
Permeability Glycoprotein
PK
Pharmacokinetic(s)
PopPK
Population Pharmacokinetics
pred
Predicted
PT
Preferred Term
REML
Restricted Maximum Likelihood
REP
Residual Effect Period


Boehringer Ingelheim                                                                        
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Term
Definition / description
RS
Randomised Set
RPM
Report Planning Meeting
SCS
Screened Set
SD
Standard deviation
SE
Standard Error
SEM
Standard Error of the Mean
6MWT
Six-Minute Walk Test
SoC
Standard of Care
SOC
System organ class
SpO2
Saturation of oxygen
TMF
Trial Master File
TS
Treated Set
TSAP
Trial Statistical Analysis Plan
ULN
Upper Limit of Normal
WHO-DD
World Health Organization Drug Dictionary
3.
INTRODUCTION
As per ICH E9 (1) the purpose of this document is to provide a more technical and detailed 
elaboration of the principal features of the analysis described in the protocol, and to include 
detailed procedures for executing the statistical analysis of the primary and secondary 
variables and other data.
This TSAP assumes familiarity with the Clinical Trial Protocol (CTP), including Protocol 
Amendments. In particular, the TSAP is based on the planned analysis specification as written 
in CTP Section 7 “Statistical Methods and Determination of Sample Size”. Therefore, TSAP 
readers may consult the CTP for more background information on the study, e.g., on study 
objectives, study design and population, treatments, definition of measurements and variables, 
planning of sample size, randomisation.
Unless stated otherwise SAS® Version 9.4 or later will be used for all analyses.


Boehringer Ingelheim                                                                        
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4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY
4.1
ADDITIONS / NEW ANALYSES
In addition to the evaluations depicted in the CTP, the following evaluations will be added:

Secondary endpoint analysis: 

Further endpoint analysis: 
4.2
CHANGES


Boehringer Ingelheim                                                                        
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5.
ENDPOINT(S)
In this section, more details are given regarding endpoints. Please note that for all endpoints 
and analyses, Section 6.7 should be consulted for baseline value definition. 
Please note, that due to the design of the study, not all time points will be available for all 
patients.
Handling of missing data points is described in Section 6.6.
For endpoints where the “date of last contact” is utilized, the following will apply:

The last contact date when the patient was known to be alive is defined as the latest 
date recorded in the electronic Case Report Form (eCRF) from the dates listed below 
(in case an Adverse Event date is planned to be imputed for the analysis, the imputed 
date will also be used for the definition of “date of last contact”):
o
Date of last visit (e.g. for spirometry), date of last reported Adverse Event 
(AE) (excluding censored dates), date of last reported concomitant treatment, 
date of last laboratory sample, date of last drug intake, date of last reported 
dose change / interruption, end of study participation date (as documented on 
the End of Study eCRF page if the reason for not completing the planned 
observation period is NOT “Death”), vital status date (from the vital status 
eCRF page if the patient is known to be alive) and the latest of vital status date 
/ last successful contact date (from the End of Study eCRF page if the patient 
was lost to follow-up).
5.1
PRIMARY ENDPOINT(S)
The primary PK endpoint is the AUCτ,ss based on sampling at steady state (at week 2 and 
week 26 visit).
For patients receiving nintedanib in Part A, PK profiles on week 2 and week 26 are planned to 
be collected. For the primary endpoint AUCτ,ss the AUCτ,ss at week 2 will be used. If the
week 2 value is missing, then it will be replaced by available AUCτ,ss at week 26 (or later, if 
PK visit was postponed). For patients receiving placebo in Part A and nintedanib in Part B, 
AUCτ,ss evaluated based on
PK profiles at week 26 (or later, if PK visit was postponed) will be used (which corresponds 
to week 2 on active treatment).
The primary safety endpoint is the N (%) of patients with treatment-emergent adverse events 
at week 24, i.e., during the planned double-blind period of the trial.
Thus, the number of patients experiencing at least one adverse event during the double-blind 
period of the trial will be analyzed, see Section 7.8.
5.2
SECONDARY ENDPOINT(S)
5.2.1
Key secondary endpoint(s)
This section is not applicable as no key secondary endpoint has been specified in the CTP.


Boehringer Ingelheim                                                                        
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5.2.2
Secondary endpoint(s)
Endpoints will be used as defined in the CTP Section 2.1.3. Additional specifications are 
given below.
5.2.2.1
N (%) of patients with treatment-emergent pathological findings of epiphyseal 
growth plate on imaging at week 24, and week 52
Pathological findings which were already present at baseline imaging will NOT be considered 
treatment-emergent in this analysis, in spite identified after start of treatment, in order to be 
able to separate:

findings that were identified on the follow-up MRI/x-ray and were already present on 
the baseline MRI/x-ray (i.e. not treatment-emergent)

findings that were identified on the follow-up MRI/x-ray and were NOT already 
present on the baseline MRI/x-ray (i.e. treatment-emergent).
There are two possible kinds of predefined pathological findings for the growth plate recorded 
in the Safety Read Results:

Pathological Findings at the Distal Femur

Pathological Findings at the Proximal Tibia
A pathological finding of epiphyseal growth plate is defined as a pathological finding at the 
distal femur or the proximal tibia. 
More precisely,

Thickening of the epiphyseal growth plates

Swelling of articular cartilage
will be captured as pathological findings.
Whereas,

Narrowing of the lucent growth plate margin compared to the baseline time point (at 
post-baseline time points only)

Metaphyseal lines

Other findings
will only be captured as pathological findings if judged pathological.
Frequencies will be reported in a cumulative way over 24 and 52 weeks, respectively.
5.2.2.2
N (%) of patients with treatment-emergent pathological findings on dental 
examination or imaging at week 24, and week 52
Pathological findings which were already present at baseline imaging/examination will NOT
be considered treatment-emergent in this analysis, in spite identified after start of treatment, in 
order to be able to separate:

findings that were identified on the follow-up panoramic x-ray and were already 
present on the baseline panoramic x-ray (i.e. not treatment-emergent)

findings that were identified on the follow-up panoramic x-ray and were NOT already 
present on the baseline panoramic x-ray (i.e. treatment-emergent).


Boehringer Ingelheim                                                                        
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For the dental examination, pathological findings will be identified through the dental 
examination eCRF pages where the question ‘Is this a new abnormal finding’ is answered 
with ‘Yes’ and thus, an AE page is filled in.
If a baseline pathological finding is reported with a post-baseline worsening, it will be 
counted as treatment-emergent from the time point of worsening. 
For the dental imaging, a pathological finding is defined as at least one tooth being reported in 
the Safety Read Results with at least one of the following findings: 
1. Change in root length (at post-baseline time points only)
o
"Stunted growth (e.g., premature closing of the apex/apices with a blunted root 
appearance)"
o
“Accelerated growth (abnormally long roots exceeding 2/3rd the total length of 
the tooth)”
2. Extra/Supernumerary teeth
3. Impacted permanent teeth
4. Additional findings (“cyst present”, “abscess is present”, “solid lesion is present”, 
“bone abnormality is present”)
5. Additional findings “other findings” (incl. comment)
Frequencies will be reported in a cumulative way over 24 and 52 weeks, respectively.
5.2.2.3
N (%) of patients with treatment-emergent adverse events over the whole trial
The analysis will include all adverse events during the double-blind and open-label periods of 
the trial, see Section 7.8.1.
5.2.2.4
Change in height, sitting height, leg length from baseline at week 24, and week 
52, week 76, and week 100
The absolute change from baseline in height, the absolute change from baseline in sitting 
height and the absolute change from baseline in leg length will each be computed and 
evaluated separately.
As the sitting height has been measured incorrectly (i.e. total distance between the floor and
the top of patient’s head with the patient in a sitting position) at some sites (2), the main 
analysis of this endpoint will contain only the correctly measured (i.e. total distance between 
the sitting surface and the patients top of patient’s head with the patient in a sitting position). 


Boehringer Ingelheim                                                                        
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5.2.2.5
Change in Forced Vital Capacity (FVC) % predicted from baseline at week 24, 
and week 52
The absolute change from baseline in FVC % predicted (percent of predicted) at week 24 and 
week 52 will be used. The predicted values are calculated by the vendor according to Global 
Lungs Initiative (GLI) 2012 equations (4).
5.2.2.6
Absolute change from baseline in Pediatric Quality of Life Questionnaire 
(PedsQL) at week 24, and week 52
Health-related quality of life will be assessed using the PedsQL™ questionnaire. Depending 
on the age there are PedsQL™Young Child Report (ages <8 years), Child Report (ages 8-12 
years) and Report for Teens (ages >13.0 years). Furthermore, the respective Parent Reports
are filled in by the parents of the child. For more details see CTP Section 5.6.1. 
The questionnaire consists of 23 items and 4 dimensions: physical functioning, emotional
functioning, social functioning and school functioning.
The PedsQL™evaluation will primarily focus on the absolute change from baseline in the 
total score at week 24, and week 52.
In addition, the absolute change from baseline in the psychosocial health summary score (sum 
of emotional, social, and school functioning scales) and the absolute change from baseline in 
the physical health summary score (physical functioning score) will be presented.
A 5-point Likert response scale (0 = never; 1=almost never; 2=sometimes; 3=often; 4=almost 
always) is used in all cases except for the Young Child Report, where a 3-point scale (0=not 
at all; 2=Sometimes; 4=a lot) is used.
Items are reverse-scored and linearly transformed to a 0-100 scale (0 = 100, 1 = 75, 2 = 50, 3 
= 25, 4 = 0), so that higher scores indicate better health-related quality of life (HrQoL).
The specific instructions for deriving the PedsQL™ total score are provided in Appendix
Section 9.1.
5.2.2.7
Change in oxygen saturation (SpO2) on room air at rest from baseline at week 24, 
and week 52
Oxygen saturation on room air at rest will be analysed.
5.2.2.8
Change in 6-min walk distance from baseline at week 24, and week 52
The exercise capacity of the patient will be recorded as distance covered in 6 minutes on the 
respective eCRF page. Furthermore, continuous pulse oximetry (SpO2) will be performed and 
additional measurements such as pulse rate and blood pressure conducted.
The 6-minute walk test evaluation will primarily focus on the absolute change from baseline in 
the distance walked. Oxygen saturation measured by SpO2, vital signs and BORG CR-10 
Scales of the patient will be presented as scatterplots (each parameter versus age).
Only one value per period (pre-test, during test, post-test and recovery) patient, parameter and 
visit will be shown: for pulse rate, blood pressure and BORG scales the highest; for oxygen
saturation and walking time the lowest value. 
For more details please refer to CTP Section 5.1.6.


