Clinical trial NCT05065190
Conditions: Lung Diseases, Interstitial
Sponsor: Boehringer Ingelheim
Start date: 2021-11-25; Completion date: 2024-05-07
Enrollment: 81 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study in China is open to people with progressive lung fibrosis (chronic fibrosing ILDs with progressive phenotype) who are at least 18 years old. The purpose of this study is to find out whether a medicine called nintedanib helps people with progressive lung fibrosis.

Participants are put into 2 groups randomly, which means by chance. 1 group gets nintedanib as capsules twice a day. The other group gets placebo as capsules twice a day. Placebo capsules look like nintedanib capsules but do not contain any medicine.

Participants are in the study for about 1 year. During this time, they visit the study site about 10 times. At some visits, participants perform a lung function test. The doctors check whether study treatment can slow down the loss of lung function. The doctors also regularly check participants' health and take note of any unwanted effects.

Detailed description:

Arms: arm 1: A soft gelatin capsule of 150 mg Nintedanib was administered orally twice daily (bid) in Chinese patients with chronic fibrosing ILD with progressive phenotype with over 52 weeks. Dose could be reduced to 100 mg bid to manage adverse events. arm 2: A soft gelatin capsule of placebo matching in size, weight, colour and shape to 150 milligram (mg) or 100 mg soft gelatin capsule of Nintedanib, was administered orally twice daily (bid) in Chinese patients with chronic fibrosing Interstitial Lung Disease (ILD) with progressive phenotype with over 52 weeks.
Interventions: intervention 1: Nintedanib intervention 2: Placebo
Intervention descriptions: intervention 1: Soft gelatin capsule intervention 2: Soft gelatin capsule

Protocol documents:
Prot_000.pdf: 
 
001-MCS-40-106_RD-03 (18.0) / Saved on: 10 Jul 2019 
Clinical Trial Protocol 
TITLE PAGE  
Document Number: 
c34975667-06 
EudraCT No. 
EU Trial No. 
Not applicable 
BI Trial No. 
1199-0434 
BI Investigational 
Medicinal Product(s) 
Ofev®, Nintedanib 
Title 
A double blind, randomized, placebo-controlled trial evaluating 
the efficacy and safety of nintedanib over 52 weeks in Chinese 
patients with Chronic Fibrosing ILDs with a Progressive 
Phenotype 
Lay Title 
A study in China to find out if a medicine called nintedanib helps 
people with progressive lung fibrosis 
Clinical Phase 
IIIb 
Clinical Trial Leader 
Phone: 
 
Coordinating 
Investigator 
Email:
Phone：
Version and Date 
 
Version: 5.0 
Date: 18 Sep 2023 
 
Page 1 of 109 
Proprietary confidential information. 
© 2025  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 
10 Feb 2021 
Revision date 
18 Sep 2023 
BI trial number 
1199-0434 
Title of trial 
A double blind, randomized, placebo-controlled trial evaluating the 
efficacy and safety of nintedanib over 52 weeks in Chinese patients 
with Chronic Fibrosing ILDs with a Progressive Phenotype 
Coordinating 
Investigator 
Trial site(s) 
Multi-centre trial conducted in China 
Clinical phase 
Phase IIIb 
Trial rationale 
The rationale of performing this trial is, upon completion of the 
international multicentre randomized placebo-controlled Phase III 
trial (INBUILD, 1199-0247), to generate additional data in Chinese 
patients with progressive fibrosing ILDs.    
Trial objective(s) 
The objective of the trial is to generate additional data on the 
efficacy of 150 mg bid nintedanib in Chinese patients with Chronic 
Fibrosing ILDs with a Progressive Phenotype compared to placebo 
over 52 weeks.  
Trial endpoints 
The primary efficacy endpoint is the annual rate of decline in Forced 
Vital Capacity (FVC; expressed in mL over 52 weeks), defined as in 
the INBUILD study. 
There are no secondary efficacy endpoints. 
Safety of nintedanib will also be assessed via laboratory tests and 
(S)AEs. 
Trial design 
Double blind, randomized, placebo-controlled design of 2 groups 
over 52 weeks  
Stratification by HRCT pattern: approximately two thirds of patients 
with UIP-like HRCT fibrotic patterns, one third of patients with 
other fibrotic patterns. 
Total number of 
patients randomized  
Approx. 90 
Number of patients on 
each treatment 
Approx. 60 in nintedanib 150 mg b.i.d. group 
Approx. 30 in placebo group 
Diagnosis 
Chronic Fibrosing ILDs with Progressive Phenotype 
Main in- and exclusion 
criteria 
 
Inclusion criteria : 
• Male or female patients aged ≥ 18 years at Visit 1. 
• Patients with physician diagnosed ILD who fulfil at least one 
of the following criteria for Progressive Phenotype within 24 
months of Visit 1 despite treatment with unapproved 
medications used in clinical practice to treat ILD, as assessed 
by the investigator: 


 
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a. Clinically significant decline in FVC % predicted based 
on a relative decline of ≥10% 
b. Marginal decline in FVC % predicted based on a relative 
decline of  ≥5-<10% combined with worsening of 
respiratory symptoms  
c. Marginal decline in FVC % predicted based on a relative 
decline of ≥5-<10% combined with increasing extent of 
fibrotic changes on chest imaging 
d. Worsening of respiratory symptoms as well as increasing 
extent of fibrotic changes on chest imaging. 
• Fibrosing lung disease on HRCT, defined as reticular 
abnormality with traction bronchiectasis with or without 
honeycombing, with disease extent of >10%, performed 
within 12 months of Visit 1 as confirmed by central readers. 
• FVC ≥ 45% predicted at Visit 2. 
 
Exclusion criteria :  
• Previous treatment with nintedanib or pirfenidone. 
• Use of any of the following medications for the treatment of 
ILD: azathioprine (AZA), cyclosporine, MMF, tacrolimus, 
oral corticosteroids (OCS) >20mg/day and the combination 
of OCS+AZA+NAC within 4 weeks of Visit 2, 
cyclophosphamide within 8 weeks of Visit 2, rituximab 
within 6 months of Visit 2. 
• Diagnosis of IPF based on ATS/ERS/JRS/ALAT 2018 
Guideline. 
• Diagnosis of Systemic Sclerosis (SSc) based on 2013 
ACR/EULAR classification. 
• Primary obstructive airway physiology (pre-bronchodilator 
FEV1/FVC < 0.7 at Visit 1. 
• The patient has a confirmed infection with SARS-CoV-2 
within the 4 weeks prior to Visit 1 and/or during the 
screening period. 
Test product(s) 
Ofev®, Nintedanib 
dose 
150 mg b.i.d (300 mg daily) 
with optional dose reduction to 100 mg bid (200 mg daily) to 
manage adverse events 
mode of administration Oral 
Comparator product(s) Placebo 
dose 
Matching 
mode of administration Oral 
Duration of treatment 
52 weeks 
Statistical methods 
The primary analysis will use a restricted maximum likelihood 
(REML)-based approach with a random slope and intercept model. 


 
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The analysis includes fixed effects for treatment, HRCT pattern, and 
baseline FVC [mL], as well as the treatment-by-time and baseline-
by-time interactions. Random effects will be included for the patient 
response for both time and intercept. The point estimate of treatment 
difference between the nintedanib and placebo group will be 
provided as well as 95%CI. No statistical testing will be performed. 


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FLOW CHART  
Visit 
 
1 
2 
3 
4 
5 
6 
6a11 
7 
7a11 
8 
8a11 
9 
EOT12 
FU12 
 
Screening* 
Treatment# 
 
FU 
Weeks  
 
 
D1 
2 
4 
6 
12 
18 
24 
30 
36 
44 
52 
 
+1 
Day 
 
Time window 
Before or  
at the latest at 
visit 1 
≥ 4d 
before 
V 2 
1 
 
15 
 
±3 
29 
 
±3 
43 
 
±3 
85 
 
±3 
127 
 
±7 
169 
 
±7 
211 
 
±7 
253 
 
±7 
309 
 
±7 
365 
 
±7 
 
+7 
 
+3 
Informed consent 
X* 
 
 
 
 
 
 
 
 
 
 
 
HRCT sent to central review1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history  
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse events, concomitant medication 
 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
X 
X 
In-/exclusion criteria 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination, vital signs 
 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
X 
X 
Safety laboratory (blood and urine) 
 
X2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Pregnancy test3 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Resting 12-lead ECG6 
 
X 
X 
 
 
 
 
 
X 
 
 
 
X 
X 
 
Randomization 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
IRT notification 
X8 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
(X) 
 
Release patient diary  
 
X 
X 
X 
X 
X 
 
X 
 
X 
 
 
 
 
Review and collect patient diary  
 
 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
 
Administer 1st  trial medication at the clinic 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Dispense trial medication 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
 


 
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Visit 
 
1 
2 
3 
4 
5 
6 
6a11 
7 
7a11 
8 
8a11 
9 
EOT12 
FU12 
 
Screening* 
Treatment# 
 
FU 
Weeks  
 
 
D1 
2 
4 
6 
12 
18 
24 
30 
36 
44 
52 
 
+1 
Day 
 
Time window 
Before or  
at the latest at 
visit 1 
≥ 4d 
before 
V 2 
1 
 
15 
 
±3 
29 
 
±3 
43 
 
±3 
85 
 
±3 
127 
 
±7 
169 
 
±7 
211 
 
±7 
253 
 
±7 
309 
 
±7 
365 
 
±7 
 
+7 
 
+3 
Collect trial drug 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
Compliance / drug accountability 
 
 
 
X 
X 
X 
X 
 
X 
 
X 
 
X 
X 
 
Trial medication termination 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Vital status assessment9 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Conclude subject participation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X10 
 
* Informed consent needs to be signed before any procedure related to the study. When it is signed before visit 1, e.g. to allow shipment of 
images for central review, all AEs and Concomitant Treatments occurring after the informed consent have to be recorded. The Screening 
period (informed consent to Visit 2) must not be longer than 8 weeks. Upon obtaining informed consent, the patient will be instructed on the 
medication wash-out and other restrictions needed. Patients will be asked to give informed consent about COVID-19 if necessary. 
# In case of dose change (reduction or re-escalation) additional visits have to be included (refer to Section 6.2.4). In case of premature 
discontinuation of trial medication, the patient will be expected to attend all visits as originally planned until the end of the trial (except for the 
laboratory visits 6a, 7a, 8a) (see Section 6.2.3). 
 1 Review of high resolution computed tomography (HRCT) for meeting the HRCT criteria for fibrosing lung disease, for extent of ILD in the 
lung (10% or more), and for HRCT pattern. Central review HRCT not older than 12 months should be sent. 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, a new HRCT can be 
performed for the purposes of participation in the trial, provided the patient meets all other inclusion and no exclusion criteria. 
2The safety laboratory of Visit 1 must be repeated if screening is longer than 6 weeks. 
3 ß-HCG will be performed at Visit 2 only, at central laboratory. Urine dipstick pregnancy tests will be provided by central laboratory and should 
be performed in all women of childbearing potential every 4-6 weeks, i.e. at least at every visit and if necessary, additionally at home or at a 
local laboratory / local doctor. If urine test is not acceptable to local authorities, a blood test can be done at a local laboratory. Documentation 
will be done in patient’s notes.  


 
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4 High resolution CT scan will be done at baseline, 24 and 52 weeks in patients who agree as part of the informed consent. Participation is 
voluntary and is not a prerequisite for participating in the trial. Baseline scan will not be performed in patients where eligibility scan was 
performed during screening.  
5 If EOT takes place before Visit 7, HRCT should not be performed at EOT.  
6 Resting ECG will be performed (if possible prior to blood draw) at Visit 2 prior to randomization (only if abnormal at Visit 1). 
 IRT needs to be notified at the latest at Visit 1 but can be notified upon informed consent’s signature. 
9 Vital status at 52 weeks (Visit 9) should be available for all randomized patients. Consent for a vital status call at 52 weeks in case of 
premature discontinuation of trial participation will be requested for all patients as part of the informed consent.  
10 Conclusion of trial participation is for all subjects who complete all treatment visits. 
11a-Visits (6a, 7a and 8a) are optional based on the investigator’s assessment. 
12 EOT should be done in cases of premature trial medication discontinuation during the study period with a follow-up Visit (FU) 1 week later.


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TABLE OF CONTENTS 
TITLE PAGE ........................................................................................................................... 1 
CLINICAL TRIAL PROTOCOL SYNOPSIS ..................................................................... 2 
FLOW CHART ........................................................................................................................ 5 
TABLE OF CONTENTS ........................................................................................................ 8 
ABBREVIATIONS ................................................................................................................ 12 
1. 
INTRODUCTION ............................................................................................... 16 
1.1 
MEDICAL BACKGROUND ............................................................................. 16 
1.1.1 
Chronic fibrosing interstitial lung diseases with a progressive phenotype.... 16 
1.1.2 
Interstitial Lung Diseases in China ................................................................... 17 
1.2 
DRUG PROFILE ................................................................................................ 18 
1.3 
RATIONALE FOR PERFORMING THE TRIAL ......................................... 20 
1.4 
BENEFIT - RISK ASSESSMENT..................................................................... 20 
1.4.1 
Benefits ................................................................................................................. 20 
1.4.2 
Risks ..................................................................................................................... 21 
1.4.3 
Discussion ............................................................................................................. 24 
2. 
TRIAL OBJECTIVES AND ENDPOINTS ...................................................... 25 
2.1 
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS........ 25 
2.1.1 
Main objectives .................................................................................................... 25 
2.1.2 
Primary endpoint(s) ............................................................................................ 25 
2.1.3 
Secondary endpoint(s) ........................................................................................ 25 
3. 
DESCRIPTION OF DESIGN AND TRIAL POPULATION ......................... 27 
3.1 
OVERALL TRIAL DESIGN ............................................................................. 27 
3.2 
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S) ...................................................................................... 28 
3.3 
SELECTION OF TRIAL POPULATION ....................................................... 29 
3.3.1 
Main diagnosis for trial entry ............................................................................ 30 
3.3.2 
Inclusion criteria ................................................................................................. 30 
3.3.3 
Exclusion criteria ................................................................................................ 31 
3.3.4 
Imaging criteria ................................................................................................... 33 
3.3.5 
Withdrawal of patients from treatment or assessments .................................. 34 
3.3.5.1 
Discontinuation of trial treatment ......................................................................... 34 
3.3.5.2 
Withdrawal of consent to trial participation ......................................................... 35 
3.3.5.3 
Discontinuation of the trial by the sponsor ........................................................... 36 
4. 
TREATMENTS ................................................................................................... 37 
4.1 
INVESTIGATIONAL TREATMENTS ........................................................... 37 
4.1.1 
Identity of the Investigational Medicinal Products .......................................... 37 


 
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4.1.2 
Selection of doses in the trial and dose modifications ...................................... 37 
4.1.3 
Method of assigning patients to treatment groups ........................................... 38 
4.1.4 
Drug assignment and administration of doses for each patient...................... 38 
4.1.5 
Blinding and procedures for unblinding ........................................................... 39 
4.1.5.1 
Blinding ................................................................................................................. 39 
4.1.5.2 
Unblinding and breaking the code ........................................................................ 39 
4.1.6 
Packaging, labelling, and re-supply................................................................... 40 
4.1.7 
Storage conditions ............................................................................................... 40 
4.1.8 
Drug accountability............................................................................................. 40 
4.2 
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS ................................................................................................ 41 
4.2.1 
Other treatments and emergency procedures .................................................. 41 
4.2.1.1 
Management of diarrhoea ..................................................................................... 41 
4.2.1.2 
Management of liver enzyme elevation ................................................................ 43 
4.2.1.3 
Management of acute ILD exacerbations ............................................................. 45 
4.2.2 
Restrictions .......................................................................................................... 45 
4.2.2.1 
Restrictions regarding concomitant treatment ...................................................... 45 
4.2.2.2 
Cautionary notes ................................................................................................... 47 
4.2.2.3 
Restrictions on diet and life style .......................................................................... 48 
4.2.2.4 
Contraception requirements .................................................................................. 48 
4.3 
TREATMENT COMPLIANCE ........................................................................ 49 
5. 
ASSESSMENTS .................................................................................................. 50 
5.1 
ASSESSMENT OF EFFICACY ........................................................................ 50 
5.1.1 
FVC ...................................................................................................................... 50 
5.2 
ASSESSMENT OF SAFETY ............................................................................. 51 
5.2.1 
Physical examination .......................................................................................... 51 
5.2.2 
Vital signs ............................................................................................................. 51 
5.2.3 
Safety laboratory parameters ............................................................................ 52 
5.2.4 
Electrocardiogram .............................................................................................. 54 
5.2.5 
Other safety parameters ..................................................................................... 54 
5.2.6 
Assessment of adverse events ............................................................................. 54 
5.2.6.1 
Definitions of AEs ................................................................................................ 54 
5.2.6.2 
Adverse event collection and reporting ................................................................ 58 
5.3 
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS ................................................................................... 59 
5.4 
ASSESSMENT OF BIOMARKER(S) .............................................................. 59 
5.5 
BIOBANKING .................................................................................................... 59 
5.6 
OTHER ASSESSMENTS................................................................................... 59 
5.7 
APPROPRIATENESS OF MEASUREMENTS .............................................. 59 
6. 
INVESTIGATIONAL PLAN............................................................................. 60 
6.1 
VISIT SCHEDULE ............................................................................................. 60 
6.2 
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS ................. 62 