Boehringer Ingelheim                                                                        
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5.2.2.9
Patient acceptability based on the size of capsules at week 24
The acceptability questionnaire will be filled in by the patient. Further, to collect the 
investigator / site staff impression about the patient’s acceptability of the study medication 
intake, the treatment acceptability questionnaire for the investigator or investigational site 
staff will be completed by the investigator / site staff.
The answer to question 3 on the patient’s questionnaire “How is the size of the capsule” of the 
“Acceptability Questionnaire for the patient” will be used with categories 
“OK (=acceptable)”, “Large”, “Very large”.
On the investigator questionnaire, the question 3 “If the drug was not taken, was this due to 
(check all answers that you consider applicable for this patient at this point in time” and 
others will be assessed to retrieve more information on the acceptability and palatability of the 
capsules.
An analysis of patients not taking the 100 mg b.i.d. or 150 mg b.i.d. form, i.e. who take 4x25 
mg b.i.d. or 6x25 mg b.i.d., will be conducted in order to examine the swallowability.
5.2.2.10
Patient acceptability based on the number of capsules at week 24
The answer to question 4 “How easy was to swallow the given number of capsules” of the 
“Acceptability Questionnaire for the patient” will be used with categories “I had no problem
swallowing them (=acceptable)”, “I swallowed them, but it was difficult”, “I could not 
swallow them sometimes”.
See also Section 5.2.2.9.
5.2.2.11
Time to first respiratory-related hospitalization over the whole trial 
Time to first respiratory-related hospitalization assessment will be based on the date of 
hospitalization collected on a specific hospitalization eCRF page.
For those patients who experience a respiratory-related hospitalization, time to first respiratory-
related hospitalization [days] will be computed as:

Date of first respiratory-related hospitalization – date of first drug intake + 1
Patients who did not experience any event during their trial participation will be censored 
according to the mechanism for censoring as described in Table 5.2.2.11: 1.


Boehringer Ingelheim                                                                        
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Table 5.2.2.11: 1
Censoring Rules for Time to first respiratory-related hospitalization
over the whole trial
Rule #
Situation
Outcome
(event or 
censored)
Date of event or censoring
1
Patient had a documented 
respiratory-related
hospitalization and the date 
of the event is known
Event
Date of event
2
Patient had a documented 
respiratory-related
hospitalization and the date 
of the event is unknown
Event
Imputed date of event
(imputation see Section 
6.6.2.2)
3
Patient did not have a 
documented respiratory-
related hospitalization (no 
matter whether the patient
is alive or died or patient 
status is unknown)
Censored
Date of last contact when 
the patient was known to be 
alive and event free
5.2.2.12
Time to first acute Interstitial Lung Disease (ILD) exacerbation or death over the 
whole trial
For those patients who either experience acute ILD exacerbations or who die due to any cause 
at any point in the study, time to first acute ILD exacerbation or death [days] will be computed 
as:

Date of first documented acute ILD exacerbation or death (whichever occurs earlier) 
– date of first drug intake + 1
Patients who did not experience any event during their trial participation will be censored 
according to the mechanism for censoring as described in Table 5.2.2.12: 1.
Table 5.2.2.12: 1
Censoring Rules for Time to first acute ILD exacerbation or death over 
the whole trial
Rule #
Situation
Outcome
(event or 
censored)
Date of event or censoring
1
Patient had a documented 
acute ILD exacerbation or 
died and the date of the 
event is known
Event
Earliest Date of event


Boehringer Ingelheim                                                                        
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Table 5.2.2.12: 1
Censoring Rules for Time to first acute ILD exacerbation or death over 
the whole trial (continued)
Rule #
Situation
Outcome
(event or 
censored)
Date of event or censoring
2
Patient had a documented 
acute ILD exacerbation or 
died and the date of the 
event is unknown
Event
Imputed date of event
(imputation see Section 
6.6.2.2)
3
Patient did not have a 
documented acute ILD 
exacerbation and is alive
Censored
Date of last contact when 
the patient was known to be 
alive and event free
4
Patient status is unknown
Censored
Date of last contact when 
the patient was known to be 
alive and event free
5.2.2.13
Time to death over the whole trial
Date of death for an individual patient will be obtained from either the AE reporting page for 
patients with AEs leading to death or the information from the vital status assessment eCRF
page. The start date of time at risk is the date of first drug intake, and, in general, patients who 
did not die during the trial will be censored at the last known date when the patient was alive.
For patients with known date of death (regardless of the cause of death) at any point within the 
trial, the time to death will be computed as:

Date of death – date of first drug intake + 1
Patients who did not experience any event during their trial participation will be censored 
according to the mechanism for censoring as described in Table 5.2.2.13: 1.
Table 5.2.2.13: 1
Censoring Rules for Time to death over the whole trial
Rule #
Situation
Outcome
(event or 
censored)
Date of event or censoring
1
Patient died and date of 
Death is known
Event
Date of event
2
Patient died and date of 
Death is unknown
Event
Imputed date of event
(imputation see Section 
6.6.2.2)
3
Patient is alive
Censored
Date of last contact when 
the patient was known to be 
alive
4
Patient status is unknown
Censored
Date of last contact when 
the patient was known to be 
alive


Boehringer Ingelheim                                                                        
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Boehringer Ingelheim                                                                        
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Boehringer Ingelheim                                                                        
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5.4.1.1
Demographic data

Gender (Male; Female)

Ethnicity (Hispanic/Latino; Not Hispanic/Latino)

Race: single race respondents, multiple race respondents (all combinations ticked), and all 
race categories regardless of how many race categories were ticked

Age [years] at time of informed consent (transferred by IRT)*

Age at time of informed consent (transferred by IRT) in categories [years] (≥6 and <12; 
≥12 and <18)*

Weight [kg] at baseline and historical weight (up to 2 years prior to screening) as 
continuous variable and in classes (<13.5; ≥13.5 and <23; ≥23 and <33.5; ≥33.5 and 
<57.5; ≥57.5)

Height [cm] (standing and sitting) at baseline and historical (up to 2 years prior to 
screening)

Tobacco consumption (Never, Current, Former)

Pack years (for patients who tick “Current” or “Former” in the variable “Tobacco 
consumption”) as continuous variable 


Boehringer Ingelheim                                                                        
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Boehringer Ingelheim                                                                        
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Boehringer Ingelheim                                                                        
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5.4.3
Exposure
The date of first administration is recorded at visit 2 (day 1) for the blinded period and at visit 
6 (week 24) for the open-label period of the trial. The blinded exposure period ends with the 
first documented intake of the open-label treatment (day of visit excluded). Vice versa, the 
open-label exposure period begins with the first documented intake of the open-label 
treatment (day of visit included).
If the open-label exposure period is not started, then the double-blind exposure period ends 
with the day of last intake of blinded treatment.
All of the following definitions regarding exposure will be calculated separately for the 
double-blind period, the nintedanib exposure period and over the whole trial.
Duration of exposure [weeks] will be calculated as
Date of last administration - date of first administration during respective period + 1[days]
7
Treatment interruptions between date of first administration and date of last administration
during the respective period will not be subtracted from this duration of exposure.
Duration of exposure will be summarized as continuous variable [weeks] and in categories: 

Double-blind period:
o
<=2 weeks (14 days)
o
>2 to <=6 weeks (42 days)
o
>6 to <=12 weeks (84 days)
o
>12 to <=18 weeks (126 days)
o
>18 to <=24 weeks (168 days)
o
>24 weeks (168 days)

Nintedanib exposure period:
o
<=2 weeks (14 days)
o
>2 to <=6 weeks (42 days)
o
>6 to <=12 weeks (84 days)
o
>12 to <=24 weeks (168 days)
o
>24 to <=36 weeks (252 days)
o
>36 to <=52 weeks (364 days)
o
>52 to <=64 weeks (448 days)
o
>64 to <=76 weeks (532 days)
o
>76 weeks (532 days)
Further categories might be defined if needed.
Duration of exposure on dose assigned according to weight range [weeks] will be calculated 
per period as
Sum of durations on-treatment with dose effectively taken according to weight range [days]
7


Boehringer Ingelheim                                                                        
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Duration of exposure on reduced dose due to AE [weeks] will be calculated per period as
Sum of durations on-treatment with reduced dose effectively taken due to AE [days]
7
Calculating the duration of exposure on dose assigned according to weight range and on 
reduced dose due to AE, time periods with treatment interruptions as well as on dose reduced
due to other reasons will be excluded.
In case the weight of the patient on reduced dose reduces in a way to match this lower dose 
level, the duration of exposure on reduced dose ends.
Summary of dose changes will be presented, containing

N (%) of patients with at least one dose reduction

Number of dose reductions 

Reasons for dose reductions 

N (%) of patients with at least one dose increase

Number of dose increases 

Reasons for dose increases
Off-treatment duration [weeks] will be calculated per period as
Sum of all treatment interruption durations between date of first administration and date of 
last administration during the respective period [days]
7
Total dose [g] will be calculated as
Sum of durations of exposure on x g in respective period [days] *2 * x g, 
with x in 0.025, 0.05, 0.075, 0.1, 0.15.
Dose intensity [%] will be calculated as the amount of drug received during respective period
multiplied by 100% and divided by the amount of drug that would have been administered, 
i.e. dose xx mg bid (depending on the body weight) over the respective period (or until study 
discontinuation).
Dose intensity [%] will be summarized as continuous variable and in categories:

<=30%

>30 to <=50%

>50 to <=90%

>90 to <100%

>= 100%
Exposure-related time-to-event analyses will be performed for the following items:

Time to first dose reduction (not due to weight-based adjustment) [days]


Boehringer Ingelheim                                                                        
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
Time to first treatment interruption [days]

Time to premature treatment discontinuation [days]
Time-to-event [days] for exposure-related analyses is derived based on first study drug intake
in the respective study period as
Date of event/censoring – Date of first treatment intake + 1 day
For the above mentioned time-to-event analyses patients with no such event occurred during 
the respective period will be censored according to the mechanism for censoring as described 
in Table 5.4.3: 1.
Table 5.4.3: 1 Censoring rules for exposure-related time-to-event analyses
Rule #
Situation
Outcome 
(event/censored)
Date of event/censoring
1
Patient had a documented event during 
the respective period and the date of 
the event is known
Event
Earliest date of event
2
Patient had a documented event during 
the respective period and the date of 
the event is unknown
Event
Imputed date of event 
(as defined in Section 6.6.3.3)
3
Patient had no documented event 
during the respective period and 
already terminated study drug (last 
intake on End of treatment eCRF page 
available)
Censored
Date of last study drug intake
4
Patient neither had a documented event 
nor terminated study drug during 
respective period
Censored
Date of last study drug intake or 
end date of respective period, 
whichever is earlier
5.4.4
Liver enzyme and bilirubin elevations
The analysis of liver enzyme and bilirubin elevation will be done separately for each period 
(double-blind period, nintedanib exposure period, over the whole trial).
Liver enzyme and bilirubin elevations will be reported using the following definitions: 

(ALT and/or AST >=3 fold ULN) and bilirubin >=2 fold ULN [1]

ALT >=5 fold ULN and/or AST >=5 fold ULN

ALT >=3 fold ULN and/or AST >=3 fold ULN
[1] within a time window of 30 days i.e. the elevation of  bilirubin should appear within 30 days after the 
elevation of AST and/or ALT
The proportion of patients presenting signs of hepatic injury will be summarised, based on the 
following definition for signs of hepatic injury:

ALT and/or AST >=8 fold ULN

ALT and/or AST >=3 fold ULN and total bilirubin >=2 fold ULN [2]


Boehringer Ingelheim                                                                        
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
ALT and/or AST >=3 fold ULN and unexplained INR >1.5 [2]

ALT and/or AST >=3 fold ULN and unexplained eosinophilia (>5%) [2]

ALT and/or AST >=3 fold ULN and appearance of fatigue, nausea, vomiting, right 
upper abdominal quadrant pain or tenderness, fever and/or rash within +/- 7 days of 
the abnormal ALT and/or AST laboratory test result (please refer to Table 9.4: 1 for 
the list of relevant MedDRA preferred terms to support the derivation of a potential 
hepatic injury)
[2] in the same blood draw sample
In addition, maximum individual elevations based on worst value on treatment will be defined 
as:

>=3 fold ULN; >=5 fold ULN; >=8 fold ULN 
for AST and ALT and AST and/or ALT

>=1.5 fold ULN; >=2 fold ULN for Bilirubin

>=1.5xULN; >=2 fold ULN for alkaline phosphatase (ALK)

>=3xULN for Gamma-Glutamyl-Transferase (GGT)
Note: ULN refers to the Upper Limit of Normal from the central or local laboratory analysing 
samples.
5.4.4.1
Time-to-event analyses for liver enzyme elevations

Time to liver enzyme and bilirubin elevation (ALT and/or AST >= 3xULN and 
bilirubin >= 2xULN)

Time to liver enzyme elevation (ALT and/or AST >= 5xULN)

Time to liver enzyme elevation (ALT and/or AST >= 3xULN)
Time to first occurrence of the above described liver enzyme elevations [days] will be 
analyzed as
Date of event/censoring – Date of first treatment intake + 1 day.
Patients with no such event occurred during the respective period will be censored according 
to the mechanism for censoring as described in Table 5.4.4.1: 1.
Table 5.4.4.1: 1 Censoring rules for time to first occurrence of liver enzyme elevations
Rule
Situation
Outcome
Date of event/censoring
1
Patient had a documented event during 
treatment or REP[1] of respective period  
Event 
Earliest date of event
2
Patient had no documented event 
during treatment or REP[1] of respective 
period.
Censored
Earliest date of 

end date of REP of 
respective period, 

date of last contact when 
patient was known to be 
alive and event free, 

date of death. 
[1] See Sec. 6.1 for definition of Residual Effect Period (REP)


Boehringer Ingelheim                                                                        
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These times to onset of first event will also be summarized in categories:

Double-blind period:
o
<=2 weeks (14 days)
o
>2 to <=6 weeks (42 days)
o
>6 to <=12 weeks (84 days)
o
>12 to <=18 weeks (126 days)
o
>18 to <=24 weeks (168 days)
o
>24 weeks (168 days)
o
Censored

Nintedanib exposure period, over the whole trial:
o
<=2 weeks (14 days)
o
>2 to <=6 weeks (42 days)
o
>6 to <=12 weeks (84 days)
o
>12 to <=24 weeks (168 days)
o
>24 to <=36 weeks (252 days)
o
>36 to <=52 weeks (364 days)
o
>52 to <=64 weeks (448 days)
o
>64 to <=76 weeks (532 days)
o
>76 weeks (532 days)
o
Censored
Further categories might be defined if needed.
5.4.5
Vital signs
Weight minimum relative change from baseline will be summarized as continuous
variable and in categories:

Relative decrease of more than 10% (excl.)

Relative decrease of between 5% (excl.) and 10% (incl.)

Relative decrease of between 0% (excl.) and 5% (incl.)

Relative increase (>=0%)


Boehringer Ingelheim                                                                        
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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENT(S)
For treatment specifications, please refer to CTP Section 4.
The following trial periods will be defined: screening, post-randomization, blinded treatment 
period (with sub-periods treatment period, off-treatment, residual effect period and follow-
up), open-label treatment period (with sub-periods treatment period, off-treatment, residual 
effect period and follow-up), nintedanib exposure period (with sub-periods treatment period, 
off-treatment, residual effect period and follow-up), and post-study as follows
(Note: As described below, the last day of each of the following periods is excluded from the 
respective period. It defines the first day of the subsequent period):

Screening: from informed consent to randomization

Post-randomization (optional[a]): from randomization to first randomized trial drug 
intake in blinded treatment period

Double-blind period:
o
Blinded treatment period: from first randomized trial drug intake (or re-start of 
treatment if interruption) to last blinded trial drug intake (or the day before 
start date of interruption, if interruption) plus one day
o
Blinded off-treatment (optional[a]): from start date of interruption to re-start of 
blinded treatment
o
Residual Effect Period: the Residual Effect Period (REP) of nintedanib for the 
pediatric program is 28 days. This is the period from the last blinded trial drug 
intake plus one day to last blinded trial drug intake plus 28 days plus one day 
or the day of first open-label treatment administration (whichever occurs 
earlier)
o
Blinded follow-up (optional[a]): from last blinded trial drug intake plus 29 days 
up to the beginning of post-study period. This period is only created if last 
blinded trial drug intake took place more than 28 days before trial completion, 
or for patients having prematurely discontinued the blinded treatment and still 
continuing the trial

Nintedanib exposure period:
o
Nintedanib treatment period: from first nintedanib intake (or re-start of 
treatment if interruption) to last nintedanib intake (or the day before start date 
of interruption, if interruption) plus one day
o
Nintedanib off-treatment (optional[a]): from start date of interruption to re-start 
of nintedanib treatment
o
Nintedanib residual effect period: from the last nintedanib intake plus one day 
to last nintedanib intake plus 28 days plus one day
o
Nintedanib follow-up (optional[a]): from last nintedanib intake plus 29 days up 
to the beginning of post-study period. This period is only created if last trial 
drug intake took place more than 28 days before trial completion, or for 


Boehringer Ingelheim                                                                        
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patients having prematurely discontinued the treatment and still continuing the 
trial

Over the whole trial:
o
Whole trial treatment period: from first randomized trial drug intake (or re-start 
of  treatment if interruption) to last study drug intake (or the day before start
date of interruption, if interruption) plus one day
o
Whole trial off-treatment (optional[a]): from start date of interruption to re-start 
of treatment
o
Whole trial residual effect period: from the last trial drug intake plus one day 
to last trial drug intake plus 28 days plus one day
o
Whole trial follow-up (optional[a]): from last trial drug intake plus 29 days up 
to the beginning of post-study period. This period is only created if last trial 
drug intake took place more than 28 days before trial completion, or for 
patients having prematurely discontinued the treatment and still continuing the 
trial