 
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6.2.1 
Screening period(s) ............................................................................................. 62 
6.2.2 
Treatment period(s) ............................................................................................ 63 
6.2.3 
Follow-up period and trial completion.............................................................. 65 
6.2.4 
Dose reduction visit / dose increase visit ........................................................... 66 
7. 
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE
 ............................................................................................................................... 68 
7.1 
NULL AND ALTERNATIVE HYPOTHESES ............................................... 68 
7.2 
PLANNED ANALYSES ..................................................................................... 68 
7.2.1 
General considerations ....................................................................................... 68 
7.2.2 
Primary endpoint analyses ................................................................................. 69 
7.2.3 
Secondary endpoint analyses ............................................................................. 70 
7.2.5 
Safety analyses ..................................................................................................... 70 
7.2.6 
Other Analyses .................................................................................................... 71 
7.2.7 
Interim Analyses ................................................................................................. 71 
7.3 
HANDLING OF MISSING DATA ................................................................... 71 
7.4 
RANDOMIZATION ........................................................................................... 71 
7.5 
DETERMINATION OF SAMPLE SIZE ......................................................... 72 
8. 
INFORMED CONSENT, TRIAL RECORDS, DATA PROTECTION, 
PUBLICATION POLICY, AND ADMINISTRATIVE STRUCTURE ........ 74 
8.1 
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED 
CONSENT ........................................................................................................... 74 
8.2 
DATA QUALITY ASSURANCE ...................................................................... 75 
8.3 
RECORDS ........................................................................................................... 75 
8.3.1 
Source documents ............................................................................................... 75 
8.3.2 
Direct access to source data and documents ..................................................... 76 
8.3.3 
Storage period of records ................................................................................... 77 
8.4 
EXPEDITED REPORTING OF ADVERSE EVENTS .................................. 77 
8.5 
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY ........ 77 
8.5.1 
Collection, storage and future use of biological samples and corresponding 
data ....................................................................................................................... 77 
8.6 
TRIAL MILESTONES....................................................................................... 77 
8.7 
ADMINISTRATIVE STRUCTURE OF THE TRIAL ................................... 78 
9. 
REFERENCES .................................................................................................... 79 
9.1 
PUBLISHED REFERENCES ............................................................................ 79 
9.2 
UNPUBLISHED REFERENCES ...................................................................... 82 
10. 
APPENDICES ..................................................................................................... 84 
10.1 
FVC LUNG FUNCTION CRITERIA............................................................... 84 
10.2 
CREATININE CLEARANCE ........................................................................... 84 
10.5 
PHARMACOKINETIC METHODS AND ANALYSES ................................ 96 


 
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10.6 
TIME SCHEDULE FOR PHARMACOKINETIC (PK) BLOOD 
SAMPLING ......................................................................................................... 96 
10.7 
TRIAL BIOMARKER PLAN............................................................................ 96 
11. 
DESCRIPTION OF GLOBAL AMENDMENT(S) ......................................... 97 
11.1 
GLOBAL AMENDMENT 1 .............................................................................. 97 
11.2 
GLOBAL AMENDMENT 2 .............................................................................. 97 
11.3 
GLOBAL AMENDMENT 3 ............................................................................ 101 
11.4 
GLOBAL AMENDMENT 4 ............................................................................ 106 


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ABBREVIATIONS  
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
ALCOA 
Attributable, Legible, Contemporaneous, Original, Accurate  
ALK 
Alkaline phosphatase  
ALT 
Alanine Aminotransferase 
aPTT 
Activated Partial Thromboplastin Time  
AST 
Aspartate Aminotransferase 
AZA 
Azathioprine  
b.i.d. 
bis in die (twice daily dosing) 
BI 
Boehringer Ingelheim 
CA 
Competent Authority 
CI 
Confidence Interval 
CK 
Creatine kinase 
Cmax 
Maximum Plasma Concentration 
Cmin 
Minimum Plasma Concentration 
CRA 
Clinical Research Associate 
CRF 
Case Report Form, paper or electronic (sometimes referred to as “eCRF”) 
CSR 
Clinical Study Report 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTD 
Connective Tissue Disease 
CT Leader 
Clinical Trial Leader 
CT Manager 
Clinical Trial Manager 
CTP 
Clinical Trial Protocol 
CHP 
Chronic Fibrosing Hypersensitivity Pneumonitis  
DBL 
Database Lock 
DILI 
Drug Induced Liver Injury 
DMARD 
Disease-Modifying Anti-Rheumatic Drug 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
(e)COA 
(electronic) Clinical Outcome Assessment 


 
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eCRF 
Electronic Case Report Form 
eDC 
Electronic Data Capture 
EoT 
End of Treatment 
EoTrial 
End of Trial 
EudraCT 
European Clinical Trials Database 
FC 
Flow Chart 
FGFR 
Fibroblast Growth Factor Receptor  
FUP 
Follow-up 
FVC 
Forced Vital Capacity 
GCP 
Good Clinical Practice 
GI 
Gastro-Intestinal  
GGT 
Gamma-glutamyl transferase  
GLI 
Global Lung Initiative  
GMP 
Good Manufacturing Practice 
HA 
Health Authority 
Hb 
Haemoglobin  
Hct 
Haematocrit  
HP 
Hypersensitivity Pneumonitis 
HR 
Hazard Ratio 
HRCT 
High-Resolution Computed Tomography 
iNSIP 
Idiopathic Non-specific Interstitial Pneumonia  
i.v. 
intravenous 
IB 
Investigator’s Brochure 
IC 
Informed Consent 
ICH 
International Council on Harmonisation 
IEC 
Independent Ethics Committee 
IIPs 
Idiopathic Interstitial Pneumonias 
ILD 
Interstitial Lung Disease 
INR 
International Normalized Ratio  
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
ISF 
Investigator Site File 


 
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IUD 
Intrauterine Device 
IUS 
Intrauterine Hormone-Releasing System 
IPF 
Idiopathic Pulmonary Fibrosis 
LDH 
Lactate dehydrogenase 
LPLT 
Last Patient Last Treatment 
LPLV 
Last Patient Last Visit 
MedDRA 
Medical Dictionary for Drug Regulatory Activities 
MMF 
Mycophenolate Mofetil  
NAC 
n-Acetylcysteine  
NSCLC 
Non-Small Cell Lung Cancer  
OCS 
Oral Corticosteroids 
OPU 
Operative Unit 
PAH 
Pulmonary Arterial Hypertension  
PDGFR 
Platelet-Derived Growth Factor Receptor  
PT 
Prothrombin Time  
QoL 
Quality of Life 
RBC 
Red Blood Cell Count  
RA 
Regulatory Authority 
RA-ILD 
Rheumatoid Arthritis-associated ILD 
REP 
Residual Effect Period 
REML 
Restricted Maximum Likelihood 
REP 
Residual Effect Period 
RS 
Randomized set  
SAE 
Serious Adverse Event 
SCS 
Screened Set  
SOP 
Standard Operating Procedure 
SSc-ILD 
Systemic Sclerosis-associated ILD  
SUSAR 
Suspected Unexpected Serious Adverse Reactions 
t1/2 
Half Life Time 
tmax 
Timepoint of Maximum Plasma Concentration 
TOEP 
Toeplitz 
TOEPH 
Heterogeneous Toeplitz 


 
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TS 
Treated Set  
TMF 
Trial Master File 
UIP 
Usual Interstitial Pneumonia 
ULN 
Upper Level of Normal 
VEGFR 
Vascular Endothelial Growth Factor Receptor  
WHO 
World Health Organisation 
WOCBP 
Woman of childbearing potential 
 
 


 
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1. 
INTRODUCTION  
1.1 
MEDICAL BACKGROUND  
1.1.1 
Chronic fibrosing interstitial lung diseases with a progressive phenotype  
The term interstitial lung disease (ILD) encompasses a large group of over 200 pulmonary 
disorders including idiopathic interstitial pneumonias (IIPs) and autoimmune or 
environmental ILDs. Idiopathic pulmonary fibrosis (IPF) is the most common disease entity 
within the group of IIPs and has a dismal prognosis, with a median survival of 2-3 years after 
diagnosis. 
 
The major abnormality in ILDs is the disruption of the distal lung parenchyma. It is generally 
agreed that some form of injury of the alveolar epithelial cells initiates an inflammatory 
response coupled with repair mechanisms. The initiating injury can be introduced via the 
airways (e.g. inhalation of mineral fibres or dust as in occupational diseases or sensitisation to 
inhaled allergens as in hypersensitivity pneumonitis [HP]) or via the circulation (e.g. 
Connective Tissue Disease [CTD] and drug-induced ILDs). The injury-repair process is 
reflected pathologically as inflammation, fibrosis or a combination of both. Irrespective of the 
underlying pathophysiology, the resulting alteration of the interstitial space leads to clinical 
symptoms such as dyspnoea and cough, and results in restrictive ventilatory and gas 
exchange deficits on pulmonary function testing [R16-0722]. 
 
There is no universally accepted single classification of ILDs. They can generally be 
categorised based on: 
• 
Aetiology: idiopathic or ILDs with known association or cause 
• 
Clinical course: acute, subacute or chronic ILDs 
• 
Main pathological features: inflammatory or fibrotic ILDs 
 
Fibrotic ILDs can be subdivided into 3 groups based on their longitudinal disease behaviour 
[P18-05024]: 
• 
Intrinsically non-progressive, e.g. drug-induced lung disease after removal of the drug or 
some cases of HP after removal of a trigger 
• 
Progressive but stabilised by immunomodulation, e.g. some cases of CTD-ILDs [R14-
5407, R14-1149, R18-0122, R18-1815] 
• 
Progressive despite treatment considered appropriate in individual ILDs 
 
To describe the group of patients with differing clinical ILD diagnoses who develop a 
progressive fibrosing phenotype during the course of their disease, BI has been using the 
terminology ‘patients with progressive fibrosing interstitial lung disease’ (Chronic Fibrosing 
ILDs with a Progressive Phenotype). These patients demonstrate a number of similarities to 
patients with IPF, with their disease being defined by the presence of progressive pulmonary 
fibrosis, worsening respiratory symptoms, declining lung function despite 
immunomodulatory therapies and, ultimately, early mortality. The working hypothesis is that 
the response to lung injury in these patients includes the development of fibrosis, which 
becomes progressive, self-sustaining, and independent of the original clinical association or 
trigger [P17-10582]. 


 
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Based on expert consensus, the main chronic fibrosing ILDs that may show a progressive 
phenotype similar to IPF include: 
• 
Idiopathic non-specific interstitial pneumonia (iNSIP) 
• 
Unclassifiable IIP 
• 
Autoimmune ILDs that include CTD-ILDs (mainly Rheumatoid Arthritis-associated ILD 
[RA-ILD] and Systemic Sclerosis-associated ILD [SSc-ILD]) 
• 
Chronic fibrosing hypersensitivity pneumonitis (CHP) 
• 
Environmental or occupational fibrosing lung diseases 
 
Nintedanib and pirfenidone are available for patients with IPF. Based on clinical and 
mechanistic parallels between IPF and other chronic fibrosing ILDs with a progressive 
phenotype, it was anticipated that nintedanib will elicit similar effects in patients with 
Chronic Fibrosing ILDs with a Progressive Phenotype  as it does in patients with IPF, that is, 
slowing the progression of the disease [c02153150-02]. This assumption was supported by 
preclinical data indicating that nintedanib impacts fundamental processes of lung fibrosis and 
that the anti-fibrotic activity of nintedanib is independent of the cause of the fibrosing lung 
disease [P14-02860, P14-17410, P15-02392, P15-06100]. The results of the INBUILD trial 
(1199-0247) showed that in patients with progressive fibrosing interstitial lung diseases, the 
annual rate of decline in the Forced Vital Capacity (FVC) was significantly lower among 
patients who received nintedanib than among those who received placebo. The absolute 
treatment effects in these patient populations were similar in magnitude to those observed in 
pooled data from the INPULSIS trials in patients with IPF. [P19-08802] 
 
Apart from IPF and SSc-ILD, no prospective, controlled clinical trials have been performed 
in other ILDs previous to the Chronic Fibrosing ILDs with a Progressive Phenotype 
programme. This is likely due to the relatively low number of patients within each different 
ILD; the number of patients with a progressive phenotype within each group, is even lower 
[R19-1104]. In order to address the unmet medical need, patients with differing clinical 
diagnoses of chronic fibrosing ILDs with a progressive phenotype were grouped together in 
trial 1199-0247. This ‘basket approach’ was considered the only feasible way to conduct an 
adequately powered clinical trial to evaluate the long-term efficacy and safety of nintedanib 
in patients with Chronic Fibrosing ILDs with a Progressive Phenotype. 
 
1.1.2 
Interstitial Lung Diseases in China  
Although there is no large-scale epidemiological study of IPF or ILD released in China, a 
gradual increase of ILD incidence and hospitalisation has been observed by clinical experts 
[R19-1170, R16-4086, R19-2980]. Some medical centres focus on the diagnosis and 
treatment of ILD as a respiratory disease specialty and follow international standards 
regarding the diagnostic procedures and treatment of IPF patients [P19-03962]. 
 
The highest official guidance institution for ILD in China is the ILD Study Group of the 
Chinese Thoracic Society, which is responsible for the introduction of the latest international 
consensus and research progress on ILD to clinicians specialised in respiratory medicine 
throughout the country via lectures and articles, as well as for nationwide clinical research 
related to ILD [P16-03854]. 


 
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IPF was listed on Rare Disease List which was released in year 2018. IPF accounts for 1/4 of 
hospitalised ILD cases [R19-1170]. Both nintedanib and pirfenidone are recommended for 
IPF maintenance treatment. Nintedanib was approved for the treatment of Systemic Sclerosis 
associated Interstitial Lung Disease (SSc-ILD) in 2020. Nintedanib is the only medication 
approved to treat patients with “chronic fibrosing Interstitial Lung Diseases (ILDs) with a 
progressive phenotype”. 
1.2 
DRUG PROFILE  
Nintedanib (Ofev®), 100 mg and 150 mg soft capsules, is an approved treatment for patients 
with IPF. It was first authorised in the USA on 15 Oct 2014 and in the EU/EEA on 15 Jan 
2015. In China, the indication of IPF was approved on 20 Sep 2017. To date, Ofev® has been 
approved for the treatment of IPF in more than 70 countries worldwide [c01783972]. The 
indication of chronic fibrosing ILDs with a progressive phenotype was approved in China on 
15 Dec 2020. 
 
Mode of action 
Nintedanib is a small molecule tyrosine kinase inhibitor that potently inhibits platelet-derived 
growth factor receptor (PDGFR) , fibroblast growth factor receptor (FGFR) 1-3, and 
vascular endothelial growth factor receptor (VEGFR) 1-3 [U02-1109, U02-1310, P08-
08684]. Nintedanib binds competitively to the adenosine triphosphate binding pocket of these 
receptors and blocks the intracellular signalling. These growth factor pathways and their 
down-stream signalling cascades have been demonstrated to be involved in the pathogenesis 
of fibrotic tissue remodelling. In addition, nintedanib inhibits Flt-3 (Fms-like tyrosine protein 
kinase), Src family kinases (Src, Lck, Lyn) [P08-08684], and colonystimulating factor 1 
receptor (CSF1R) [P18-00197]. 
 