Open-label period:
o
Open-label treatment period: from first open-label nintedanib intake (or re-start 
of  treatment if interruption) to last open-label nintedanib intake (or the day 
before start date of interruption, if interruption) plus one day
o
Open-label off-treatment (optional[a]): from start date of interruption to re-start 
of open-label treatment
o
Open-label residual effect period: from the last open-label trial drug intake plus 
one day to last open-label trial drug intake plus 28 days plus one day
o
Open-label follow-up (optional[a]): from last open-label trial drug intake plus 
29 days up to the beginning of post-study period. This period is only created if 
last open-label trial drug intake took place more than 28 days before trial 
completion, or for patients having prematurely discontinued the open-label 
treatment and still continuing the trial

Post-study period: from the latest of
o
last trial drug intake plus 29 days
o
end of study participation date (from the End of Study page of the eCRF)
o
follow-up visit
o
early end of treatment visit plus 1 day .
This period is not created if date of first trial drug intake in extension trial is before 
last trial drug intake plus 28 days.
[a] This period is optional insofar as it does not necessarily exist for all patients.
Assessments on day of first open-label intake will be handled as follows: 

Assessments with time record: period is assigned based on time stamp (if time lies 
prior to open-label start then double-blind period; otherwise, open-label period)

Assessments without time record: assigned to double-blind period, even if interruption 
prior to open-label start (if interruption longer than REP, then assessment falls into 
double-blind follow up period and thus, will not be evaluated anymore).

Exception: AEs and concomitant medications with start date on day of open-label start 
will be assigned to the open-label period.


Boehringer Ingelheim                                                                        
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Further details will be specified in the ADS plan.
If in the double-blind period an interruption is not followed by a re-start of blinded treatment
then this is counted as (early) discontinuation of the blinded treatment period.
Over the whole trial, this will be counted as whole trial off-treatment period.
For safety analyses, data up to the end of the double-blind residual effect period / whole trial
residual effect period / nintedanib residual effect period will be considered on-treatment. 
For on-treatment efficacy analyses, data up to the day after last trial drug intake (included) 
will be considered.
6.2
IMPORTANT PROTOCOL DEVIATIONS
Handling of iPDs in analysis is included in the DV domain specifications and stored within 
the TMF in EDMS. 
6.3
SUBJECT SETS ANALYZED
The following analysis sets are defined for this trial:

Screened set (SCS): 
This patient set includes all patients having signed informed consent.

Randomised set: (RS)
This patient set includes all randomised patients, whether treated or not.

Treated Set (TS):
The Treated Set (TS) consists of patients who are randomized to a treatment group and 
receive at least one dose of study medication.

Pharmacokinetic parameter analysis set (PKS): 
This set includes all patients in the treated set (TS) who provide at least one PK 
endpoint that was not excluded due to a protocol deviation relevant to the evaluation 
of PK or due to PK non-evaluability (as specified in the CTP Sec. 7.2.1.). Thus, a 
patient will be included in the PKS, even if he/she contributes only one PK parameter 
value for one period to the statistical assessment. Descriptive and model based 
analyses of PK parameters will be based on the PKS. 
Analyses for PK endpoints will be based on the PKS. All other analyses will be based on the 
TS except for disposition.


Boehringer Ingelheim                                                                        
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Table 6.3: 1
Patient sets analyzed
Patient set
Class of endpoint
SCS
TS
PKS
Primary endpoint PK 
X
Primary endpoint Safety 
X
Secondary endpoints 
X
Further endpoints Efficacy
X
Further endpoints PK
X
Safety endpoints 
X
Demographic/baseline 
characteristics
X
Disposition
X
Note that the number of patients with available data for an endpoint may differ. For details, see Section 6.6


Boehringer Ingelheim                                                                        
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6.5
POOLING OF CENTRES
This section is not applicable because centre/country is not included in the statistical model.
6.6
HANDLING OF MISSING DATA AND OUTLIERS
In general, missing data will not be imputed. Exceptions are detailed in the subsequent 
subsections.
6.6.1
Primary endpoint
Missing data and outliers of PK data are handled according to (7). For patients receiving 
nintedanib in Part A, PK profiles on week 2 and week 26 are planned to be collected. For the 
primary endpoint AUCτ,ss the AUCτ,ss at week 2 will be used. If the week 2 value is 
missing, then it will be replaced by available AUCτ,ss at week 26 (or later, if PK visit was 
postponed).
Missing or incomplete AE dates will be imputed according to BI standards (see “Handling of
missing and incomplete AE dates”) (8).
6.6.2
Secondary and further endpoints
6.6.2.1
Change from baseline endpoints
The statistical Mixed effect Model for Repeated Measures (MMRM) used for the analysis of 
continuous secondary endpoints allows for missing data, assuming they are missing at 
random. 
Item-level data for the PedsQLTM questionnaires will be handled according to the instructions 
provided by the instrument developer (see Appendix Section 9.1). 
If no FVC measurement prior to first trial drug intake is available, the baseline FVC value 
will be imputed with the earliest FVC value obtained after (but on the same day as) the first 
trial drug intake. 


Boehringer Ingelheim                                                                        
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According to (7), other missing biomarker data (NOS - no sample available, NOR - no valid 
result, NOA - not analysed) will not be imputed.
Data below or above the limit of quantification (BLQ or ALQ) for biomarkers will be handled 
as follows:

BLQ data will be replaced by 0.5 LLOQ (lower limit of quantification). Hereby LLOQ 
will be the maximum used lower reference limit for classification of BLQs. All values 
lower than LLOQ will be imputed (regardless of whether they are classified as BLQ or 
not).

ALQ data will be replaced by ULOQ (upper limit of quantification), if ULOQs are 
available and are greater than observed study values (i.e. the highest solution will be 
applied for the measurement). Otherwise, ALQ data will be excluded from the 
analysis.
6.6.2.2 
Time-to-event endpoints
In the analyses of the time-to-event endpoints, missing or incomplete data will be managed by 
standard survival analysis techniques (i.e. censoring). If a patient has no event then he will be 
censored as described in Section 5.2.2.
A missing or incomplete date of death will be imputed/completed that the derived date is the 
earliest possible date which is on or after date of onset of the fatal AE, and on or after 
treatment start (in case this AE is treatment-emergent), and on or after derived date of last 
contact.
For the time to first respiratory-related hospitalization, or time to first acute ILD exacerbation, 
in case of partially missing dates, the following imputation will be done:

If day is missing, then imputed day will be the 15th of the month

If day and month are missing, then imputed date will be the 1st of July of the (non-
missing) year

If year is missing, date will not be imputed
6.6.2.3 
Categorical endpoints
In the analyses of the binary endpoints, multiple imputation will be used to handle missing 
data at week 24. For week 52 and later, data will not be imputed and only observed values 
will be used. 
The following process describes the multiple imputation for spirometry data (FVC % pred.
and SpO2) and for PedsQLTM point data. Therefore, the words “data” and “value” stand for 
the data and value of the respective kind of data to be imputed.
In a first step non-monotone missing data will be imputed m = 100 times using MCMC 
(Markov Chain Monte Carlo) to generate m data sets of longitudinal data with monotone 
missingness pattern. Such a missingness pattern is the pre-requisite for subsequently applying 
sequential imputation and means that once a patient has a missing value at a particular time 
point, the corresponding values at all subsequent time points also have missing values. The 
seemingly large number of imputations (m=100) is chosen to minimize the standard error of 
those estimates that are produced to fill the missing values. The seed number will be set to 


Boehringer Ingelheim                                                                        
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1199337. For this step all available data of the respective kind will be used, restricted to one 
value per patient and analysis time window according to selection process described in 
Section 6.7 below.
In a second step a regression model including baseline value and measurements at all post-
baseline analysis visits scheduled (see Table 6.7: 1 and Table 6.7: 6, respectively) by 
treatment, will be used to complete the imputation in each dataset. 
For each imputed complete dataset, the proportion of non-responders (and the corresponding 
standard error) will be used for the analysis. The results will be pooled following the standard 
multiple imputation procedure (9).
Patients with missing baseline value will be excluded from the analysis.
6.6.2.4
Endpoints based on MRI/x-ray
Patients will complete the baseline MRI/x-ray within the first 2 weeks after randomization. As 
for the imaging variables we do not expect a change through treatment within the first two 
weeks wherefore a measurement within the first two weeks can still be considered as baseline 
in this special case. The same holds for dental examination.
6.6.2.5
6-min walk test (6MWT)
In case the earliest assessment of the 6MWT is on treatment start day after treatment start 
time, then the whole 6MWT (pre-, during and after) assessment can still be counted as 
baseline assessment.


Boehringer Ingelheim                                                                        
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6.6.3.3 
Exposure
6.6.3.3.1 
Permanent trial drug discontinuation
A missing or incomplete date of last trial drug intake will be imputed that the derived date is
the latest possible date which is on or before date of death, and on or before last contact date
from End of Study eCRF page.
6.6.3.3.2
Treatment interruptions
For the definition of off-treatment periods an incomplete start or end date for a treatment
interruption will be imputed the same way as specified for time-to-event analyses in
Section 6.6.2.2. For duration of interruption no imputation will be applied, i.e. interruptions
with missing or incomplete start or end date will have duration missing. Overall duration of
interruptions per patient will be missing in these cases as well.
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
As a general rule, the last assessment/measurement observed prior to start of trial medication
will be used as baseline. If the time of the assessment/measurement was not captured, and it 
was on the same day trial medication started, it will be assumed that it was taken prior to the 
intake of trial medication. For the nintedanib-exposure period, the last measurement prior to 
the first nintedanib intake was defined as the baseline measurement.
Visit windowing will be performed as described in the following tables, in order to assign 
data to the relevant study visit based on the actual day of the assessment. Data will be
analyzed using the re-calculated visits in the statistical tables. However, in the listings, all
visits performed will be displayed (even if outside time-window), along with the re-calculated
visit. 
Exception:
to account for the short timespan between planned visit 6 (with first open-label intake) and 
visit 7, a special rule is applied to analyses by visit (not cumulative across visits) in case 
assignment to visit windows leads to missing values at visit 6 or subsequent visit to take 
possible multiple measurements in the respective other time window into account. 
If such an assessment lies in analysis visit window of visit 7, but not later than 1 month after 
the planned day of visit 7 and still within the double-blind period, then it is allocated to the 
analysis visit 6. 


Boehringer Ingelheim                                                                        
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Similarly, if such an assessment lies in analysis visit window of visit 6, but after the planned 
day of visit 6 and not within the double-blind period, then it is allocated to the subsequent
visit where this assessment is planned.
If after windowing of visits at baseline, two or more values fall within the same baseline 
interval, then the last value prior to first drug intake will be taken into account. If after 
windowing of post-baseline visits, two visits fall in the same interval, then the measurement
closest to the planned visit will be taken into account. If only on-treatment values are to be 
considered, this rule will be applied to on-treatment assessments only. In case two 
measurements are equidistant from the planned visit, then the last one will be picked.
Table 6.7: 1
Time windowing rules for FVC, SpO2, missed school days, vital signs (syst. 
and diast. blood pressure, pulse rate) and laboratory tests (incl. LDH)
Time window of actual day[1,2]
Allocated to
Start day
End day 
(included)
Length of the 
time-window 
[days]
Visit 
number
Visit name
Planned day 
of the visit
-84
1
85
2
Baseline
1
2
29
28
3
2 weeks
15
30
64
35
4
6 weeks
43
65
127
63
5
12 weeks
85
128
176
49
6
24 weeks
169
177
218
42
7
26 weeks
183
219
309
84
8
36 weeks
253
310
407
112
9 (p)
52 weeks
365 (Vp)
(Vp + 1) + 
(Vp+1 - Vp)/2
Vp+1 + 
(Vp+2 - Vp+1)/2
(Vp+2 - Vp)/2
p+1
Vp+1 = 
Vp + 12 x 7
…
...
…
…
Every 12 
weeks 
thereafter
…
Vp denotes the planned day of the visit
[1] First trial drug intake date is taken into account as reference to calculate time windows
[2] Only for LDH biomarker analyses: Biomarker values are only considered up to + 7 days after last drug intake.


Boehringer Ingelheim                                                                        
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Table 6.7: 2
Time windowing rules for weight
Time window of actual day[1]
Allocated to
Start day
End day 
(included)
Length of the 
time-window 
[days]
Visit 
number
Visit name
Planned day 
of the visit
-84
1
85
2
Baseline
1
2
29
28
3
2 weeks
15
30
64
35
4
6 weeks
43
65
127
63
5
12 weeks
85
128
211
84
6
24 weeks
169
212
309
84
8
36 weeks
253
310
407
112
9 (p)
52 weeks
365 (Vp)
(Vp + 1) + 
(Vp+1 - Vp)/2
Vp+1 + 
(Vp+2 - Vp+1)/2
(Vp+2 - Vp)/2
p+1
Vp+1 = 
Vp + 12 x 7
…
...
…
…
Every 12 
weeks 
thereafter
…
Vp denotes the planned day of the visit
[1] First trial drug intake date is taken into account as reference to calculate time windows


Boehringer Ingelheim                                                                        
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Table 6.7: 3
Time windowing rules for height and leg length
Time window of actual day[1]
Allocated to
Start day
End day 
(included)
Length of the 
time-window 
[days]
Visit 
number
Visit name
Planned day 
of the visit
-84
1
85
2
Baseline
1
2
127
126
5
12 weeks
85
128
211
84
6
24 weeks
169
212
309
98
8
36 weeks
253
310
449
140
9 (p)
52 weeks
365 (Vp)
(Vp + 1) + 
(Vp+1 - Vp)/2
Vp+1 + 
(Vp+2 - Vp+1)/2
(Vp+2 - Vp)/2
p+1
Vp+1 = 
Vp + 24 x 7
…
...
…
…
Every 24
weeks 
thereafter
…
Vp denotes the planned day of the visit
[1] First trial drug intake date is taken into account as reference to calculate time windows


Boehringer Ingelheim                                                                        
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Table 6.7: 4
Time windowing rules for dental examination and bone imaging
Time window of actual day[1]
Allocated to
Start day
End day 
(included)
Length of the 
time-window 
[days]
Visit 
number
Visit name
Planned day 
of the visit
-84
15
99
2
Baseline[2]
1
16
127
112
5
12 weeks
85
128
211
84
6
24 weeks
169
212
309
98
8
36 weeks
253
310
449
140
9 
52 weeks
365 (Vp)
450
617
168
11 (p)
76 weeks
533
(Vp + 1) + 
(Vp+1 - Vp)/2
Vp+1 + 
(Vp+2 - Vp+1)/2
(Vp+2 - Vp)/2
p+1
100 weeks
Vp+1 = 
Vp + 24 x 7
…
...
…
…
Every 24
weeks 
thereafter
…
Vp denotes the planned day of the visit
[1] First trial drug intake date is taken into account as reference to calculate time windows
[2] For assessments in baseline window: if available prior to first trial drug intake, use the latest one of those. If only 
assessments available after first trial drug intake, use the one closest to the planned day as baseline value.


Boehringer Ingelheim                                                                        
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Table 6.7: 5
Time windowing rules for dental imaging
Time window of actual day[1]
Allocated to
Start day
End day 
(included)
Length of the 
time-window 
[days]
Visit 
number
Visit name
Planned day 
of the visit
-84
15
99
2
Baseline[2]
1
16
267
252
6
24 weeks
169
268
533
266
9 (p)
52 weeks
365 (Vp)
(Vp + 1) + 
(Vp+1 - Vp)/2
Vp+1 + 
(Vp+2 - Vp+1)/2
(Vp+2 - Vp)/2
p+1
Vp+1 = 
Vp + 48 x 7
…
...
…
…
Every 48
weeks 
thereafter
…
Vp denotes the planned day of the visit
[1] First trial drug intake date is taken into account as reference to calculate time windows
[2] For assessments in baseline window: if available prior to first trial drug intake, use the latest one of those. If only 
assessments available after first trial drug intake, use the one closest to the planned day as baseline value.
Table 6.7: 6
Time windowing rules for data from PedsQL questionnaire, 6MWT, Borg CR-
10 scale®
Time window of actual day[1]
Allocated to
Start day
End day 
(included)
Length of the 
time-window 
[days]
Visit 
number
Visit name
Planned day 
of the visit
-84
1
85
2
Baseline
1
2
267
266
6
24 weeks
169
268
463
196
9
52 weeks
365
[1] First trial drug intake date is taken into account as reference to calculate time windows
This time windowing will be applied to the following data: PedsQL and 6MWT, Borg CR-10 scale 


Boehringer Ingelheim                                                                        
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Table 6.7: 7
Time windowing rules for data from acceptability questionnaire
Time window of actual day[1]
Allocated to
Start day
End day 
(included)
Length of the 
time-window 
[days]
Visit 
number
Visit name
Planned day 
of the visit
2
92
91
3
2 weeks
15
93
309
217
6
24 weeks
169
[1] First trial drug intake date is taken into account as reference to calculate time windows


Boehringer Ingelheim                                                                        
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7.
PLANNED ANALYSIS
Unless otherwise specified, all analyses described in this section will be done on the Treated 
Set. The labelling and display format of statistical parameters will follow BI standards (10). 
For End-Of-Text (EoT) tables, the set of summary statistics is: N / Mean / SD / Min / Median 
/ Max. 
In descriptive statistics tables, mean, SD and median will be rounded to one additional digit 
than the raw individual value. In case some endpoints show some extreme data outside the 
expected range, quartiles and percentiles will be presented additionally.
Tabulations of frequencies for categorical data will include all possible categories and will
display the number of observations in a category as well as the percentage (%) relative to the 
respective treatment group (unless otherwise specified, all patient in the respective subject set
whether they have non-missing values or not). The precision for percentages should be one 
decimal point. The category missing will be displayed only if there are actually missing 
values.
Unless otherwise specified, all analyses will be provided by randomized treatment group 
(placebo or nintedanib) and overall (total).
For efficacy and safety end point analyses by time point, as well as for the safety analyses of 
Part A, patients switching during Part A to Part B will be censored at the time point of the 
switch and for the safety analyses of Part A (due to the definition of the double-blind period). 
Patients who started directly in Part B will be analyzed as a separate cohort, in addition to 
those randomized to nintedanib and those randomized to placebo.
All analyses performed after DBL1 will be repeated after DBL2 to include newly emerging 
data.
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Only descriptive statistics are planned for this section of the report. A table in the CTR will 
present the number of patients screened, randomised and treated. The number of patients 
prematurely discontinuing their study treatment will be shown with the reasons for 
discontinuation. The number and percent of patients completing the end of treatment visit and 
the number of patients with treatment ongoing will also be presented. Please note there will be 
ongoing patients at the time of the data cut-off for the primary analysis; at the time point when 
the final analysis will take place there will not be any more ongoing patients in this trial. Where 
percentages are shown, the denominator will be the number of patients treated in each treatment 
group.
Descriptive statistics as well as frequency counts will be provided for all demographic and 
baseline characteristics depicted in Section 5.4.1. The CTR tables will show the relevant 
descriptive statistics (number and percent within categories; other descriptive statistics for 
continuous variables) by treatment arm.