Nintedanib inhibited the proliferation and migration of human lung fibroblasts from patients 
with IPF. It demonstrated anti-fibrotic and anti-inflammatory activity in 3 animal models of 
lung fibrosis and in more specific models of SSc-ILD and RA-ILD. Although different in 
origin, these model systems share a final common pathway: progressive fibrotic lung 
pathology with proliferation, migration, and transformation of fibroblasts into pathogenic 
myofibroblasts [U06-1451, U06-1479, U12-2437-01, U12-2066-01, n00239669, n00247887]. 
 
Key pharmacokinetic characteristics 
A soft gelatin capsule formulation of nintedanib is used in humans. Maximum Plasma 
Concentration (Cmax) occur between 2 to 4 hours after oral administration. Steady state is 
reached at the latest within 1 week of dosing. After food intake, a trend towards an increased 
systemic exposure (around 20%) and a delayed absorption is observed compared to 
administration under fasted conditions. 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 hours. The 
absolute bioavailability of nintedanib is slightly below 5%. Nintedanib is recommended to be 
taken with food and is mainly eliminated via faeces. 
 


 
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For further details on the pharmacokinetics of nintedanib including drug-drug interaction 
studies, refer to the Investigator’s Brochure [c01783972]. 
 
Residual Effect Period 
The Residual Effect Period (REP) of nintedanib is 7 days. This is the period after the last 
dose with measurable drug levels and/or pharmacodynamic effects still likely to be present. 
 
Data from clinical studies 
The clinical efficacy of nintedanib has been studied in over 1400 patients with IPF in 
1 Phase II dose finding trial (TOMORROW [P11-11216]) and 2 replicate Phase III trials 
(INPULSIS® 1 and 2 [P14-07514]). These were randomised, double-blind, placebo-
controlled trials comparing treatment with nintedanib twice daily to placebo for 52 weeks. A 
statistically significant reduction in the annual rate of decline in FVC was demonstrated in 
patients receiving nintedanib 150 mg bid compared with patients receiving placebo. The 
magnitude of the effect on FVC was similar in all 3 studies, i.e. a relative reduction of decline 
of approximately 50%. Supporting the effect of nintedanib on slowing disease progression, 
nintedanib 150 mg bid significantly reduced the risk of first acute exacerbation compared 
with placebo in INPULSIS® -2 and in the TOMORROW trial and reduced the risk of acute 
exacerbations (adjudicated) by 68% in a pre-specified sensitivity analysis of pooled data from 
the INPULSIS ® trials. 
  
Nintedanib was investigated in a Phase III trial in patients with SSc-ILD (287 patients treated 
with nintedanib 150 mg bid and 288 patients treated with placebo). The trial met its primary 
endpoint: nintedanib significantly reduced the annual rate of decline in FVC over 52 weeks 
compared with placebo. The decline in the nintedanib group was about 44% lower than in the 
placebo group [c22686034-01]. 
 
Nintedanib was also investigated in a Phase III trial in patients with Chronic Fibrosing ILDs 
with a Progressive Phenotype (332 patients treated with nintedanib 150 mg bid and 331 
patients treated with placebo). Nintedanib significantly reduced the annual rate of decline in 
FVC [mL/year] over 52 weeks compared with placebo in both co-primary populations 
(p<0.0001), namely the overall population and patients with HRCT with Usual Interstitial 
Pneumonia (UIP)-like fibrotic pattern. The results in the complementary population were 
consistent. The treatment effect was independent of HRCT pattern (interaction p-value 
0.2268). The adjusted differences for the annual rate of decline represent relative reductions 
of 57% in the overall population, 61% in patients with HRCT with UIP-like fibrotic pattern, 
and 49% for patients with other HRCT fibrotic patterns. Analyses of time-to-event endpoints 
indicated reductions in clinically meaningful outcome events and provided supportive 
evidence for a slowing of disease progression by nintedanib [c26471552-02].  
 
The observed safety profile of nintedanib in patients with progressive fibrosing ILD 
comprised risks that were manageable or occurred at a low frequency. The most frequently 
reported AEs were gastrointestinal disorders, in particular diarrhoea, nausea, and vomiting. 
Common AEs were mostly mild or moderate in intensity. In addition, treatment with 
nintedanib was associated with elevations in liver enzymes. The large majority of liver 


 
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enzyme elevations normalised upon treatment interruption, dose reduction, treatment 
discontinuation, or spontaneously with continued treatment. 
 
More details on nintedanib can be found in the Investigator’s Brochure [c01783972]. 
 
1.3 
RATIONALE FOR PERFORMING THE TRIAL  
The efficacy and safety of nintedanib were confirmed in the multinational pivotal trial (1199-
0247), but a very limited number of Chinese patients (15 patients accounting for 2.3% of the 
entire study population) were randomized in this study. The new indication of “chronic 
fibrosing Interstitial Lung Diseases with a progressive phenotype” was conditionally 
approved in China on 15 Dec 2020, it was also requested by the Center for Drug Evaluation 
(CDE) to complete a post marketing study and submit the CSR of this post-approval 
commitment study(1199-0434) within 5 years since Chronic Fibrosing ILDs with a 
Progressive Phenotype  approval date (before Dec 14th 2025). 
 
The rationale of performing this trial is, upon completion of the international multicentre 
randomized placebo-controlled Phase III trial (INBUILD, 1199-0247), to generate additional 
data in Chinese patients with progressive fibrosing ILDs.   
 
The aim of the current study is to generate additional data on the efficacy of 150 mg bid 
nintedanib over 52 weeks in Chinese patients with Chronic Fibrosing ILDs with a 
Progressive Phenotype. The definition of the patient population is the same as in the 
INBUILD trial i.e. is  defined as patients who present with features of diffuse fibrosing lung 
disease of >10% extent on high-resolution computed tomography (HRCT) and whose lung 
function and respiratory symptoms or chest imaging have worsened despite treatment with 
unapproved medications used in clinical practice to treat ILD. 
 
Patients were selected for participation in trial 1199-0247 based on the common progressive 
disease behaviour – or phenotype – of their ILD. Baseline characteristics of the patients and 
data describing the clinical course of the placebo group in trial 1199-0247 provide supportive 
evidence that chronic fibrosing ILDs with a progressive phenotype represent a serious or life-
threatening condition similar to idiopathic pulmonary fibrosis (IPF). 
 
1.4 
BENEFIT - RISK ASSESSMENT  
1.4.1 
Benefits  
In the group of patients with Chronic Fibrosing ILDs with a Progressive Phenotype, the 
natural history of the disease appears to follow a course similar to IPF with worsening of 
respiratory symptoms, lung function, quality of life (QoL) and functional status, as well as 
early mortality. The trial population of INBUILD trial (1199-0247) was characterised by 
moderate lung function impairment and an overall progressive phenotype similar to IPF, 
while representing different major categories of underlying fibrosing ILDs. 
 


 
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In the entire patient population, the primary endpoint of the trial was met in both co-primary 
populations. Treatment with nintedanib significantly reduced the annual rate of decline in 
FVC [mL/year] over 52 weeks compared with placebo in the overall population and in 
patients with HRCT with UIP-like fibrotic pattern. Analyses of time-to-event endpoints 
indicated reductions in clinically meaningful outcome events and provided supportive 
evidence for a slowing of disease progression by nintedanib.  
 
In INBUILD trial (1199-0247), efficacy on FVC decline rate in East Asian patients which 
included Chinese patients was consistent with the entire study population. And it is not 
recommended to perform any subgroup analysis with a small sample size (15 randomized 
patients accounting for 2.3% of the entire study population) since the findings may be due to 
chance and lack clinical representativeness or statistical robustness. On the other hand, in 
INPULSIS trials (1199-0032 and 1199-0034), efficacy on FVC decline rate in Chinese 
patients was consistent with the entire study population. It is expect that Chinese patients 
with chronic fibrosising ILDs with a progressive phenotype can benefit from nintedanib 
treatment. In this study, two thirds of Chinese patients will be randomized to receive 
nintedanib and are expected to benefit from nintedanib treatment. 
 
1.4.2 
Risks  
The observed safety profile of nintedanib for chronic fibrosing ILDs with a progressive 
phenotype was largely consistent with the known safety profile of nintedanib in patients with 
IPF and SSc-ILD. Common AEs were mostly mild or moderate in intensity. The most 
frequently reported AEs were gastrointestinal disorders, especially diarrhoea, nausea, and 
vomiting. To a lesser extent, treatment with nintedanib was associated with elevations in liver 
enzymes, which mostly resolved upon treatment interruption, dose reduction, or treatment 
discontinuation. Close monitoring is recommended in patients with risk factors for liver 
enzyme elevations (Asian race, females, low body weight, and advanced age). There were no 
new or unexpected safety concerns observed in patients with chronic fibrosing ILDs with a 
progressive phenotype. 
 
Risks of nintedanib treatment also include gastrointestinal perforations, thromboembolism 
and bleeding. Therefore, patients who have planned major elective surgery or suffer from 
severe vascular disease will be excluded from this trial. Patients requiring full dose 
therapeutic anticoagulation, fibrinolysis or high-dose antiplatelet therapy may be considered 
for inclusion and/or continuation in the trial (if the requirement arises after commencement of 
trial participation) if the anticipated benefit of nintedanib outweighs the potential risk of 
bleeding. Patients with severe pulmonary hypertension will be excluded. 
Echocardiography is used to monitor patients with mild to moderate pulmonary hypertension. 
 
Nintedanib may cause foetal harm. Women of childbearing potential should be advised to 
avoid becoming pregnant while receiving treatment with nintedanib and to use highly 
effective contraceptive methods during the clinical trial and at least 3 months after the last 
dose of nintedanib. 
 


 
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Based on the pharmacological mechanism, existing non-clinical, clinical and post-marketing 
data there is no indication that treatment with nintedanib may increase the risk for infection 
with SARS-CoV-2 or for worsening the disease course of COVID-19. 
 
It is currently unknown if chronic fibrosing ILDs with a progressive phenotype conveys a 
higher risk for adverse outcomes in case of COVID-19. 
 
Table 1.4.2:1 Overview over trial related risks  
Possible or known risks of 
clinical relevance for this 
trial 
Summary of data, rationale 
for the risk 
Mitigation strategy 
Investigational Medicinal Product and concomitant treatments 
Gastrointestinal disorders (e.g. 
diarrhoea, nausea, vomiting) 
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 gastrointestinal 
disorders 
Hepatic enzyme increased 
Frequent, mostly non-serious and 
reversible with dose reductions, 
temporary drug interruption or 
drug discontinuation. 
Increased awareness of symptoms 
and early management, guideline 
to liver enzyme elevations. 
Drug-induced liver 
injury (DILI) 
Rare but severe event, thus under 
constant surveillance by sponsors 
and regulators. 
Increased awareness and expedite 
reporting (AESI). 
Careful monitoring of liver 
function and early management, 
guideline to liver enzyme 
elevations. 
Timely detection, evaluation, and 
follow-up of laboratory 
alterations in selected liver 
laboratory parameters to ensure 
patients´ safety. 
Teratogenic potential 
Nintedanib is teratogenic. 
Women of childbearing potential 
not willing or able to comply with 
contraception requirements are 
excluded from trial participation. 
Pregnancy testing in all female 
patients, even pre-menarche, 
every 4-6 weeks. 
 
 
 
 


 
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Table 1.4.2:1 Overview over trial related risks (cont.) 
Trial procedures 
Blood Sampling 
As with all blood sampling, there 
is a risk of mild pain, local 
irritation, or bruising (a black or 
blue mark) at the puncture site. 
Furthermore, there is a small risk 
of light-headedness and/or 
fainting. In rare cases, the 
puncture site can also become 
infected or nerves may be 
damaged, inducing long-lasting 
abnormal sensations (paresthesia), 
impaired sensation of touch and 
persistent pain. 
These risks will be addressed by 
careful safety monitoring and risk 
mitigation measures such as 
- close clinical monitoring for 
AEs; 
- selection of experienced sites 
and site staff; 
Lung function 
measurements   
Risks and discomforts associated 
with lung function testing may 
include shortness of breath, 
dizziness, or headache during the 
breathing tests. 
These risks will be addressed by 
careful monitoring and risk 
mitigation measures such as 
- close clinical monitoring for 
AEs; 
- selection of experienced sites 
and site staff; 
Other risks 
Placebo 
If the patient is randomized to 
receive a placebo, the patient´s 
condition could get worse during 
the course of the trial. 
Patients will be randomized in 2:1 
ratio to either nintedanib or 
placebo in this trial, and more 
patients will benefit from the 
treatment of Nintedanib. 
Patients are allowed to be treated 
with the selected medication if 
judged necessary by the 
investigator 
 
Infection with SARS-CoV-2 
Based on the pharmacological 
mechanism, existing non-clinical, 
clinical and post-marketing data 
there is no indication that 
treatment with nintedanib may 
increase the risk for infection with 
SARS-CoV-2 or for worsening 
the disease course of COVID-19. 
It is currently unknown if chronic 
fibrosing ILDs with a progressive 
phenotype conveys a higher risk 
for adverse outcomes in case of 
COVID-19. 
Even though an increased risk of 
SARS-CoV-2 infection – or of a 
more severe COVID-19 disease 
in case of such an infection 
appears unlikely, patients with 
active or recent SARS CoV-2 
infection will not be included in 
the trial. 
In addition, during the course of 
the trial, whether or not treatment 
with nintedanib will be continued 
for a confirmed SARS-CoV-2 
infection, which will be based on 
investigator judgement. 
 


 
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Table 1.4.2:1 Overview over trial related risks (cont.) 
Risk related to 
Pandemic situations 
COVID-19 
Travelling to site, being at site for 
assessments, increased infection 
risk for lung function testing. 
Patients may receive COVID-19 
vaccination in line with local 
recommendations/guidance and 
approved laboratoryels. 
Site visits could be reduced by 
using telephone visit or shipping 
medication to patient’s home. 
Local laboratory could also be 
considered. 
Every subject or patient will be 
assessed thoroughly, and 
individual benefit-risk 
assessments are made prior to 
study entrance and during the 
study by the investigator. 
 
1.4.3 
Discussion  
The benefit-risk profile of nintedanib for the treatment of chronic fibrosing ILDs with a 
progressive phenotype is well established and considered positive based on the evidence 
collected in the multiregional pivotal trial (1199-0247). A positive benefit-risk profile for 
nintedanib in East-Asian patients with Chronic Fibrosing ILDs with a Progressive Phenotype 
was shown in a subgroup analysis report of the same pivotal trial.  
 
The aim of the current study is to generate additional data on the efficacy of 150 mg bid 
nintedanib over 52 weeks in Chinese patients with Chronic Fibrosing ILDs with a 
Progressive Phenotype. A placebo group is needed to allow for a true assessment of the 
effects of nintedanib on the rate of decline in FVC in Chinese patients. However, two thirds 
of Chinese patients will be randomized to receive nintedanib so that more patients can benefit 
from the active treatment. 


 
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2. 
TRIAL OBJECTIVES AND ENDPOINTS  
 
While the efficacy and safety of nintedanib were confirmed in the multinational pivotal trial 
(1199-0247), in which a very limited number of Chinese patients were randomized.  The aim 
of the post approval commitment study is to generate additional data on the efficacy and 
safety of 150 mg bid nintedanib over 52 weeks in Chinese patients with Chronic Fibrosing 
ILDs with a Progressive Phenotype.  
2.1 
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS  
2.1.1 
Main objectives  
The objectives of the current trial are based on those of the INBUILD trial (1199-0247). The 
objective of the current trial is to generate additional data on the efficacy of 150 mg bid 
nintedanib in Chinese patients with Chronic Fibrosing ILDs with a Progressive Phenotype 
compared to placebo over 52 weeks. The primary endpoint is defined the same way as in the 
INBUILD trial (1199-0247). The efficacy of reduction in lung function decline will be 
measured by the annual rate of decline in FVC for nintedanib compared to placebo over 52 
weeks. 
2.1.2 
Primary endpoint(s)  
The primary efficacy endpoint is the same as in the INBUILD trial (1199-0247), the annual 
rate of decline in Forced Vital Capacity (FVC; expressed in mL over 52 weeks). 
2.1.3 
Secondary endpoint(s)  
Not applicable since there is no secondary endpoint. 
 