Boehringer Ingelheim                                                                        
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Boehringer Ingelheim                                                                        
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7.4
PRIMARY ENDPOINT(S)
The primary endpoints are the PK endpoint AUCτ,ss based on sampling at steady state (at 
week 2 and week 26) and the safety-endpoint N (%) of patients with treatment-emergent 
adverse events at week 24.
7.4.1
Primary analysis of the primary endpoint(s)
7.4.1.1
PK endpoint
AUCτ,ss based on sampling at steady state will be calculated as specified in the CTP Sections
7.2.1 and 7.2.2. For patients receiving nintedanib in Part A, PK profiles on week 2 and week 
26 are planned to be collected. For the primary endpoint AUCτ,ss the AUCτ,ss at week 2 will 
be used. If the week 2 value is missing, then it will be replaced by available AUCτ,ss at week 
26 (or later, if PK visit was postponed). For patients receiving placebo in Part A and 
nintedanib in Part B, AUCτ,ss evaluated based on PK profiles at week 26 (or later, if PK visit 
was postponed) will be used as primary endpoint (which corresponds to week 2 on active 
treatment). See also Section 6.6.1.


Boehringer Ingelheim                                                                        
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To account for potential dose reductions, AUCτ,ss will be dose normalized by the actual dose 
taken by the patient corresponding to that PK sampling. The dose normalized AUCτ,ss for 
nintedanib (AUCτ,ss_D) will be summarised descriptively.
AUCτ,ss will additionally be derived using population PK modelling (for all patients with at 
least one valid PK sample). Details of the analysis will be reported separately in the popPKPD 
report, but the main AUCτ,ss results also will be included in the CTR.
The 95% CI of nintedanib CL/Fss will be calculated according to company standards.
All PK analyses will be based on the pharmacokinetic analysis set (PKS), see Section 6.3.
7.4.1.2
Safety endpoint
Only descriptive analyses will be performed. The number and frequency of patients with 
treatment-emergent adverse events by primary system organ class (SOC) and preferred term 
(PT) during the double-blind period, as described in Section 7.8.1, will be displayed.
7.5
SECONDARY ENDPOINT(S)
Please note that any p-value presented will be considered nominal in nature and no adjustment for 
multiplicity will be made.
7.5.1
Key secondary endpoint(s)
This section is not applicable as no key secondary endpoint has been specified in the protocol.


Boehringer Ingelheim                                                                        
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7.5.2
(Other) Secondary endpoint(s)
7.5.2.1
Continuous (change from baseline) endpoints 
The continuous secondary endpoint analysis will be based on the TS (according to randomised 
treatment), using available data from all visits (after time-windowing) from Part A and Part B 
and the estimate and contrast between treatments at the applicable endpoint visits will be 
used.
The analysis of continuous secondary endpoints is a restricted maximum likelihood (REML) 
based approach using a Mixed effect Model for Repeated Measures (MMRM). The analysis 
will include the fixed, categorical effects of treatment at each visit, age-group and the fixed 
continuous effects of baseline at each visit. Visit will be treated as the repeated measure with 
an unstructured covariance structure used to model the within-patient measurements.
Patients will be analyzed according to the age group stratum to which they belong to based on 
the data entered in the eCRF, which may not necessarily coincide with data used for 
randomisation.
The Kenward-Roger approximation will be used to estimate denominator degrees of freedom
and adjust standard errors. Significance tests will be based on least-squares means (two-sided 
95% confidence intervals will be presented). The primary treatment comparison will be the 
contrast between treatments at the endpoint visit.
In the event of non-convergence, the following methods will be attempted (in order) to
overcome it:
1. Add the ‘singular=1e-10’ option in the model statement – This raises the threshold 
at which columns are declared linearly dependent (from typically 1e-12).
2. Set ‘maxiter=100’ in the Proc Mixed statement – This increases the number of
convergence iterations used from a default of 50.
3. Set ‘scoring=4’ to specify use of the Fisher scoring algorithm in the first 4 iterations.
4. Exclude all visits > 24 weeks and report weeks > 24 data only descriptively (ANOVA) 
using observed data.
5. Include the statement ‘performance nothread’ – this removes multi-threading from 
the calculations.
6. Provide starting values for covariance parameters using a ‘ parms ’ statement.
Estimates will be obtained from using a simpler covariance matrix.
7. Should none of the previous methods work, the covariance matrix will be changed from 
unstructured to Toeplitz with heterogeneous variances (TOEPH). Should this also not 
converge, a standard Toeplitz matrix (TOEP) will be fitted. Finally, if convergence still 
does not occur, then an order-1 autoregressive matrix (AR(1)) will be fitted.
Additionally, a descriptive analysis for all time points will be done. 


Boehringer Ingelheim                                                                        
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7.5.2.2
Time-to-event endpoints
Separate Kaplan-Meier plots will be presented by randomised treatment group and overall 
(total group) for time-to-event endpoints defined in Section 5.2.2. Kaplan Meier estimates and 
confidence intervals (using Greenwood variance formula) for the cumulated time-to-event 
rate will be calculated at 24 weeks and at 52 weeks. Q1, median and Q3 of the time to event 
will be presented, if reached. No statistical test will be performed.
7.5.2.3
Categorical endpoints, safety and tolerability endpoints
Only descriptive analyses in the form of frequency tables will be performed.


Boehringer Ingelheim                                                                        
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Boehringer Ingelheim                                                                        
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Boehringer Ingelheim                                                                        
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Boehringer Ingelheim                                                                        
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Boehringer Ingelheim                                                                        
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7.8
SAFETY ANALYSIS
7.8.1
Adverse Events
Adverse events will be coded using the current Medical Dictionary for Regulatory Activities
(MedDRA) version in use at BI at the time of database lock. The analyses of AEs will be 
descriptive in nature.
All analyses of AEs will be based on the number of patients with AEs and NOT on the 
number of AEs. To account for the variable length of exposure to treatment in both study 
periods tables will be presented including count and percentage of patients with AE and the 
incidence rates of AEs with time at risk and rate per 100 patient years. Please refer to Section 
7.8.1.1 for further details on the derivation of time at risk and exposure-adjusted incidence 
rates.
Since this study consists of a double-blind, placebo-controlled part and an open-label part
with nintedanib treatment only, three treatment periods will be used for analysis and 
definition of “treatment-emergent”:
1. Double-blind period: Analyses of AEs will be presented by treatment group and overall. 
Only adverse events with onset or worsening on or after date of treatment start until end of 
double-blind period (defined as the day before first intake of open-label nintedanib or last 
double-blind drug intake + residual effect period, whichever is earlier) will be considered as 
treatment-emergent and will be included in the analysis. Adverse events will be counted under
the treatment as randomized for the double-blind period.
2. Nintedanib exposure period: Analyses of AEs will be presented by randomized treatment 
group and overall. All adverse events with onset or worsening on or after first intake of 
nintedanib (double-blind or open-label period) until last intake of nintedanib (double-blind or 
open-label period) + residual effect period will be considered as treatment-emergent and will 
be included in the analysis.


Boehringer Ingelheim                                                                        
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3. Over the whole-trial: Analyses of AEs will be presented by treatment group and overall. 
All adverse events with onset or worsening on or after date of treatment start until last drug 
intake + residual effect period will be considered as treatment-emergent and will be included 
in the analysis. Adverse events will be counted under the treatment as randomized for the 
double-blind period.
In case an AE starts on first day of open-label treatment, it is assigned to the open-label period 
(and not to the double-blind period).
For further details on summarization of AE data, please refer to (8, 17).
All AEs occurring before first trial drug intake will be assigned to ‘Screening period’ and all 
AEs occurring after the residual effect period will be assigned to ‘Follow-up period’ or ‘Post-
study period’ (for listings only). All adverse events occurring between the start and the end of 
an interruption of the trial drug will be assigned to ‘off-treatment’ period in the listings. For 
details on the treatment definition, see Section 6.1.
According to ICH E3 (18), in addition to deaths and serious adverse events, ‘other significant’ 
AEs need to be listed in the clinical trial report. These will be any non-serious adverse event 
that led to an action taken with study drug (e.g. discontinuation or dose reduced).
Summary tables will be produced for non-serious adverse events meeting part (i) of the
definition. Part (ii) of the definition will be covered by the analysis of laboratory data. Please
refer to Section 7.8.2 for further information.
Adverse events related to gastrointestinal perforation, bleeding and hepatic injury, 
pathological findings identified on bone imaging and stunted growth identified on dental 
imaging are considered as protocol-specified AEs of special interest (AESIs), and are ticked 
as such in the eCRF.
Analysis of AEs in double-blind period:
An overall summary of AEs will be presented by treatment group and overall for the double-
blind period of the study.
The following tables will also present number and percentages of patients with respective AEs 
and in addition the incidence rates of AEs with time at risk and rate per 100 patient years by 
treatment and overall. Please refer to Section 7.8.1.1 for further details on the derivation of 
time at risk and exposure-adjusted incidence rates.
The frequency of patients with adverse events, will be summarized by primary system organ 
class (SOC) and preferred term (PT). The system organ classes (SOC) will be sorted 
according to the standard sort order specified by EMA, preferred terms will be sorted by 
decreasing frequency in the total column (within SOC).
Separate tables will also be provided for patients with

serious AEs (SAEs)

severe AEs

other significant AEs (as defined by point (i) of the ICH E3 definition indicated 
above)