 
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3. 
DESCRIPTION OF DESIGN AND TRIAL POPULATION  
3.1 
OVERALL TRIAL DESIGN  
This is a multi-centre, national, prospective, randomized, placebo-controlled, double blind 
clinical trial to generate additional data on the efficacy and safety of nintedanib at a dose of 
150 mg bid, in Chinese patients with Chronic Fibrosing ILDs with a Progressive Phenotype 
over 52 weeks. 
Figure 3.1:1 Trial design  
 
 
 
A total of approximately 90 patients will be randomized, 60 in the active treatment group and 
30 in the placebo group. It is planned to randomize two thirds of patients (60 patients) with 
UIP-like HRCT fibrotic pattern.  
 
After signing informed consent (IC), the initial screening visit (Visit 1) will be performed to 
determine eligibility. Following completion of Visit 1, patients with established Chronic 
Fibrosing ILDs with a Progressive Phenotype, as assessed by the Investigator, will enter a 
screening period of maximum 8 weeks to confirm HRCT eligibility and determine HRCT 
pattern for randomization, and to allow for wash-out of restricted medications, if applicable. 
 
Written confirmation by the central readers that the protocol criteria for qualifying HRCT are 
met will be mandatory for randomization.  
 
Once HRCT eligibility is confirmed, Visit 2 will be scheduled to collect all clinical and safety 
information, and review all inclusion and exclusion criteria.  Patients will be randomized in 
2:1 ratio to either nintedanib or placebo and then enter the treatment phase for 52 weeks 
treatment. Randomization (stratified by HRCT pattern: “UIP-like fibrotic pattern”, or “Other 
fibrotic patterns”) will be performed by phone or Internet, using an Interactive web Response 
System (IRT). 
 
The treatment duration of the study will consist of Visits 2 through 9, which will occur within 
one year of randomization. A follow-up visit will be performed 7 days after treatment 
completion. 


 
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For each patient, the study period is from the signature of the Informed Consent until their 
last visit. Adverse events are collected during the entire study period and are considered 
treatment-emergent from first study drug intake until 7 days after drug discontinuation. 
 
All patients who prematurely discontinue trial medication will need to complete an End of 
Treatment (EOT) visit and a Follow-up (FU) visit 1 week later. Patients who prematurely 
discontinue trial medication will be asked to remain in the study and to return to all regularly 
scheduled visits until the end of the trial. This request will be outlined in the patient 
information / informed consent procedure prior to randomization. 
 
For those patients who are unable to complete the scheduled visits, every attempt will be 
made to get information on vital status at 52 weeks after randomization, as well as at the end 
of the trial. The need for vital status information will be explained to patients prior to their 
participation in the trial and will be part of the patient information / informed consent 
procedure prior to randomization. 
 
3.2 
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)  
Placebo control 
Chronic Fibrosing ILDs with a Progressive Phenotype is an important phenotype of ILDs 
introduced into academia in recent years. Due to the lack of historical data on the 
corresponding Chinese population there is currently no consensus on domestic and foreign 
guidelines for the treatment of patients with this phenotype. In the international multi-center 
phase III clinical trial (INBUILD trial), few Chinese subjects were included (15 cases in total, 
only account for 2.3% of the study population). The new indication of Nintedanib for the 
treatment of "Chronic Fibrosing ILDs with a Progressive Phenotype" was conditionaly 
approved by the CDE on 15 Dec 2020. 1199-0434 trial is asked to continue to collect data on 
effectiveness and safety of Nintedanib in Chinese population. Main design features from 
INBUILD also apply to this clinical trial, so that the results of patients in the placebo group 
of 1199-0434 trial will provide a control group for the effectiveness and safety of Nintedanib 
in Chinese patients. 
 
In addition, patients who meet inclusion criteria of the study will be randomized into the 
Nintedanib group and the placebo group at a ratio of 2:1, so as a whole more patients may 
benefit from Nintedanib therapy. 
 
Dose regimen 
The dosing regimen to be investigated is the same as approved for IPF indication, i.e. 150 
mg bid with the option of dose reduction to 100 mg and/or interruptions to manage adverse 
events (AEs).  
 
The primary assessment of benefit-risk of nintedanib in patients with Chronic Fibrosing ILDs 
with a Progressive Phenotype will be based on efficacy and safety data over 52 weeks (12 
months) of study treatment. As shown in INBUILD this is based on that Chronic Fibrosing 


 
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ILDs with a Progressive Phenotype is similar to IPF and the treatment effect of nintedanib 
demonstrated in IPF will be reproduced in Chronic Fibrosing ILDs with a Progressive 
Phenotype. 
 
In IPF, the association between decline in FVC over one year and clinical outcome has been 
examined in the scientific literature (R10-6539, R06-4127, P12-10347, R14-1150, P14- 
06844, R14-1149). While these publications do not, by stringent statistical criteria, prove 
that reduction in the annual rate of FVC decline is a surrogate for improved survival, they do 
strongly suggest that an increased rate and extent of decline in FVC at 12 months is 
associated with an increased risk of death. Due to the shown similarity in disease 
progression, especially for FVC decline and mortality, between Chronic Fibrosing ILDs 
with a Progressive Phenotype patients and IPF patients, the proposed benefit-risk assessment 
over12 months is regarded as the most appropriate period to detect a difference in the 
reduction of FVC decline between nintedanib and placebo in Chronic Fibrosing ILDs with a 
Progressive Phenotype patients. 
 
Primary endpoints 
The primary endpoint of the study is the annual rate of decline in forced vital capacity 
(FVC). In clinical trials in IPF, FVC is an established efficacy parameter; mean changes in 
FVC over time are considered relevant to assess the effect of a pharmacologic intervention 
at population level (P11-13635, P12-10347, R06-4126, R06-4127). FVC as primary 
endpoint has served as basis for worldwide regulatory approvals for nintedanib and 
pirfenidone in IPF (P14-07514, P10-13367). 
Similar to IPF, in other interstitial lung diseases (ILDs) the accelerated decline in lung 
function over time is considered consistent with disease progression and is thought to be 
associated with mortality (R10-6539, R06-4127, P12-10347, R14-1150, P14-06844, R14- 
1149). In Chronic Fibrosing ILDs with a Progressive Phenotype, and even more so for 
patients with Chronic Fibrosing ILDs with a Progressive Phenotype with histologic usual 
interstitial pneumonia (UIP) pattern, it is expected that the placebo decline in FVC is 
similar to the decline observed in patients with IPF and that nintedanib will slow the decline 
in FVC in a similar way as it does in IPF. 
 
3.3 
SELECTION OF TRIAL POPULATION  
A total of approximately 90 patients with Chronic Fibrosing ILDs with a Progressive 
Phenotype will be randomized (60 in the active dose group and 30 in placebo) in China.  
It is planned to randomize approximately two thirds of patients with UIP-like HRCT fibrotic 
pattern. This will allow for a certain enrichment of patients with more rapid progression, as 
has been shown in INBUILD. Patients with clinical diagnosis of IPF will be excluded from 
the current study. 
 
Screening of patients for this trial is competitive, i.e. screening for the trial will stop at all 
sites at the same time once a sufficient number of patients has been screened. Investigators 
will be notified about screening completion and will then not be allowed to screen additional 
patients for this trial. 


 
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A log of all patients enrolled into the trial (i.e. who have signed informed consent) will be 
maintained in the Investigator Site File (ISF) irrespective of whether they have been treated 
with investigational drug or not. 
 
If a patient is enrolled in 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. 
 
3.3.1 
Main diagnosis for trial entry  
Outpatients aged ≥ 18 years with Chronic Fibrosing ILDs with a Progressive Phenotype, 
defined as patients who present with features of diffuse fibrosing lung disease of >10% extent 
on HRCT and whose lung function and respiratory symptoms or chest imaging have 
worsened despite treatment with unapproved medications used in clinical practice to treat 
ILD, are eligible for inclusion if they fulfil all the inclusion criteria (Section 3.3.2) and do not 
present any of the exclusion criteria (Section 3.3.3). 
 
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. Written Informed Consent consistent with ICH-GCP and local laws signed prior to 
entry into the study (and prior to any study procedure including shipment of HRCT to 
reviewer). 
2. Male or female patients aged ≥ 18 years at Visit 1. 
3. Patients with physician diagnosed ILD who fulfil at least one of the following criteria 
for Progressive Phenotype within 24 months of screening visit (Visit 1) despite 
treatment with unapproved medications used in clinical practice to treat ILD, as 
assessed by the investigator (refer to Section 3.3.3): 
a. Clinically significant decline in FVC % predicted based on a relative decline of 
≥10% 
b. Marginal decline in FVC % predicted based on a relative decline of  ≥5-<10% 
combined with worsening of respiratory symptoms  
c. Marginal decline in FVC % predicted based on a relative decline of ≥5-<10% 
combined with increasing extent of fibrotic changes on chest imaging 
d. Worsening of respiratory symptoms as well as increasing extent of fibrotic 
changes on chest imaging 
[Note: Changes attributable to comorbidities e.g. infection, heart failure must be 
excluded. Unapproved medications used in the clinical practice to treat ILD include 
but are not limited to corticosteroid, azathioprine, mycophenolate mofetil (MMF), n-
acetylcysteine (NAC), rituximab, cyclophosphamide, cyclosporine, tacrolimus]. 


 
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4. Fibrosing lung disease on HRCT, defined as reticular abnormality with traction 
bronchiectasis with or without honeycombing, with disease extent of >10%, 
performed within 12 months of Visit 1 as confirmed by central readers. 
5. For patients with underlying CTD: stable CTD as defined by no initiation of new 
therapy or withdrawal of therapy for CTD within 6 weeks prior to Visit 1.  
6. FVC ≥ 45% predicted at Visit 2. 
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 Cockcroft–Gault 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 
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). 
5. Previous treatment with nintedanib or pirfenidone. 
6. Other investigational therapy received within 1 month or 6 half-lives (whichever was 
greater) prior to screening visit (Visit 1). 
7. Use of any of the following medications for the treatment of ILD: azathioprine 
(AZA), cyclosporine, MMF, tacrolimus, oral corticosteroids (OCS) >20mg/day and 
the combination of OCS+AZA+NAC within 4 weeks of Visit 2, cyclophosphamide 
within 8 weeks of Visit 2, rituximab within 6 months of Visit 2. Equivalent Doses of 
Corticosteroids refer to Appendix 10.3. 
Note: Patients whose RA/CTD is managed by these medications should not be 
considered for participation in the current study unless change in RA/CTD medication 
is medically indicated (refer to Inclusion Criterion #5) 
8. Diagnosis of IPF based on ATS/ERS/JRS/ALAT 2018 Guideline [R18-2794]. 
9.  Diagnosis of Systemic Sclerosis (SSc) based on 2013 ACR/EULAR classification 
10. 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 


 
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11. Primary obstructive airway physiology (pre-bronchodilator FEV1/FVC < 0.7 at Visit 
1). 
12. In the opinion of the Investigator, other clinically significant pulmonary 
abnormalities. 
13. Major extrapulmonary physiological restriction (e.g. chest wall abnormality, large 
pleural effusion) 
14. Cardiovascular diseases, any of the following: 
a. Severe hypertension, uncontrolled under treatment (≥160/100 mmHg), within 6 
month of Visit 1 
b. Myocardial infarction within 6 months of Visit 1 
c. Unstable cardiac angina within 6 months of Visit 1 
15. 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 (Investigators judgment). 
e. Coagulation parameters: International normalized ratio (INR) >2, prolongation of 
prothrombin time (PT) and activated partial thromboplastin time (aPTT) by >1.5 x 
ULN at Visit 1. 
16. History of thrombotic event (including stroke and transient ischemic attack) within 6 
months of Visit 1. 
17. Known hypersensitivity to the trial medication or its components (i.e. soya lecithin) 
18. Patients with peanut allergy. 


 
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19. 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. 
20. Life expectancy for disease other than ILD < 2.5 years (Investigator assessment). 
21. Planned major surgical procedures. 
22. Women who are pregnant, nursing, or who plan to become pregnant while in the trial. 
23. Women of childbearing potential* not willing or able to use highly effective methods 
of birth control per ICH M3 (R2) that result in a low failure rate of less than 1% per 
year when used consistently and correctly as well as one barrier method for 28 days 
prior to and 3 months after nintedanib administration. A list of contraception methods 
meeting these criteria is provided in the patient information. 
24. In the opinion of the Investigator, active alcohol or drug abuse. 
25. Patients not able to understand or follow trial procedures including completion of self-
administered questionnaires without help. 
26. The patient has a confirmed infection with SARS-CoV-2** within the 4 weeks prior 
to Visit 1 and/or during the screening period. 
 
*A woman is considered of childbearing potential, i.e. fertile, following menarche and until 
becoming post-menopausal unless permanently sterile. Permanent sterilisation methods 
include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. 
**Testing for SARS-CoV-2 is not the part of this trial. If required this needs to be done per 
local requirements or investigator’s assessment. 
3.3.4 
Imaging criteria  
Patients with original physician diagnosis of different fibrosing ILDs, e.g. CTD-ILD, chronic 
fibrosing HP, iNSIP, unclassifiable IIP and environmental/ occupational fibrosing lung 
disease will be included if they meet the protocol criteria for PF-ILD. While the clinical ILD 
diagnosis will not be verified, central review of the screening HRCT images will ensure that 
relevant lung fibrosis is present and the HRCT pattern is not indicative of other causes of 
progression. 
 
At screening the recent (not older than 12 months at screening) HRCT image of the 
patient will be evaluated; previous HRCT images will not be collected or reviewed. Hence 
inclusion based on increasing extent of fibrotic changes on chest imaging within 24 months 
will reflect the investigator’s judgement. 
 
Eligible patients will have fibrosing lung disease on HRCT, defined as reticular abnormality 
with traction bronchiectasis with or without honeycombing with disease extent of >10%. 
 
The following co-existing features will be accepted: 
• 
Ground glass opacity 


 
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• 
Upper lung or peribronchovascular predominance 
• 
Mosaic attenuation 
• 
Air trapping 
• 
Centrilobular nodules 
 
The following co-existing features will not be allowed: 
• 
Widespread consolidation 
• 
Progressive massive fibrosis 
 
In addition, determination of the HRCT pattern will also be done by central review and will 
be used for randomization stratification. The study will be enriched for patients meeting 
either criteria A, B and C, criteria A and C, or criteria B and C as described below. These 
patients will be referred to as “patients with HRCT with UIP-like fibrotic pattern only”. 
Patients with PF-ILD who do not meet these criteria will be referred to as “patients with other 
HRCT fibrotic patterns”. 
A=Definite honeycomb lung destruction with basal and peripheral predominance 
B=Presence of reticular abnormality AND traction bronchiectasis consistent with fibrosis 
with basal and peripheral predominance 
C=Atypical features are ABSENT, specifically: nodules and consolidation. Ground glass 
opacity, if present, is less extensive than reticular opacity pattern 
 
Specifications for the HRCT acquisition will be provided in the ISF. Screening HRCT can be 
performed as part of the study in case the available HRCT does not meet the required image 
acquisition specifications. 
3.3.5 
Withdrawal of patients from treatment or assessments  
Patients may discontinue trial treatment or withdraw consent to trial participation as a whole 
(“withdrawal of consent”) with very different implications; please see Sections 3.3.5.1 and 
3.3.5.2 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 CRF. If applicable, consider the 
requirements for Adverse Event collection reporting (please see Sections 5.2.6.2). 
3.3.5.1 
Discontinuation of trial treatment  
Short term interruptions for adverse events (see also Section 4.2) are possible and should be 
used whenever possible to avoid permanent discontinuation of trial medication 


 
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The following will require a permanent discontinuation of trial treatment of an individual 
patient: 
• The patient wants to discontinue trial treatment, without the need to justify the decision. 
• The patient can no longer receive trial treatment for medical reasons (such as chronic use 
of concomitant medication, adverse events, other diseases that puts a patient at risk, 
parenteral feeding requirement or pregnancy). 
• The patient experiences signs of hepatic injury, defined in Section 5.2.6.1.4. 
• No further dose reduction is possible for patients on the 100 mg bid regimen. In case of 
persistent adverse events observed at this dose, or severe effects at 150 mg bid, permanent 
treatment discontinuation should be considered. 
 
Temporary interruption (see also Section 4.2.1) or permanent discontinuation of trial 
treatment is recommended (at the investigators discretion) for the following situations: 
• Major surgery, including any abdominal or intestinal surgery. 
• Major thrombo-embolic events e.g. stroke, deep vein thrombosis, pulmonary embolism, 
myocardial infarction. 
• Increased risk of bleeding e.g. hemorrhagic CNS event, haemoptysis or haematuria, 
active gastro-intestinal bleeding or GI-ulcers. 
• The patient experiences an infection with SARS-CoV-2. 
 