AEs leading to dose reduction

AEs leading to permanent treatment discontinuation


Boehringer Ingelheim                                                                        
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
investigator defined drug-related AEs

AEs leading to death

protocol-specified AEs of special interest (AESIs) (as ticked on the AE page of the 
eCRF)

investigator defined drug-related SAEs

AEs grouped by safety topic
Adverse event groupings by safety topic have been defined outside the trial protocol, which 
will be continuously updated at project level (19). These safety topics are deemed of 
particular importance, and these definitions can be based on selection of coded terms based on 
MedDRA. The latest approved version of the project level overview archived prior to the 
respective DBL will be used in the CTR. 
The frequency of patients with adverse events within these groupings will be summarized by 
system, safety topic, subcategory (if applicable) and preferred term. These displays will focus 
on patients with any adverse event, patients with serious adverse events and patients with 
investigator defined drug-related adverse events. 
Systems will be presented in alphabetical order. Safety topics, subcategories (if applicable) 
and preferred term will be sorted by decreasing frequency in the total column (within system, 
safety topic or subcategory).
Analysis of AEs during nintedanib exposure period:
All tables as described for double blind period will be repeated for AEs during nintedanib 
exposure period for nintedanib treatment only.
Analysis of AEs over the whole-trial:
All tables as described for double blind period will be repeated for AEs in the whole-trial 
period presenting results by treatment group and overall.
7.8.1.1 
Adjudicated adverse events
An independent adjudication committee will review all fatal cases and adjudicate cause of 
death to respiratory, cardiovascular or other. The adjudication committee will also review all 
AEs categorized as MACE according to the definition in the adjudication charter.
In addition to standard safety analyses, the frequency of patients with AEs leading to death 
will be summarized by treatment, adjudicated cause of death (Cardiovascular, Respiratory or 
Other), and PT.
The frequency of patients with AEs categorized as MACE (that is all AEs categorized as 
MACE and therefore sent for adjudication) will be summarized by treatment and outcome of 
adjudication (adjudicated as MACE or adjudicated as not MACE). The frequency of patients 
with AEs adjudicated as MACE will also be summarized by treatment and PT.
7.8.1.2 
Exposure adjusted analysis of adverse events over the whole trial
Time at risk and incidence rates per 100 patient-years will be calculated based on the first
onset of an AE in the trial.
Time at risk:
For a specific AE, the total AE time at risk [years] is defined as


Boehringer Ingelheim                                                                        
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∑Time at risk (days) across all contributing patients
365.25
with for each subject the time at risk [days] is defined as follows:

Date of first onset of the AE – date of first study drug intake +1 day
for patients with the specific AE,

End of time at risk – date of first study drug intake + 1 day
for patients without the specific AE.
The end of time at risk is defined as the minimum of 

end date of the double-blind, whole-trial and nintedanib exposure treatment period, 
respectively (incl. REP)

date of last contact (for definition see Sec. 5)

date of death

date of the (interim) database lock.
For the double-blind treatment period, end of time at risk is the day before start of open-label 
period, in case the patient started open-label treatment before end of double-blind REP.
AE incidence rate:
The AE incidence rate [1/100 patient-years (pt-yrs)] will be calculated as
100 x (Number of patients with specific AE)    
Total specific AE time at risk [years]
The 95% confidence intervals for incidence rates are derived using the method described by
Rothman and Greenland (2008) (20).
7.8.1.3
Adverse events with additional information collection
Diarrhea, bleeding and ILD are AEs with additional AE-specific information collected on the 
eCRF. These are investigator reported on the eCRF and will be identified using this 
information for this analysis. That is if the diarrhea information has been completed for an 
adverse event then the adverse event will be considered as diarrhea for this analysis regardless 
of subsequent MedDRA coding of the verbatim term. Likewise, if the bleeding information 
has been completed for an adverse event then the adverse event will be considered as bleeding 
for this analysis regardless of subsequent MedDRA coding of the verbatim term. The same 
applies to ILD.
The frequency of patients with AEs with additional information collection will be 
summarized by treatment group and overall, primary SOC and PT and separately for diarrhea, 
bleeding and ILD. The additional information collected will also be summarized at the AE 
level (occurrence level) rather than at the patient level separately for diarrhea, bleeding and 
ILD. These analyses will be provided by analysis periods and treatment group and overall, 
where applicable.


Boehringer Ingelheim                                                                        
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For the time to first onset of diarrhea, bleeding or ILD, respectively, Kaplan-Meier plots by 
treatment will be created taking into account the respective data over the whole trial. Kaplan-
Meier plots of the double-blind period and the nintedanib exposure period will be created as 
well. The same censoring rules as for time to first liver enzyme elevation trial will be used, 
see Section 5.4.4.1 for details.
7.8.1.4
Pathological findings of epiphyseal growth plate on imaging, on dental
examination or dental imaging
Adverse events identified based on imaging or dental examination will be reported in the 
Adverse Event page of the eCRF and will be listed in the standard AE tables and listings.
7.8.2
Laboratory Data
7.8.2.1
Standard laboratory analyses
The analyses of laboratory data will be descriptive in nature and will be based on BI standards
(21). The variables to be recorded are listed in Table 7.8.2.1: 1 and Table 7.8.2.1: 2 below 
(see also Section 5.2.3 of the CTP).
Table 7.8.2.1: 1 
Safety laboratory tests at regular site visits
The laboratory tests at regular site visits will include:
Category
Laboratory test 
Haematology
Red blood cell count (RBC)
Haemoglobin (Hb)
Haematocrit (Hct)
Mean corpuscular volume
White blood cell count including differential count
Platelet count
Biochemistry 
Aspartate aminotransferase (AST)
Alanine transaminase (ALT)
Gamma-glutamyl transferase (GGT)
Alkaline phosphatase (ALK)
Creatine kinase (CK)
Lactate dehydrogenase (LDH)
Total protein
Total bilirubin
Creatinine
Glucose (non fasting, V1 and V2 only)
Uric acid
Thyroid stimulating hormone
ß-HCG (at all visits requiring blood  sampling for laboratory tests –in all and 
only female patients)*


Boehringer Ingelheim                                                                        
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Table 7.8.2.1: 1 
Safety laboratory tests at regular site visits (continued)
Category
Laboratory test 
Electrolytes
Sodium
Potassium
Calcium
Chloride
Inorganic phosphorus
Coagulation
International normalized ratio (INR)
Activated partial thromboplastin time (aPTT)
Prothrombin time (PT)
Urinalysis 
pH, glucose, erythrocytes, leukocytes, protein, nitrite (semi-quantitative 
measurements; -, +, ++, +++)
*Pregnancy test is required in all female patients every 4-6 weeks (in Poland: every 4 weeks), 
either at home or at site. ß-HCG test on blood will be conducted at all visits on blood 
collected for laboratory tests. Locally provided urine dipstick pregnancy tests will be 
dispensed for use between clinic visits starting from Visit 4.
Table 7.8.2.1: 2 
Safety laboratory tests at intermediate ‘a’-visits
The laboratory tests at intermediate ‘a’-visits will include:
Category
Laboratory test 
Biochemistry
Total protein, creatinine, electrolytes and liver function (AST, ALT, GGT, 
alkaline phosphatase, and total bilirubin)
Urinalysis 
pH, glucose, erythrocytes, leukocytes, protein, nitrite (semi-quantitative 
measurements; -, +, ++, +++)
As described in Section 7.2.5 of the CTP, laboratory data will be analyzed 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 summarized. Treatment 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.
Data will be received from a central laboratory, the respective reference ranges will be 
provided in the ISF.
For INR measurements, no reference range is transmitted by the central laboratory, because 
the central laboratory does not have information on concomitant medication taken by the 
subjects, and the reference range for INR depends on whether a subject is taking 
anticoagulants. The reference ranges for INR will therefore by imputed with 0.8 for the lower 
limit of normal (LLN) and with 1.2 for the ULN, which correspond to the


Boehringer Ingelheim                                                                        
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reference range defined by the central laboratory for subjects not taking anticoagulants and 
which is more conservative than the range for subjects taking anticoagulants (LLN=2, 
ULN=3).
Analyses of laboratory variables will be displayed by treatment and overall for the double-
blind period, for the nintedanib exposure period and over the whole trial; please refer to Table 
6.7: 1 for time windowing definition.
7.8.2.2
Liver enzyme and bilirubin elevations
A thorough description of liver enzymes and bilirubin elevations, as defined in Section 5.4.4,
will be given for the double-blind period, for the nintedanib exposure period and over the 
whole trial by treatment group and overall, including:

Summary table of liver enzyme elevation

Summary of signs of hepatic injury (see Section 5.4.4)

Summary table of individual maximum liver enzyme and bilirubin elevations

Time to first onset and number of patients with liver enzyme elevation. The time to 
onset of first liver enzyme and bilirubin elevation [days] will be summarized 
according to both, quartiles from Kaplan-Meier curve 

Kaplan-Meier plot of time to first liver enzyme elevation. No statistical test will be 
performed. Separate plots will be presented by treatment group.