The investigator, after assessment of available clinical data and taking into consideration the 
potential risks associated with administration of nintedanib, may decide not to permanently 
discontinue the trial medication. In such a case, continuation of treatment with trial 
medication should be discussed with the patient, and the decision and reasoning documented 
in the source data. 
 
If a patient becomes pregnant during the trial, the investigational product must be stopped 
and the patient should 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 BI drug safety database. 
Refer to Section 5.2.6.2.3 for detailed information on event reporting in case of pregnancy. 
 
If new efficacy/safety information becomes available, Boehringer Ingelheim will review the 
benefit-risk-assessment and, if needed, pause or discontinue the trial treatment for all patients 
or take any other appropriate action to guarantee the safety of the trial patients. 
 
If a patient discontinues the trial medication prematurely, it is of utmost importance for the 
robustness and integrity of the trial results that his/her lung function parameters and safety 
data are further recorded until the end of the trial. Patients, who prematurely discontinue trial 
medication, will be asked to follow their original visit schedule (refer to Section 6.2.3). 
 
3.3.5.2 
Withdrawal of consent to trial participation  
Patients may withdraw their consent to trial participation at any time without the need to 
justify the decision. 


 
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If a patient wants to withdraw consent, the investigator should be involved in the discussion 
with the patient and explain the difference between permanent trial treatment discontinuation 
and withdrawal of consent to trial participation, as well as explain the importance for 
continued follow-up after trial treatment discontinuation. 
 
Withdrawal of consent to trial participation is defined as the refusal to provide any further 
data, not even provide a vital status (either by contact or medical records) at the end of the 
planned observation period. 
3.3.5.3 
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. New efficacy or safety information invalidating the earlier positive benefit-risk-
assessment, please see Section 3.3.5.1. 
3. Deviations from GCP, the trial protocol, or the contract impairing the appropriate conduct 
of the trial. 
Further treatment and follow up of patients affected will occur as described in Section 
3.3.5.1. The investigator / the trial site will be reimbursed for reasonable expenses incurred in 
case of trial termination (except in case of the third reason). 


 
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4. 
TREATMENTS  
4.1 
INVESTIGATIONAL TREATMENTS  
4.1.1 
Identity of the Investigational Medicinal Products  
Table 4.1.1:1 Identity of BI investigational product(s )
Substance: 
Nintedanib 
Pharmaceutical formulation: 
Soft gelatin capsule 
Source: 
BI Pharma GmbH & Co. KG 
Unit strength: 
150 mg,100mg 
Posology: 
b.i.d 
Mode of administration: 
Oral (swallowed) 
 
Substance: 
Placebo matching in size, weight, colour and shape 
to 150 mg and 100mg soft gelatin capsule of 
Nintedanib 
Pharmaceutical formulation: 
Soft gelatin capsule 
Source: 
BI Pharma GmbH & Co. KG 
Unit strength: 
n.a 
Posology: 
b.i.d 
Mode of administration: 
Oral (swallowed) 
 
4.1.2 
Selection of doses in the trial and dose modifications  
Based on the efficacy and safety from trials investigating nintedanib in IPF and the 
multiregional pivotal trial (1199-0247), a dose of 150 mg bid is selected for the Chronic 
Fibrosing ILDs with Progressive Phenotype program. With 150 mg bid, acceptable 
tolerability in Chronic Fibrosing ILDs with Progressive Phenotype patients is expected based 
on the risk profile seen in IPF patients. Similar to IPF and SSc-ILD, a prior dose reductions 
are not indicated and the proposed dosing regimen of 150 mg bid including the option to 


 
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reduce the dose to 100 mg bid or interrupt treatment to manage adverse event is considered to 
offer the best benefit-risk ratio, i.e. to optimize exposure-efficacy versus exposure-tolerability 
in the individual patient taking into account the moderate to high inter-patient variability in 
plasma exposure. 
4.1.3 
Method of assigning patients to treatment groups  
After the assessment of all in- and exclusion criteria, each eligible patient will be randomized 
to treatment groups according to a randomization plan in a 2:1 ratio at visit 2 via Interactive 
Response Technology (IRT). Note that the medication number is different from the patient 
number (the latter is generated during screening via the IRT System). 
 
The randomization will be stratified according the background status of the patient (either 
UIP-like or non-UIP) via Interactive Response Technology (IRT). When we recruit 30 non-
UIP patients (or 60 UIP patients), we will stop recruiting non-UIP patients (or UIP patients). 
 
Each patient fulfilling all in- and exclusion criteria will be randomized via IRT at Visit 2 to 
one of the 2 following arms in a 2:1 ratio: 
• Nintedanib 150 mg b.i.d 
• Placebo b.i.d 
4.1.4 
Drug assignment and administration of doses for each patient  
Table 4.1.4: 1 Dosage and treatment schedule  
Treatment arm 
Nintedanib  
150 mg 
Placebo matching  
150 mg 
Nintedanib  
150 mg 
Placebo matching  
150 mg 
 
Morning 
Evening 
Nintedanib 150 mg 
1 
 
1 
 
Placebo 
 
1 
 
1 
 
Based on the treatment allocated at randomization, the IRT system will be used to dispense 
the appropriate medication kits at each visit. Patient will receive either active drug at a dosage 
of 150 mg bid or placebo bid. 
 
The patients should take the trial medication with food, swallow whole with water, and 
should not be chewed or crushed because of a bitter taste, and should observe a dose interval 
of 12 hours as far as possible. Effort should be made to ensure that drug administration 
occurs at the same time every day +/- 30 min (between 06:00 and 11:00 in the morning, and 
between 18:00 and 23:00 in the evening). A forgotten dose should be skipped if the time 
window to the next dose is less than 8 hours. The next dose should be taken as scheduled. 
The recommended maximum daily dose of 300 mg should not be exceeded. 
 
The dose may be reduced to 100 mg bid due to AE after the investigator assessment. The 
investigator can dispense new medication kits with 100mg to the patient via IRT system. 
 


 
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A patient diary will be used to record the daily intake of the trial medication. 
 
Trial medication will consist of 1 capsule twice daily (bid) administered orally throughout the 
study. Wallets covering 30 days + 5 days reserve treatment will be dispensed to the patient: 
 
• 1 wallet at Day 1 (randomization = Visit 2) ( 30 days plus  5 days reserve) 
• 2 wallets from Visit 4 (60 days plus 10 days reserve) 
• 3 wallets from Visit 6 (90 days plus 15 days reserve) 
• 3 Wallets from Visit 7 (90 days plus 15 days reserve) 
• 4 wallets from Visit 8 (120 days plus 20 days reserve) 
 
To ensure patients receive adequate supply of study medication, kits will be dispensed at 
clinical visits in quantities as outlined in Table 4.1.4: 2. 
 
Table 4.1.4: 2 Number of IMP kits dispensed at each visit  
Study visits 
2 
    3 
4 
5 
6 
6a 
7 
7a 
8 
8a 
9 
Number of 
IMP kits 
dispensed 
 
     1 
─ 
2 
─ 
 
   3 
 
─ 
 
3 
 
─ 
 
4        
 
─ 
 
─ 
 
During the COVID-19 pandemic, 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 and trial 
medication may be shipped directly to the patients’ home if acceptable according to local law 
and regulations. In agreement with the sponsor, a home visit service or telemedicine may 
assist the patient with medication administration. 
4.1.5 
Blinding and procedures for unblinding  
4.1.5.1 
Blinding  
Patients, investigators, central reviewers, and everyone involved in trial conduct or analysis 
or with any other interest in this double-blind trial will remain blinded with regard to the 
randomized treatment assignments until after database lock. 
The access to the randomization code will be kept restricted until its release for analysis. 
4.1.5.2 
Unblinding and breaking the code  
Emergency unblinding will be available to the investigator via IRT. It 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. However, treatment information is not to be further distributed. 
 


 
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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 randomization 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. 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. 
For details of packaging and the description of the label, refer to the ISF. 
4.1.7 
Storage conditions  
Drug supplies will be kept in their original packaging and in a secure limited access storage 
area according to the recommended storage conditions on the medication label. A 
temperature log must be maintained for documentation. 
If the storage conditions are found to be outside the specified range, the Clinical Research 
Associate CRA (as provided in the list of contacts) must be contacted immediately. 
4.1.8 
Drug accountability  
The investigator or designee will receive the investigational drugs delivered by the sponsor 
when the following requirements are fulfilled: 
• Approval of the clinical trial protocol by the IRB / ethics committee , 
• Availability of a signed and dated clinical trial contract between the sponsor and the 
investigational site, 
• Approval/notification of the regulatory authority, e.g. competent authority, 
• Availability of the curriculum vitae of the Principal Investigator, 
• Availability of a signed and dated clinical trial protocol, 
• Availability of the proof of a medical license for the Principal Investigator,  
 
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 


 
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sponsor, the investigator or designee must verify that all unused or partially used drug 
supplies have been returned by the clinical trial patient and that no remaining supplies are in 
the investigator’s possession. 
4.2 
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS  
4.2.1 
Other treatments and emergency procedures  
Rescue medication to reverse the action of nintedanib is not available. 
Dose reduction from 150 mg bid to 100 mg bid or treatment interruption should be 
considered to manage adverse events. No further dose reduction is possible for patients on the 
100 mg bid regimen. In case of persistent adverse events observed at this dose, or severe 
effects at 150 mg bid, permanent treatment discontinuation should be considered. 
Treatment interruption, reduction and re-increase are allowed at multiple occasions. 
Table 4.2.1: 1 Allowed treatment reduction / interruption periods:  
AEs considered related to 
study drug 
AEs not considered related to 
study drug 
Maximum interruption 
4 weeks 
8 weeks 
Recommended restart 
with reduced dose (100 mg bid) 
with the same dose as before 
interruption 
(100 mg bid or 150 mg bid) 
Re-escalation 
within 4 weeks to 150 mg bid 
N/A 
4.2.1.1 
Management of diarrhoea  
Diarrhoea is a known side effect of nintedanib treatment (see Section 1.4.2). However, 
potential causes for diarrhoea other than study medication should always be considered and 
treated accordingly (e.g. viral infections, bacterial overgrowth, 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 to 100 mg bid should be considered according to the 
recommendations described in Table 4.2.1.1: 1. 
 
 


 
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Table 4.2.1.1: 1 Management of diarrhoea (considered related to trial medication)  
 
 
Footnotes: 
* Other potential causes for diarrhoea should always be considered and treated accordingly (e.g. viral infections, SSc 
related diarrhoea, bacterial overgrowth, antibiotic treatment) 
1 Baseline defined as usual stools/day prior randomization. 
 
Description 
Symptomatic Treatment* 
Action with trial medication 
Diarrhoea with 
increase of <4 stools 
per day over baseline1. 
Initiate anti-diarrheal medicines at 
first signs of symptoms (e.g. 4 mg 
loperamide followed by 2 mg after 
each loose stool or every 2-4 hours 
to a maximum of 16 mg/day) until 
bowel movements cease for 12 
hours. 
Continue same trial medication 
dose. 
Diarrhoea with 
increase of 4 to 6 
stools per day over 
baseline1. 
Initiate/continue anti-diarrheal 
medicines; 
If diarrhoea of this severity 
persists for ≥48 to 72 hours assess 
for dehydration and electrolyte 
imbalance; 
In addition, consider IV 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 100 mg bid 
after recovery. 
3. Re-escalate to 150 mg bid 
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 IV 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 100 mg bid 
after recovery. 
3. Consider re-escalation within 4 
weeks to 150 mg bid 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. 


 
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4.2.1.2 
Management of liver enzyme elevation  
Nintedanib can be associated with increased liver enzymes (see Section 1.4.2). Concomitant 
use of other drugs known to cause liver enzyme elevations should be evaluated. For a detailed 
guidance on how to manage liver enzyme elevations, please refer to Table 4.2.1.2: 1. 


 
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Table 4.2.1.2: 1 Recommendations for managing liver enzyme elevations  
 
AST and/or ALT increase to 
Signs of hepatic injury* 
(Section 5.2.6) 
>1.5x to <3x 
ULN 
≥3x to <5x 
ULN and no 
signs of hepatic 
injury 
(see Section 
5.2.6) 
≥5x to <8x 
ULN and no 
signs of hepatic 
injury 
(see Section 
5.2.6) 
Visit 2 
(randomization) 
Withdraw trial 
medication or 
justify 
continuation1 
Withdraw trial 
medication 
Withdraw trial 
medication 
Withdraw trial medication 
Any other Visit Continue as 
planned2 
Reduce dose or 
interrupt trial 
medication 3 
Interrupt trial 
medication 
Withdraw trial medication 
CLINICAL 
EVALUATION OF 
HEPATIC INJURY 
(Section 5.2.6.1.4) 
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 bi- 
weekly for at 
least 8 weeks 
Permanently 
discontinue trial 
medication 
Close 
observation4 
Restart at 
reduced dose 
Monitor weekly 
for 4 weeks, 
then bi-weekly 
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 
1 Investigator to confirm in writing that continuation is justified (e.g. intermittent fluctuation of transaminases). 
2 According to visit schedule. Consider additional control visits as adequate. 
3 To be decided by Investigator, based on individual risk assessment. 
4 Close 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 laboratory kit. 
 


 
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4.2.1.3 
Management of acute ILD exacerbations  
In case of acute ILD exacerbation (see Section 5.1.2), all treatment options considered 
adequate by the Investigator are allowed. The patient may interrupt study treatment for up to 
8 weeks, if necessary (e.g. if short-term full anticoagulation is performed). 
 
4.2.2 
Restrictions  
4.2.2.1 
Restrictions regarding concomitant treatment  
The aim of the study is to generate additional data on the efficacy and safety of nintedanib in 
patients whose progressive lung disease is the main contributor to morbidity. 
 
Treatment of ILD 
 
Immunomodulatory medications i.e. Azathioprine, cyclosporine, tacrolimus, Rituximab, 
Cyclophosphamide, mycophenolate mofetil, OCS have been utilized in the clinical practice 
for the treatment of ILD although their benefit-risk profiles in ILD have not been established 
and they are not approved for the treatment of ILD in China. In order to avoid the potential 
impact of these drugs on the assessment of the efficacy and safety of nintedanib in PF-ILD, 
their use will not be allowed at randomization and during the first six months of the treatment 
period.  
Patients who receive any of these medications for the treatment of their ILD will have to 
discontinue these drugs prior to randomization. As the protocol requires that eligible patients 
progress despite treatment with these medications (i.e. do not or no longer benefit from these 
drugs), prohibition of these medications is considered justified. In case of acute worsening of 
PF-ILD during the treatment period, the use of any of these drugs after six months of study 
treatment will be allowed if judged necessary by the investigator. 
 
Treatment of the underlying diseases associated with ILD 
The largest group of patients with Chronic Fibrosing ILDs with a Progressive Phenotype that 
has an underlying disease associated with ILD is the group of patients with CTD. Eligible 
patients with underlying CTD should have stable CTD defined as no initiation or withdrawal 
of therapy for CTD within six weeks prior to screening. In addition, investigators are 
encouraged to maintain the baseline treatment of CTD during the entire study unless change 
is medically indicated. 
 
The majority of the eligible patients with CTD is expected to have RA and to be receiving 
disease-modifying anti-rheumatic drug (DMARD) e.g. methotrexate or TNF inhibitors. All 
approved RA/CTD medications are allowed at stable doses at Baseline (Visit 2) and during 
the study with the exceptions of the following, less frequently used medications: 
Azathioprine, cyclosporine, tacrolimus, high dose steroids, and Rituximab. The use of these 
medications will not be allowed in this study. In addition, the following drugs used off-label 


 
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for the treatment of RA/CTD will not be allowed throughout the study: Cyclophosphamide 
and MMF.  
 
The rationale for these limitations is that, as described above, these drugs have also been 
utilized in the clinical practice for the treatment of ILD. In order to avoid the potential impact 
of these drugs on the assessment of the efficacy and safety of nintedanib in Chronic Fibrosing 
ILDs with a Progressive Phenotype, their use will not be allowed.  
 
Patients whose RA/CTD is well managed by these medications should not be considered for 
participation in the current study. In case a change in the RA/CTD treatment to another non-
restricted medication is indicated, the patient’s disease has to be stable (i.e. no initiation of 
new therapy or withdrawal of therapy for CTD within 6 weeks prior to Visit 1) before 
entering in the current trial. 
 