Single time course profiles of liver enzymes and other laboratory parameters (ALT, 
AST, alkaline phosphatase, total bilirubin, absolute eosinophils, eosinophils/
leukocytes, GGT) for all patients (maximum individual elevations given in Section 
5.4.4).

Graphical displays of potential Hy’s law cases
7.8.3
Vital signs
Only descriptive statistics are planned for this section of the report.
7.8.4
ECG
Not applicable (ECG findings are reported as adverse events).


Boehringer Ingelheim                                                                        
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Boehringer Ingelheim                                                                        
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8.
REFERENCES
1.
CPMP/ICH/363/96: “Statistical Principles for Clinical Trials”, ICH Guideline Topic 
E9, Note For Guidance on Statistical Principles for Clinical Trials, current version.
2.
c37069138: ”sitting-height-measurement-note-to-file-2021-09-15”; TMF.
3.
Philip H. Quanjer, Multi-ethnic reference values for spirometry for the 3–95 year age 
range: The global lung function 2012 equations. [R15-0845]
4.
Onis MD, Onyango AW, Borghi E, Siyam A, Nishida C, Siekmann. Development of a 
WHO growth reference for school-aged children and adolescents. Bulletin of the 
World health Organization, 85. 2007; 660-667 [R21-1869]
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Website: https://www.who.int/tools/growth-reference-data-for-5to19-
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6.
Cole TJ, Green PJ. Smoothing reference centile curves: The LMS method and 
penalized likelihood. Statistics in Medicine. 1192. 1992;11:1305-1319 [R21-0301]
7.
001-MCS-30-476: “TMCP Data Analysis”, current version, Group “TMCP”, IDEA for 
CON.
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KMED-BDS-HTG-0035: “Handling of Missing and Incomplete AE Dates”, current 
version KMED.
9.
Rubin, DB. Multiple Imputation for Nonresponse in Surveys. New York: John Wiley 
& Sons. 1987 [R12-2378]
10.
BI-KMED-BDS-HTG-0045: “Reporting of clinical trials and project summaries”, 
current version; KMED.
11.
Bonella F, Maher TM, Cottin V, Valenzuela C, Wijsenbeek M, Voss F, et al. 
Consistent effect of nintedanib on reducing decline in forced vital capacity (FVC) 
across interstitial lung diseases (ILDs). 33rd Ann Mtg and Expo of the Academy of 
Managed Care Pharmacy (AMCP), Virtual, 12 - 16 Apr 2021 (Poster). 2021. [P21-
03717]
12.
Best N, Price RG, Pouliquen IJ, Keene ON. Assessing efficacy in important subgroups 
in confirmatory trials: An example using Bayesian dynamic borrowing. Pharm Stat. 
2021; 20(3): 551-562 [R21-1783]
13.
Schmidli H, Gsteiger S, Roychoudhury S, O’Hagan A, Spiegelhalter D, 
Neuenschwander B. Robust meta-analytic-predictive priors in clinical trials with 
historical control information. Biometrics. 2014; 70(4): 1023-32 [R16-0281]
14.
c38440025: “8-08-other-expert-elicitation-workshop-briefing-2021-09-09”; TMF.
15.
c38440027: “8-08-other-expert-elicitation-workshop-presentations-2021-09-09” ; 
TMF.
16.
c38440031: “8-08-other-expert-elicitation-workshop-results-2021-09-14”; TMF.
17.
BI-KMED-BDS-HTG-0066: “Analysis and Presentation of Adverse Event Data from 
Clinical Trials”, current version KMED.


Boehringer Ingelheim                                                                        
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18.
CPMP/ICH/137/95: “Structure and Content of Clinical Study Reports”, ICH Guideline 
Topic E3 Note For Guidance on Structure and Content of Clinical Study Reports,
current version, EMA webpage.
19.
Specifications for adverse event groupings by safety topic for Nintedanib:
Nintedanib / Clinical / Systemic sclerosis/ Project Data Management and Statistics / 
Section 8 PSAP and Programming / 8-07-other-safety-topic-definition, current 
version.
20.
Rothman KJ, Greenland S, Lash TL. Modern epidemiology. 3rd ed. Philadelphia: 
Lippincott Williams & Wilkins, 2008 [R10-1239]
21.
BI-KMED-BDS-HTG-0042: “Handling, Display and Analysis of Laboratory Data”, 
current version; KMED.
22.
Varni JW, Scaling and scoring of the Pediatric Quality of Life Inventory PedsQL. 
Mapi Research Trust; 2017. http://www.pedsql.org/PedsQL-Scoring.pdf (access date: 
11 May 2021) [R21-1786]
23.
Neuenschwander B, Capkun-Niggli G, Branson M, Spiegelhalter DJ. Summarizing 
historical information on controls in clinical trials. Clin Trials. 2010; 7(1): 5-18 [R16-
0278]
24.
Neuenschwander B, Schmidli H. Use of Historical Data. In: Lesaffre E, Baio G, 
Boulanger B (editors). Bayesian Methods in Pharmaceutical Research. 2020, CRC 
Press [R21-1784]
25.
Weber S (2020). RBesT: R Bayesian Evidence Synthesis Tools. R package version 
1.6-1. Website: https://cran.r-project.org/web/packages/RBesT/RBesT.pdf (access
date: 11 May 2021) [R21-1785]


Boehringer Ingelheim                                                                        
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9.
ADDITIONAL SECTIONS
9.1
PEDSQL SCORING INSTRUCTIONS
The Reports of the PedsQLTM 4.0 Generic Core Scales (22) for: 
- Young Children (ages 5-7), 
- Children (ages 8-12), 
- Teens (ages 13-18), 
and respective parent reports, are composed of 23 items comprising 4 dimensions.
1. On the PedsQL Generic Core Scales, for ease of interpretability, items are reversed 
scored and linearly transformed to a 0-100 scale, so that higher scores indicate better 
HRQOL (Health-Related Quality of Life). 
2. To reverse score, transform the 0-4 scale items to 0-100 as follows: 0=100, 1=75, 
2=50, 3=25, 4=0.
3. To create Scale Scores, the mean is computed as the sum of the items over the number 
of items answered (this accounts for missing data). If more than 50% of the items in 
the scale are missing, the Scale Score should not be computed. Imputing the mean of 
the completed items in a scale when 50% or more are completed is generally the most 
unbiased and precise method. To do this, count the number of missing values in the 
scale (call it nmiss). Next, sum the item scores and divide by the number of items in 
the scale minus nmiss. 
4. To create the Psychosocial Health Summary Score, the mean is computed as the sum 
of the items over the number of items answered in the Emotional, Social, and School 
Functioning Scales. The Physical Health Summary Score is the same as the Physical 
Functioning Scale Score. 
5. To create the Total Scale Score, the mean is computed as the sum of all the items over 
the number of items answered on all the Scales.


Boehringer Ingelheim                                                                        
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Figure 9.1: 1 Description of the PedsQL questionnaire


Boehringer Ingelheim                                                                        
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Boehringer Ingelheim                                                                        
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Boehringer Ingelheim                                                                        
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Boehringer Ingelheim                                                                        
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Boehringer Ingelheim                                                                        
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Boehringer Ingelheim                                                                        
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Boehringer Ingelheim                                                                        
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Boehringer Ingelheim                                                                        
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Boehringer Ingelheim                                                                        
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Boehringer Ingelheim                                                                        
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Boehringer Ingelheim                                                                        
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Boehringer Ingelheim                                                                        
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Boehringer Ingelheim                                                                        
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Boehringer Ingelheim                                                                        
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9.4
LIST OF POTENTIAL TERMS FOR HEPATIC INJURY DERIVATION
The table below shows the list of potentially relevant MedDRA preferred terms to support the 
derivation of a potential hepatic injury.
Table 9.4: 1
List of potentially relevant MedDRA preferred terms
Symptom
Selection via
MedDRA decode
MedDRA code
Vomiting 
Preferred Term
Vomiting
10047700
Fatigue
Preferred Term
Fatigue
10016256
Nausea
Preferred Term
Nausea
10028813
Right upper abdominal 
quadrant pain or tenderness
High Level Term
Gastrointestinal and abdominal 
pains (excl oral and throat)
10017926
Fever
Preferred Term
Pyrexia
10037660
Rash
BIcMQ
Skin rash potentially related to 
drug use (BIcMQ) (narrow)
30000087


Boehringer Ingelheim                                                                        
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Boehringer Ingelheim                                                                        
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Boehringer Ingelheim                                                                        
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Boehringer Ingelheim                                                                        
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Boehringer Ingelheim                                                                        
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Boehringer Ingelheim                                                                        
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Boehringer Ingelheim                                                                        
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Boehringer Ingelheim                                                                        
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Boehringer Ingelheim                                                                        
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Boehringer Ingelheim                                                                        
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Boehringer Ingelheim                                                                        
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Boehringer Ingelheim                                                                        
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Boehringer Ingelheim                                                                        
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Boehringer Ingelheim                                                                        
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Boehringer Ingelheim                                                                        
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Boehringer Ingelheim                                                                        
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Boehringer Ingelheim                                                                        
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Boehringer Ingelheim                                                                        
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10.
HISTORY TABLE
Table 10: 1
History table
Version
Date
(DD-MMM-
YY)
Author
Sections 
changed
Brief description of change
Final
09 MAR 22
None
This is the final TSAP.