Table 4.2.2.1: 1 Medication restrictions  
Restricted medications:  
Azathioprine, cyclosporine, tacrolimus, Rituximab, Cyclophosphamide, mycophenolate 
mofetil, OCS >20mg/day, investigational drugs 
 
For ILD 
For CTD 
Baseline 
Not allowed at V2*  
Not allowed  
Within first 6 months 
of study treatment 
Not allowed 
Not allowed 
After 6 months of 
study treatment 
Allowed in case of significant 
deterioration#   
Allowed case of significant 
deterioration # 
After EOT 
Allowed 
Allowed  
* Wash-out periods to be observed as described in Table 4.2.2.1: 2 below 
 # All can be used in case of clinically significant deterioration of Chronic Fibrosing ILDs with a Progressive Phenotype or 
worsening CTD at the discretion of the Investigator, except for investigational drugs. Introduction of new therapy for CTD 
should be minimized. 
 


 
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Table 4.2.2.1: 2 Wash-out schedule. Wash-out rules apply only for medications used for ILD 
treatment.  
Medication 
Wash-out period 
Azathioprine 
Cyclosporine 
Tacrolimus 
Mycophenolate mofetil 
OCS >20mg/day 
 
4 weeks prior to Visit 2 
Rituximab 
6 months prior to Visit 2 
Cyclophosphamide 
8 weeks prior to Visit 2 
Investigational drug(s) 
4 weeks or 6 half-lives (whichever is 
longer) prior to Visit 1 
 
In case of clinically significant deterioration, initiation of additional therapy for ILD i.e. on 
top of the study medication is allowed after completion of the 6-month study visit (Visit 7) as 
described in Table 4.2.2.1:1, as determined by the Investigator. For example, introduction of 
additional therapy may be considered if the patient experiences ≥ 10% relative decline in 
FVC% pred from baseline that is not attributed to a reversible process (i.e. respiratory 
infection). Detailed (S)AE information following such events should be recorded in the 
eCRF. Please also refer to cautionary notes (Section 4.2.2.2). 
 
Prohibited medications 
 
As detailed in the exclusion criteria, patients receiving pirfenidone, 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.  
 
The use of pirfenidone and nintedanib are prohibited throughout the study, including the 
Follow-up period. 
 
4.2.2.2 
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. 
 
 


 
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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. 
 
As the most common side effects known for nintedanib are GI effects i.e. diarrhoea, nausea 
and vomiting (see Section 4.2.1.1) 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 laboratory kit are recommended. 
 
4.2.2.3 
Restrictions on diet and life style  
There are no restrictions on diet and life style. 
4.2.2.4 
Contraception requirements  
The anti-angiogenic properties of nintedanib indicate a high potential for teratogenicity and 
embryotoxicity, including fetotoxicity and lethality.  
 
WOCBP (A woman is considered of childbearing potential, i.e. fertile, following menarche 
and until becoming post-menopausal unless permanently sterile. Permanent sterilisation 
methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy.) and men 
able to father a child must use two medically approved methods of birth control throughout 
the trial, and for a period of at least 3 months after last trial drug intake, and 28 days before 
treatment initiation, one barrier method, and one highly effective non-barrier method. 
Men able to father a child must use two medically approved methods of birth 
controlthroughout the trial, and for a period of at least 3 months after last trial drug intake: 
one barrier method, and one highly effective non-barrier method. 
Men (trial participant or partner of a trial participant) must be vasectomised with documented 
absence of sperm or use a condom if their sexual partner is a WOCBP. 
WOCBP (trial participant or partner of a trial participant) must use a highly effective method 
of birth control per ICH M3 (R2) that results in a low failure rate of less than 1% per year 
when used consistently and correctly if their sexual partner is a man able to father a child. 
• 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 
 


 
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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 tablet counts , treatment compliance will be calculated as shown in the formula 
below. Compliance will be verified by the CRA authorised by the sponsor. 
Treatment compliance (%) = 
 
Number of tablets actually taken  100 
     Number of tablets 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 the 
importance of treatment compliance. 


 
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5. 
ASSESSMENTS  
5.1 
ASSESSMENT OF EFFICACY  
5.1.1 
FVC  
Spirometry measurements will be performed according to ATS/ERS 2005 guideline (P05- 
12782). FVC will be assessed using standardised spirometry equipment which will be 
provided centrally with supplies of pre-calibrated disposable flow sensors. These sensors 
demonstrate variability within the required standards of +/-3% determined by the American 
Thoracic Society (ATS)/European Respiratory Society (ERS) [P05-12782]. As such there is 
no need to conduct daily calibration prior to use. Only these spirometers are to be used for 
this trial. Spirometry performance will be centrally reviewed. 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 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 primary endpoint measurement a central 
spirometry review is put in place to provide feedback to the investigational site and the CRA 
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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5.2 
ASSESSMENT OF SAFETY  
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.  
Measurement of height and body weight will be performed at the time points specified in the 
Flow Chart. 
The results must be included in the source documents available at the site.  
 
5.2.2 
Vital signs  
Vital signs will be evaluated at the time points specified in the Flow Chart, prior to blood 
sampling. 
This includes systolic and diastolic blood pressure and pulse rate (electronically or by 
palpation count for 1 minute) in a seated position after 5 minutes of rest. The results must be 
included in the source documents available at the site. 


 
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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. 
 
In case the criteria for hepatic injury are fulfilled, a number of additional measures will be 
performed (please see Section 5.2.6.1.4 and the DILI Checklist provided in the ISF 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. 
Table 5.2.3:1 Safety laboratory tests  
Category 
Laboratory test 
Haematology 
Red blood cell count (RBC) 
Haemoglobin (Hb) 
Haematocrit (Hct) 
Mean corpuscular volume 
White blood cell count including differential 
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 
Brain natriuretic peptide (BNP at V2, V7, V9 and EOT) 
Creatinine 
Glucose (non fasting) 
Uric acid 
 


 
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Table 5.2.3:1 Safety laboratory tests (cont.) 
Biochemistry 
Thyroid stimulating hormone (only at V2, V7, V9, and EOT) 
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; -, +, ++, +++) 
ß-HCG will be performed at Visit 2 only, at central laboratory. Urine dipstick pregnancy 
tests will be provided by central laboratory and should be performed in all women of 
childbearing potential every 4-6 weeks. If urine test is not acceptable to local authorities, a 
blood test must be done at a local laboratory. 
 
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; -, +, ++, +++) 
Local Urine dipstick pregnancy test in all women of childbearing potential. If urine test is 
not acceptable to local authorities, a blood test must be done at a local laboratory. 
 
At ‘a-Visits’, safety blood, pregnancy tests 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 Section 4.2.2.2 for additional safety monitoring). 
 
The samples and pregnancy tests 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. 
 
Creatinine clearance will be calculated based on serum creatinine according to Cockcroft and 
Gault (R96-0690, Appendix 10.2). 
 
If laboratory values indicate abnormality, adequate and more frequent blood sampling may be 
performed at the discretion of the Investigator. 
 


 
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In case of liver function value elevations, close monitoring must be ensured by the 
Investigator. Refer to Section 4.2.1.2 for monitoring elevations and Section 3.3.5 for 
withdrawal criteria. 
 
Laboratory analysis will be done using central laboratory services. Venous whole blood will 
be collected through the assigned central laboratory. 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. 
5.2.4 
Electrocardiogram  
The 12-lead ECGs must be administered by a qualified technologist and results will be 
recorded as scheduled in the Flowchart. The investigator or a designee will evaluate whether 
the ECG is normal or abnormal and assess clinical relevance. ECGs may be repeated for 
quality reasons and a repeated recording used for analysis.  
 
Additional ECGs may be recorded for safety reasons. Dated and signed printouts of ECG 
with findings should be documented in patient’s medical record. 
 
Clinically relevant abnormal findings will be reported either as baseline condition (if 
identified at the screening visit) or otherwise as AEs and will be followed up and/or treated as 
medically appropriate. 
 
5.2.5 
Other safety parameters  
Not applicable. 
5.2.6 
Assessment of adverse events  
5.2.6.1 
Definitions of AEs  
5.2.6.1.1 
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 or of other pre-existing conditions  
• Changes in vital signs, ECG, physical examination and laboratory test results, if they 
are judged clinically relevant by the investigator. 


 
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If such abnormalities already exist prior to trial inclusion, they will be considered as baseline 
conditions and should be collected in the eCRF only. 
5.2.6.1.2 
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.  
5.2.6.1.3 
AEs considered “Always Serious”  
In accordance with the European Medicines Agency initiative on Important Medical Events, 
Boehringer Ingelheim has set up a list of AEs, which by their nature, can always be 
considered to be “serious” even though they may not have met the criteria of an SAE as 
defined above. 
The latest list of “Always Serious AEs” can be found in the eDC system. A copy of the latest 
list of “Always Serious AEs” will be provided upon request. These events should always be 
reported as SAEs as described in Section 5.2.6.2. 
 
Cancers of new histology and exacerbations of existing cancer must be classified as a serious 
event regardless of the time since discontinuation of the drug and must be reported as 
described in Section 5.2.6.2, subsections “AE Collection” and “AE reporting to sponsor 
and timelines”. 
5.2.6.1.4 
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 5.2.6.2.2. 
 


 
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Adverse events relating to gastrointestinal perforation and hepatic injury will be considered 
AESIs. 
 
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 laboratory findings constitute a hepatic injury alert and the patients showing these 
laboratory abnormalities need to be followed up according to the “DILI checklist” provided 
in the ISF.  
In case of clinical symptoms of hepatic injury (icterus, unexplained encephalopathy, 
unexplained coagulopathy, right upper quadrant abdominal pain, etc.) without laboratory 
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. 
5.2.6.1.5 
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. 
 
 In addition the intensity of diarrhoea adverse events should be classified and recorded in the 
eCRF according to the Common Terminology Criteria for adverse events (CTCAE) (Version 
4) 
Table 5.2.6.1.5:1 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 
 


 
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Table 5.2.6.1.5:1 CTCAE Categorization for diarrhoea (cont.) 
3 
Increase of ≥7 stools per day over baseline; stool incontinence 
4 
Life threatening consequences 
5 
Death 
 
5.2.6.1.6 
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. 
• 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. 


 
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5.2.6.2 
Adverse event collection and reporting  
5.2.6.2.1 
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 (the 
End of Trial (EoTrial) visit):  
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 5.2.6.2.2), but not on the CRF. 
 
Vital Status Data Collection 
  
Patients who discontinue trial medication prematurely, who agree to be contacted further but 
do not agree to physical visits, should be followed up as described in Section 3.3.5.1, 
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.  
5.2.6.2.2 
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 contact details 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. 
5.2.6.2.3 
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. 


 
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Similarly, potential drug exposure during pregnancy must be reported if a partner of a male 
trial participant becomes pregnant. This requires written consent of the pregnant partner. 
Reporting and consenting must be in line with local regulations. The ISF will contain the trial 
specific information and consent for the pregnant partner.  
The outcome of the pregnancy associated with the drug exposure during pregnancy must be 
followed up and reported to the sponsor’s unique entry point on the Pregnancy Monitoring 
Form for Clinical Studies (Part B). 
The ISF will contain the Pregnancy Monitoring Form for Clinical Studies (Part A and B). 
 
As pregnancy itself is not to be reported as an AE, in the absence of an accompanying SAE 
and/or AESI, only the Pregnancy Monitoring Form for Clinical Studies and not the SAE form 
is to be completed. If there is an SAE and/or AESI associated with the pregnancy an SAE 
form must be completed in addition. 
 
5.3 
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS  
Not applicable. 
5.4 
ASSESSMENT OF BIOMARKER(S)  
Not applicable. 
5.5 
BIOBANKING  
Not applicable. 
5.6 
OTHER ASSESSMENTS  
Not applicable. 
5.7 
APPROPRIATENESS OF MEASUREMENTS  
Not applicable. 


 
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6. 
INVESTIGATIONAL PLAN  
In the event of force majeure or other disruptive circumstances (e.g. pandemic, war) the 
investigational plan as per this clinical trial protocol may not be feasible at a site. With the 
consent of the patient, sponsor and investigator may agree on alternative, back-up or rescue 
methodology which may include but will not be limited to virtual patient visits and 
assessments, home healthcare nurse visits, and direct-to-patient shipments of trial treatment. 
Such alternative measures may be described in a specific Crisis Management Manual as part 
of the initial submission package, and will also be mentioned in the patient information 
leaflet. The implementation of these measures will depend on patient’s consent, operational 
feasibility, local law and regulations. If alternative methodology is implemented, the 
deviations from the original plan will be precisely documented. 
6.1 
VISIT SCHEDULE  
The study will consist of three sequential periods, a Screening period of up to 8 weeks, a 
treatment period of 52 weeks and a follow-up period of 1 week. The maximum duration is 
expected to be 437 days.  
 
After giving his/her informed consent, the patient will be screened for inclusion (see Section 
3.3.2) and exclusion criteria (see Section 3.3.3) for the trial at Visit 1 and Visit 2 (refer to 
Flow Chart). 
 
Visit 2 can be performed once the results from central laboratory of Visit 1 and central HRCT 
review are obtained. 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 must be no longer than 8 weeks. The patient will be 
randomized at Visit 2 if all inclusion and none of the exclusion criteria are fulfilled. 
 
The results of laboratory parameters from Visit 2 will become available only after Visit 2. 
Therefore, laboratory results from Visit 2 cannot qualify as exclusion criteria; laboratory 
results from Visit 1 will be used instead. In case laboratory results of Visit 2 would 
retrospectively fulfil an exclusion criterion, the patient should not continue receiving trial 
medication unless continuation is justified in writing by the Investigator. 
 
A window of ±3 days for Visits 3 to 6, ±7 days for Visits 6a to 9 is allowed to accommodate 
scheduling problems. If a delay is observed for a particular visit, the original calendar 
schedule should be kept for subsequent visits (delays should not accumulate).  
 
If treatment is discontinued, an end of treatment visit (EOT) will be performed in all patients. 
 
If a patient misses an appointment, it will be rescheduled if possible. The relevance of 
measurements outside the permitted time windows will be assessed no later than at the Report 
Planning Meeting. 
 


 
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In exceptional cases, if standard visits at the trial sites are impossible because of COVID-19 
related safety risks, the investigator needs to further discuss with the sponsor and then makes 
a decision how to arrange the related visits. 
 
All home/remote visits need to be discussed with and approved by the sponsor`s trial team. 
Local regulatory and legal requirements still apply. 
 
For the details of the modifications refer to Section 6.2. 
 
All COVID-19 related deviations from the original schedule of visits and procedures will be 
documented and the implications considered for the analysis of the trial data. 
 
Except for visit 1, visit 2 and EOT visit, in the event of force majeure or other disrupting 
circumstances the other visits may have to be performed at the patient’s home after 
alignment with sponsor, remotely (by phone) or as a combination of home and remote visits. 
At these visits, the following assessments can be performed at the Patient’s home or 
remotely: 
• 
Concomitant therapy 
• 
Pregnancy testing (urine) if need 
• 
review results if some assessments can be done at local hospital except for FVC, 
please refer to Flow Chart for more details. 
• 
all AEs / SAEs / AESIs 
• 
IRT call after completing the above assessment, include the test results review from 
local laboratory 
• 
Dispense trial medication  
• 
compliance check 
 
Trial medication will not be collected at visits performed remotely. Instead, the medication 
should be collected when the patient next visits the site, or when a visit is performed at the 
patient’s home (see below). 
 
The following assessments can be performed at the patient’s home: 
• 
vital signs 
• 
physical examination if possible 
• 
resting 12-lead ECG (using a portable ECG machine) if possible 
• 
safety laboratory sampling and review of results if possible 
• 
collect trial medication 
 
If safety laboratory sampling via the central laboratory is not possible from the 
investigational site (and is instead performed at the patient’s home or local hospital), 
analyses can be performed at a local laboratory. The results of the safety laboratory tests 
must be transferred to the Investigator who must ensure a medical review and document any 
clinically relevant safety issues as AEs. For a list of “minimum required safety laboratory 
parameters” refer to Section 5.2.3 and Table 5.2.3: 1. 
 


 
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When scheduling such visits every effort should be made to ensure a continuous supply of 
trial medication for the patient, whilst also taking into account that the next kit(s) of trial 
medication may need to be shipped from the site to the patient’s home and, that medical pre-
requisites should be performed and confirmed prior to shipment of new supplies. 
 
The investigators should ensure as much as possible that FVC assessment can be finished on 
site for every visit. 
 
All deviations from the original schedule of assessments as defined in the Flow Chart will be 
documented and the implications considered for the analysis of the trial data. 
 
6.2 
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS  
6.2.1 
Screening period(s)  
Screening Period 
All trial procedures at selected visits will be done according to Flowchart and footnotes and 
the CTP. 
 
Informed consent (before or at the latest at Visit 1) 
 
• Informed consent will be obtained prior to patient participation in the trial, which includes 
any medication wash-out procedures or restrictions as well as HRCT transfer to central 
review. Upon obtaining informed consent, the patient will be instructed on the medication 
washout and other restrictions needed. 
• A preliminary check of in-/exclusion criteria is recommended at time of informed consent 
to avoid unnecessary wash-out procedures in non-eligible patients. 
• An HRCT not older than 12 months will be sent for central review, after the investigator’s 
evaluation, 
○ to confirm that the extent of features of fibrosis is >10% is in accordance with the 
inclusion criteria (see Section 3.3.2), 
○ to assess HRCT pattern for stratification. 
 
Provided the patient meets all other eligibility criteria, the HRCT can be performed for the 
purposes of participation in the trial if the patient does not have a HRCT within 12 months at 
the time of the scheduled Visit 2 or the HRCT available does not meet the image acquisition 
specifications of the study. 
• Site personnel will perform a screening registration in IRT to ensure in-time trial 
medication shipment. 
• Upon obtaining informed consent the patient will receive a trial identification card. 
 
Observations and procedures at Visit 1 
 
• If a separate informed consent Visit was not done, obtaining informed consent and the 
above mentioned procedures will be done prior to any further procedure at this visit. 


 
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• Demographics will be recorded. 
• Medical history including pre-existing conditions and smoking status will be recorded. 
• Concomitant therapy including previous medications will be recorded. 
• Any adverse events (since consent, if applicable) will be recorded. 
• Local urine pregnancy test (dipstick) will be done, if applicable (see Section 5.2.3). 
• Physical examination including vital signs will be performed. 
• A resting 12-lead electrocardiogram using site’s own equipment will be performed and 
evaluated by the Investigator (if possible prior to blood draw). 
• FVC measurement will be conducted with the spirometer. 
• Blood and urine samples (safety laboratory) will be collected and submitted to the central 
laboratory (for details refer to Section 5.2.3). Prior to blood draw a pre-assessment of all 
inclusion and exclusion criteria is highly recommended. 
• Site personnel will send/upload HRCT to central review (if not already done at time of 
informed consent). 
• For patients qualified to enter the screening period, Visit 2 will be scheduled. 
6.2.2 
Treatment period(s)  
At the beginning of each visit during treatment phase, Investigator and site personnel should 
ensure the well-being of the patient as well as prepare all requirements for conduct of the 
visits that are necessary. 
 
The order of the different trial procedures should follow the protocol and should be planned 
for taking into account the specific structure of the investigational site and following the 
mandatory needs outlined in the clinical trial protocol. 
 
Mandatory needs: the following has to be ensured during trial visits according to the study 
Flow Chart. 
• Patient reported L-PF Symptoms and Impact questionnaires have to be filled out always 
prior to any other procedures by the patient in a quiet area and in the following order. 
• Urine pregnancy test and any laboratory sample collection must be performed prior trial 
medication administration. 
• FVC measurement at all visits should be performed approximately at the same time of the 
day to reference time point at Visit 2. 
 
Baseline Visit 2 (randomization) 
The following prerequisites must be available for randomization: 
• Eligibility confirmation and HRCT pattern from central HRCT review. 
• Safety laboratory results including haemoglobin and creatinine from Visit 1. 
 
Procedures: 
• All patients will be asked to fill out the patient reported L-PF Symptoms and Impact 
questionnaires prior to any other visit procedure.  
• Site personnel will review questionnaires for completeness. 
• Physical examination including vital signs will be performed. 


 
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• Adverse events and concomitant therapy since last visit will be reviewed and recorded. 
• Medical history will be reviewed. 
• Repeated resting 12-lead electrocardiogram using site’s own equipment will be performed  
and evaluated if resting ECG was abnormal at Visit 1 (if possible prior to blood draw). 
• FVC measurement will be conducted with the spirometer. 
• All in/exclusion criteria will be assessed based on Visit 1 laboratory and Visit 2 measures. 
• HRCT will be performed in patients who agree to have follow-up HRCT done as part of 
the trial, unless a screening HRCT was done as part of the study to determine eligibility. 
• Safety blood and urine samples will be collected and submitted to the central laboratory. 
• Local urine dipstick pregnancy test (if applicable). 
• If a patient is eligible for the trial, randomization will be performed by using the IRT 
system. 
• Treatment will be dispensed. 
• Patient diary release. 
• The next visit will be scheduled and prepared. 
 
Visit 3, 4, 5, 6 and 8 (‘medium visits’) procedures 
Please note that not all medium visits are drug dispensation visits (please always refer to 
Flow Chart). However, compliance of patients regarding drug intake should always be 
reviewed (see also treatment compliance in Section 4.3). 
• Physical examination including vital signs will be performed. 
• Adverse events and concomitant therapy since last visit will be reviewed and recorded. 
• L-PF Symptoms and Impact questionnaire will be scheduled prior to any other procedure 
and in the above described order and will be reviewed for completeness by site personal 
at Visits 6 and 8. 
• Local dipstick pregnancy test (if applicable). 
• Safety blood and urine samples will be collected and submitted to the central laboratory. 
• Spirometry (FVC) in the allowed time window will be performed. 
• Acute ILD exacerbations will be recorded. 
• Treatment compliance will be reviewed by site personal at every visit (except at 
randomization visit). 
• Trial medication will be collected and/or dispensed according to Flow Chart. 
• Patient diary will be collected & reviewed and/or dispensed according to Flow Chart. 
 
Visit 7, Visit 9 and EOT (‘big visits’) procedures 
At Visit 7, Visit 9 and EOT (primary endpoint visit), the same procedures will be performed 
as done at baseline Visit 2. Exceptions are the typical randomization measures, e.g. eligibility 
review, medical history assessment and randomization which is only taken once. In addition, 
if EOT takes place before Visit 7, HRCT should not be repeated. For Visit 7, Visit 9 and EOT 
always refer to the Flow Chart. 
 
General rules 
• Treatment compliance will be reviewed by site personal. 
• Trial medication will be collected and/or dispensed according to Flow Chart. 


 
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• Patient diary will be collected & reviewed and/or dispensed according to Flow Chart. 
• Visit 9 and end of treatment visit (EOT) are identical visits. EOT is to be used in eCRF at 
any time a patient ends trial medication (scheduled or prematurely). 
• Patient who prematurely discontinued trial medication will attend all originally planned 
visits until the end of the trial. In case on-site visit is not available, at least vital status 
needs to be collected via telephone call. 
• IRT should always be notified on end of treatment (EOT). 
• Vital status will be collected for patients who prematurely discontinued trial medication 
and failed to attend future visits as planned, as well as for those who did not attend 
scheduled visits as planned at week 52 (scheduled Visit 9/EOT). 
• Adverse events and concomitant therapy since last visit will be reviewed and recorded. 
• Drug intake at Visit 7 should always be performed at site and after blood and urine 
sample collection and pregnancy test. 
• Spirometry (FVC) measurements should always be in the allowed time window and the 
described order (reference visit = Visit 2). 
• Resting 12-lead electrocardiogram using site’s own equipment will be performed and 
evaluated (if possible prior to blood draw). 
Intermediate ‘a-Visit’ procedures 
• Safety blood, pregnancy tests 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 Section 4.2.2.2). 
6.2.3 
Follow-up period and trial completion  
A Follow-up Visit has to be scheduled 7 days after End of Treatment Visit for all patients. 
This Follow-up Visit is the safety follow-up after treatment discontinuation. 
• Physical examination including vital signs. 
• Adverse events and concomitant therapy will be assessment since last visit. 
• Local dipstick pregnancy test (if applicable). 
• Spirometry (FVC) in the allowed time window will be performed. 
 
 
 
Patient’s participation will be concluded for all subjects who complete all treatment visits.  
 
Trial completion 
The trial completion eCRF page has to be filled-in when the patient has terminated the trial. 
The end of the trial for the individual patient is: 


 
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• For patients who complete all study visits, end of trial is follow-up (FU) visit (after the 
end of treatment visit (EOT)). 
• For patients who discontinue trial medication prematurely during the study period and 
complete an End of Treatment (EOT) visit and a Follow-up (FU) visit 1 week later, end 
of trial is visit at Week 52.  
• For patients who withdraw consent, end of trial is the date of consent withdrawn 
 
Patients who prematurely discontinued trial medication 
In case a patient has to permanently discontinue trial medication, for whatever reason, 
he/she will be encouraged to attend all future visits up to end of trial as originally planned 
(except for the laboratory ‘a-Visits’). 
 
1. During these visits, the patient will undergo all planned examinations according 
to Flow Chart, especially spirometry (FVC) and
 however he/she will not have to 
afety 
laboratory. 
2. These visits will be regarded as part of the trial despite the patient 
having discontinued trial medication. 
 
The need for coming to future visits in case of prematurely discontinuation of trial 
medication will be explained to patients prior to their participation in the trial. 
 
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 52 
weeks after his/her randomization and at the end of the trial for patients who have 
withdrawn consent. 
 
Patients will be asked to agree to be contacted by the site personnel, which could be 
by telephone calls, to allow collection of the vital status. 
 
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.  
 
Collection of vital status will be performed in accordance with national ethical and 
regulatory guidelines. 
 
6.2.4 
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 4.2.1. In both cases, the patient 
will have to come back to a visit where the following will be performed: 
• 
Physical examination including vital signs. 
• 
Adverse events and concomitant therapy will be assessment since last visit. 


 
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• 
Local dipstick pregnancy test (if applicable). 
• 
Safety blood and urine samples will be collected and submitted to the central laboratory. 
• 
Spirometry (FVC) in the allowed time window will be performed. 
• 
Trial medication will be collected and treatment compliance will be reviewed. 
• 
IRT registration for reduction or increase of the dose and trial medication dispensation. 
 


 
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7. 
STATISTICAL METHODS AND DETERMINATION OF 
SAMPLE SIZE  
This is a multi-centre, randomized, placebo-controlled, double-blind clinical trial to 
investigate the efficacy and safety of nintedanib at a dose of 150 mg bid, in Chinese patients 
with Chronic Fibrosing ILDs with a Progressive Phenotype over 52 weeks. Patients will be 
randomized to one of the treatment groups in a 2:1 ratio (nintedanib/placebo) with 60 patients 
in nintedanib group and 30 patients in placebo group. Randomization will be stratified by 
HRCT pattern: “UIP-like fibrotic pattern” vs. “other fibrotic patterns”. It is planned to 
randomize two thirds of patients (60 patients) with UIP-like HRCT fibrotic pattern and one 
thirds of patients (30 patients) with other fibrotic patterns. 
7.1 
NULL AND ALTERNATIVE HYPOTHESES  
No formal hypothesis is tested. 
7.2 
PLANNED ANALYSES  
All analyses on efficacy endpoints are exploratory including primary endpoint analysis since 
the objective of this study is to explore the nintedanib treatment effect in Chinese patients. 
Point estimate and 95% CI will be provided without statistical testing.  
The efficacy and safety analyses will be conducted on the treated set (TS), which consists of 
patients who are randomized to a treatment group and receive at least one dose of study 
medication. 
 
All analyses will be based on the treatment group (nintedanib 150 mg bid or placebo) as 
randomized by IRT. 
 
No subgroup analysis is planned. All analyses will be performed on the overall population. 
7.2.1 
General considerations  
The following analysis sets will be defined for statistical analyses: 
Randomized set (RS): This patient set includes all randomized patients, whether treated or 
not. 
Treated set (TS): This patient set includes all randomized patients who received at least one 
dose of trial medication.  
 
Data from patients who are screened but not randomized will be listed but not included in any 
summary statistics or inferential statistics. Important protocol deviations will be summaried 
and all decisions concerning IPDs will be made before un-blinding. 
Further Analysis Sets will be defined in the TSAP, if needed. 


 
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7.2.2 
Primary endpoint analyses  
The primary endpoint is the annual rate of decline in FVC [mL] over 52 weeks. The primary 
analysis will be based on all randomized patients who received at least one dose of trial 
medication, using all available data from baseline (excluded) up to Week 52, including visits 
done after premature treatment discontinuation, EOT visits and follow-up visits done before 
Week 52 (i.e. including all measurements after first drug intake and before or on day 373). 
The primary analysis will use a restricted maximum likelihood (REML)-based approach with 
a random slope and intercept model. The analysis includes fixed effects for treatment, HRCT 
pattern, and baseline FVC [mL], as well as the treatment-by-time and baseline-by-time 
interactions. Random effects will be included for the patient response for both time and 
intercept.  Baseline FVC in mL will be included as a covariate in the analysis model. Baseline 
FVC is defined as the FVC result recorded at Visit 2, unless missing in which case the 
screening result will be used. The HRCT pattern (“UIP-like fibrotic pattern” or “Other 
fibrotic patterns”) will also be used as a covariate for the analysis performed. The point 
estimate of treatment difference between the nintedanib and placebo group will be provided 
as well as 95%CI. No statistical testing will be performed. 
 
A sensitivity analysis including only on-treatment measurements of FVC (ml) will be 
presented. The same model as for the primary analysis will be used. This model implies that 
data are assumed to be missing at random (MAR) and it is implicitly supposed that patients 
who dropout would have behaved similarly to those who remained in the study. 


 
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7.2.3 
Secondary endpoint analyses  
Not applicable since there is no secondary endpoint. 
7.2.5 
Safety analyses  
Safety data will be analyzed descriptively. 
 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) coding dictionary. Standard BI summary tables and listings will be produced.  
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.  
 
Statistical analysis and reporting of adverse events will concentrate on treatment-emergent 
adverse events. To this end, all adverse events occurring between start of treatment and end 
of the residual effect period will be considered ‘treatment-emergent’.  The residual effect 
period is defined as the 7 days after the date of the last dose of trial medication. Adverse 


 
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events that start before first drug intake and deteriorate under treatment will also be 
considered ‘treatment-emergent’.  
 
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 MedDRA. 
 
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 highlighted in the 
listings. 
 
Vital signs, physical examinations, or other safety-relevant data observed at screening, 
baseline, during the course of the treatment and at the end-of-treatment evaluation will be 
assessed with regard to possible changes. 
 
7.2.6 
Other Analyses  
No other analysis is planned. 
 
7.2.7 
Interim Analyses  
No interim analysis is planned. 
 
7.3 
HANDLING OF MISSING DATA  
For the primary endpoint, missing data will not be imputed. The mixed effect model will 
handle missing data based on a likelihood method under the “missing at random assumption”. 
Even patients with only one post-baseline assessment can be included in the model and can 
therefore participate in variance estimation. The statistical model assumes that patients who 
prematurely discontinue study participation would have behaved similarly to those who 
remained in the study. 
 
For the categorical endpoints, missing data will be imputed using multiple imputation 
method. 
7.4 
RANDOMIZATION  
Patients will be randomized to one of the treatment groups in a 2:1 ratio (nintedanib/placebo) 
with 60 patients in nintedanib group and 30 patients in the placebo group. Randomization 
will be stratified by HRCT pattern: “UIP-like fibrotic pattern” vs. “other fibrotic patterns”. It 
is planned to randomize two thirds of patients (60 patients) with UIP-like HRCT fibrotic 
pattern and one thirds of patients (30 patients) with other fibrotic patterns. 
 


 
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The randomization system will include caps for the two HRCT pattern strata so that 
approximately two thirds of the patients are randomized to the “UIP-like fibrotic pattern” 
stratum and one third is randomized to the “Other fibrotic patterns” stratum. 
 
The Sponsor will arrange for the randomization and the packaging and labelling of trial 
medication. The randomization 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  
The pivotal phase 3 trial 1199-0247 has confirmed the superior effect of nintedanib over 
placebo in terms of annual rate of FVC [mL] decline. The objective of this trial is to explore 
the nintedanib treatment effect in Chinese patients. The main assumption of the study is the 
results from trial 1199-0247 as shown in below Table 7.5:1. 
 
Table 7.5: 1 Annual rate of decline in FVC [ml/year] over 52 Weeks  
 
 
Rate of FVC decline 
over  52weeks 
 
 
 
 
Comparision vs. 
placebo 
Treatment 
Number 
analysed 
Adjusted 
rate 
SE 
95% CI 
 
Adjusted 
difference 
SE 
95% CI 
 
p-value 
Placebo 
331 
-187.78 
14.84 
(-216.92,-158.64) 
 
 
 
 
 
 
 
Nintedanib 
150 mg b.i.d 
332 
-80.82 
15.07 
(-110.42,  -51.22) 
106.96 
21.15 
(65.42, 148.50) 
<0.0001 
 
The sample size evaluations are conducted for several scenarios to assess the probability of 
the point estimate of treatment effect size from this study (Chinese patients) is equal to or 
greater than a critical value. 
• Assuming treatment effect size (107ml/yr) is the same as observed in trial 1199-0247    
• Different critical values based on percentage of treatment effect from trial 1199-0247 
• Different sample sizes with 2:1 randomization ratio 
With the same treatment effect size (approx. 107mL/year) as observed in trial 1199-0247, a 
sample size of 90 (60 vs. 30) will have 81.7% probability to observe point estimate of 
treatment effect size in this study is greater than or equal to 53.5 mL/year (107*50%); and 
86.0% probability to observe point estimate of treatment effect size >=42.8 mL/year  
(107*40%); and 89.6% probability to oberserve point estimate of treatment effect size >=32.1 
mL/year (107*30%).  


 
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Table 7.5: 2   Sample size assessment based on the probability to observe point estimate of 
annual FVC decline rate is >= K% effect size of trial 1199-0247  
Treatment 
effect size 
(ml/year) 
Sample 
size 
(nintedanib 
vs. 
placebo) 
Prob. to observe at 
least 50% 
(107*50%) effect 
size of the global 
data in Chinese 
population  
Prob. to observe at 
least 40% 
(107*40%) effect 
size of the global 
data in Chinese 
population  
Prob. to observe at 
least 30% 
(107*30%) effect 
size of the global 
data in Chinese 
population  
107 
40 vs 20 
0.762 
0.804 
0.841 
50 vs 25  
0.793 
0.836 
0.870 
60 vs 30  
0.817 
0.860 
0.896 
 
 


 
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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) 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 each 
patient (or the patient’s legally accepted representative) 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 any additional patient-
information form retained by the investigator as part of the trial records. A signed copy of the 
informed consent and any additional patient information must be given to each patient or the 
patient’s legally accepted representative.” 
The investigator or delegate must give a full explanation to trial patients based on the patient 
information form. A language understandable to the patient should be chosen, technical terms 
and expressions avoided, if possible.  
 


 
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The patient must be given sufficient time to consider participation in the trial. The 
investigator or delegate obtains written consent of the patient’s own free will with the 
informed consent 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. 
If a trial collaborator has given a supplementary explanation, the trial collaborator also signs 
(or places a seal on) and dates the informed consent. 
 
Re-consenting may become necessary when new relevant information becomes available and 
should be conducted according to the sponsor’s instructions. 
 
The consent and re-consenting process should be properly documented in the source 
documentation. 
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 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  
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. 
 
For eCRF all data need to be derived from source documents, which need to be available 
onsite (this could be for example physician’s notes in patient files, printouts, patient diaries). 
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 


 
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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 
retrieve previous medical records. If this fails, a verbal history from the patient, documented 
in their medical records, would be acceptable. 
 
Copies of source files (HRCT) necessary for central eligibility reads will be provided to an 
imaging vendor., the investigator must ensure that all patient identifiers (e.g. patient’s name, 
initials, address, phone number, social security number) have properly been removed or 
redacted from any copy of the patients’ source documents. 
 
If the patient is not compliant with the protocol, any corrective action e.g. re-training must be 
documented in the patient file. 
For the CRF, data must be derived from source documents, 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 was 
informed) 
• Dates of patient’s visits, including dispensing of trial medication 
• Medical history (including trial indication and concomitant diseases, if applicable) 
• Medication history 
• Adverse events and outcome events (onset date (mandatory), and end date (if available)) 
• Serious adverse events (onset date (mandatory), and end date (if available)) 
• Concomitant therapy (start date, changes) 
• Originals or copies of laboratory results and other imaging or testing results, with proper 
documented medical evaluation (in validated electronic format, if available) 
• Completion of patient’s participation in the trial” (end date; in case of premature 
discontinuation document the reason for it). 
• Prior to allocation of a patient to a treatment into a clinical trial, there must be 
documented evidence in the source data (e.g. medical records) that the trial participant 
meets all inclusion criteria and does not meet any exclusion criteria. The absence of 
records (either medical records, verbal documented feedback of the patient or testing 
conducted specific for a protocol) to support inclusion/exclusion criteria does not make 
the patient eligible for the clinical trial. 
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. The accuracy of the data will 


 
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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. 
8.3.3 
Storage period of records  
Trial site(s): 
The trial site(s) must retain the source and essential documents (including ISF) according to 
contract or the local requirements valid at the time of the end of the trial (whatever is longer). 
Sponsor: 
The sponsor must retain the essential documents according to the sponsor’s SOPs. 
8.4 
EXPEDITED REPORTING OF ADVERSE EVENTS  
BI is responsible to fulfil their legal and regulatory reporting obligation in accordance with 
regulatory requirements.  
8.5 
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY  
Data protection and data security measures are implemented for the collection, storage and 
processing of patient data in accordance with the principles 7 and 12 of the WHO GCP 
handbook.  
Individual patient data obtained as a result of this trial is considered confidential and 
disclosure to third parties is prohibited with the following exceptions: 
Personalised treatment data may be given to the patient’s personal physician or to other 
appropriate medical personnel responsible for the patient’s welfare. Data generated at the site 
as a result of the trial need to be available for inspection on request by the participating 
physicians, the sponsor’s representatives, by the IRB / IEC and the regulatory authorities. 
8.5.1 
Collection, storage and future use of biological samples and corresponding data  
Not applicable due to no biological samples. 
8.6 
TRIAL MILESTONES  
The start of the trial is defined as the date when the first patient in the whole trial signs 
informed consent. 
The end of the trial is defined as the date of the last visit of the last patient in the whole trial 
(“Last Patient Completed”). The “Last Patient Last Treatment” (LPLT) date is defined as 
the date on which the last patient in the whole trial is administered the last dose of trial 
treatment (as scheduled per protocol or prematurely). Individual investigators will be notified 
of SUSARs occurring with the trial medication until 30 days after LPLT at their site. Early 
termination of the trial is defined as the premature termination of the trial due to any reason 
before the end of the trial as specified in this protocol. 
Temporary halt of the trial is defined as any unplanned interruption of the trial by the 
sponsor with the intention to resume it. 
Suspension of the trial is defined as an interruption of the trial based on a Health Authority 
request. 


 
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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 to incorporate and consider all data in the report. 
 
The sponsor will submit to the database a summary of the final trial results within one year 
from the end of a clinical trial as a whole. 
8.7 
ADMINISTRATIVE STRUCTURE OF THE TRIAL  
The trial is sponsored by Boehringer Ingelheim (BI).  
A Coordinating Investigator is responsible to coordinate investigators at the different sites 
participating in this trial. 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 web portal Clinergize to access documents 
provided by the sponsor. 
 
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. 
 
Data Management and Statistical Evaluation will be done by BI according to BI SOPs. 
 
Tasks and functions assigned in order to organise, manage, and evaluate the trial are defined 
according to BI SOPs. A list of responsible persons and relevant local information can be 
found in the ISF. 
A central laboratory service, a central images service and an IRT vendor will be used in this 
trial. Details will be provided in the IRT Manual and Central Laboratory Manual, available in 
the ISF. 
 


 
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9. 
REFERENCES  
9.1 
PUBLISHED REFERENCES  
P05-12782 
Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R et al. 
Standardisation of spirometry. Eur Respir J 2005. 26(2):319-338. 
P08-08684 
Hilberg F,Roth GJ, Krssak M,et al. BIBF 1120: Triple Angiokinase Inhibitor 
with Sustained Receptor Blockade and Good Antitumor Efficacy. Cancer 
Research 68(12) 4774-4782 (2008). 
P10-13367 
Overview of the FDA background materials for New Drug Application 
(NDA) 22-535, Esbriet (pirfenidone) for the treatment of patients with 
idiopathic pulmonary fibrosis (IPF) to reduce the decline in lung function. 
http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMa 
terials/Drugs/Pulmonary-AllergyDrugsAdvisoryCommittee/UCM203081.pdf 
(access date: 19 November 2010) (2010). 
P11-11216 
Luca Richeldi, M.D., Ph.D., Ulrich Costabel, M.D., Moises Selman, M.D et 
al. Efficacy of a Tyrosine Kinase Inhibitor in Idiopathic Pulmonary Fibrosis. 
N Engl J Med. 2011; 365:1079-1087  
P11-13635  Bois RM du, Weycker D, Albera C, Bradford WZ, Costabel U, Kartashov A, 
Lancaster L, Noble PW, Raghu G, Sahn SA, Szwarcberg J, Thomeer M, 
Valeyre D, King TE. Ascertainment of individual risk of mortality for 
patients with idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 
184(4), 459 - 466 (2011) 
P12-10347  Bois RM du, Nathan SD, Richeldi L, Schwarz MI, Noble PW. Idiopathic 
pulmonary fibrosis: lung function is a clinically meaningful endpoint for 
phase 3 trials. Am J Respir Crit Care Med 186 (8), 712 - 715 (2012) 
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 349, 209 - 220 
(2014). 
P14-06844 
Richeldi L, Cottin V, Flaherty KR, Kolb M, Inoue Y, Raghu G, Taniguchi H, 
Hansell DM, Nicholson AG, Maulf F le, Stowasser S, Collard HR. Design of 
the Inpulsis trials: two phase 3 trials of nintedanib in patients with idiopathic 
pulmonary fibrosis. Respir Med 108 (7), 1023 - 1030 (2014) 
P14-07514 
Luca Richeldi, M.D., Ph.D., Roland M. du Bois, M.D., Ganesh Raghu, M.D 
et al. Efficacy and Safety of Nintedanib in Idiopathic Pulmonary Fibrosis. N 
Engl J Med. 2014; 370:2071-2082 
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) 15, 157 (2014). 


 
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P15-02392 
Wollin L, Wex E, Pautsch A, Schnapp G, Hostettler KE, Stowasser S, Kolb 
M. Mode of action of nintedanib in the treatment of idiopathic pulmonary 
fibrosis. Eur Respir J 45 (5), 1434 - 1445 (2015). 
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 75 (5), 883 - 890 (2016). 
P16-03854 
Richeldi et al. Idiopathic pulmonary fibrosis in BRIC countries: the cases of 
Brazil, Russia, India,and China. BMC Medicine 13,237 - 249 (2015). 
P16-06899 
Collard HR, Ryerson CJ, Corte TJ, Jenkins G, Kondoh Y, Lederer DJ, et al. 
Acute exacerbation of idiopathic pulmonary fibrosis: an international 
working group report. Am J Respir Crit Care Med, (2016). 
P17-10582 
Flaherty KR, Brown KK, Wells AU et al. Design of the Chronic Fibrosing 
ILDs with a Progressive Phenotype trial: a double-blind, randomized, 
placebo-controlled phase III trial of nintedanib in patients with progressive 
fibrosing interstitial lung disease. BMJ Open Resp Res. 2017; 4:e000212. 
P18-00197 
Hilberg F, Tontsch-Grunt U, Baum A, et al. Triple Angiokinase Inhibitor 
Nintedanib Directly Inhibits Tumor Cell Growth and Induces Tumor 
Shrinkage via Blocking Oncogenic Receptor Tyrosine Kinases. Journal of 
Pharmocology and Experimental Therapeuties 364(2), 494-503. 
P18-05024 
Wells AU. Approach to diagnosis of diffuse lung disease. Clinical respiratory 
medicine 2nd Ed. Albert RK, Spiro SG & Jett JR (Eds.). Mosby [Elsevier 
Science] 2004. 
P19-08802 
Flaherty K, et al, the INBUILD Trial Investigators. Nintedanib in 
Progressive Fibrosing Interstitial Lung Diseases. N Engl J Med 2019; 
381:1718-27. 
P19-03962 
Rivera-Ortega P and Molina-Molina M. Interstitial Lung Diseases in 
Developing Countries. Annals of Global Health 85(1), 4,1-14 (2019). 
R06-4126 
Latsi PI, Bois RM du, Nicholson AG, Colby TV, Bisirtzoglou D, 
Nikolakopoulou A, Veeraraghavan S, Hansell DM, Wells AU. Fibrotic 
idiopathic interstitial pneumonia: the prognostic value of longitudinal 
functional trends. Am J Respir Crit Care Med 168, 531 - 537 (2003). 
R06-4127 
Collard HR, King TE, Bartelson BB, Vourlekis JS, Schwarz MI, Brown KK. 
Changes in clinical and physiologic variables predict survival in idiopathic 
pulmonary fibrosis. Am J Respir Crit Care Med 168, 538 - 542 (2003). 
R10-6539 
Flaherty KR, Mumford JA, Murray S, Kazerooni EA, Gross BH, Colby TV, 
Travis WD, Flint A, Toews GB, Lynch JP, Martinez FJ. Prognostic 
implications of physiologic and radiographic changes in idiopathic interstitial 
pneumonia. Am J Respir Crit Care Med 168, 543 - 548 (2003). 
R14-1149 
Schmidt SL, Nambiar AM, Tayob N, Sundaram B, Han MK, Gross BH, 
Kazerooni EA, Chughtai AR, Lagstein A, Myers JL, Murray S, Toews GB, 


 
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Martinez FJ, Flaherty KR. Pulmonary function measures predict mortality 
differently in IPF versus combined pulmonary fibrosis and emphysema. Eur 
Respir J 38 (1), 176 - 183 (2011). 
R14-1150 
Schmidt SL, Tayob N, Han MK, Zappala C, Kervitsky D, Murray S, Wells 
AU, Brown KK, Martinez FJ, Flaherty KR. Predicting pulmonary fibrosis 
disease course from past trends in pulmonary function. Chest, (2014). 
R14-5407 
Tashkin DP, Elashoff R, Clements PJ et al. Scleroderma Lung Study 
Research Group. Cyclophosphamide versus placebo in scleroderma lung 
disease. N Engl J Med. 2006; 354:2655-66. 
R15-0845 
Quanjer PH, Stanojevic S, Cole TJ, Baur X, Hall GL, Culver BH, Enright 
PL, Hankinson JL, Ip MSM, Zheng J, Janet Stocks on behalf of the ERS 
Global Lung Function Initiative. Multi-ethnic reference values for spirometry 
for the 3 - 95 year age range: the global lung function 2012 equations: report 
of the Global Lung Function Initiative (GLI), ERS task force to establish 
improve lung function reference values. Eur Respir J 
2012; 40(6); 1324-1343. 
R15-2073 
Kubota M, Kobayashi H, Quanjer PH, Omori H, Tatsumi K, Kanazaw M, 
Clinical Pulmonary Functions Committee of the Japanese Respiratory 
Society. Reference values for spirometry, including vital capacity, in 
Japanese adults calculated with the LMS method and compared with 
previous values. Respir Invest 2014; 52(4); 242-250. 
R16-0281 
Shmidili 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, 1023-1032. 
R16-0722 
Schwartz MI, King TE, Interstitial lung disease. 5th ed. Shelton: People’s 
Medical Publishing House (2011). 
R16-4086 
Huang H, Peng X, Zhong C. Idiopathic pulmonary fibrosis: the current status 
of its epidemiology, diagnosis, and treatment in China. Intractable Rare Dis 
Res 2 (3), 88 - 93 (2013). 
R18-0122 
Morisset J, Johannson KA, Vittinghoff E et al. Use of mycophenolate mofetil 
or azathioprine for the management of chronic hypersensitivity pneumonitis. 
Chest. 2017; 151:619-625. 
R18-1815 
Adegunsoye A, Oldham JM, Fernández Pérez ER et al. Outcomes of 
immunosuppressive therapy in chronic hypersensitivity pneumonitis. ERJ 
Open Res. 2017; 3:00016-2017. 
R18-2794 
Raghu G, Remy-Jardin M, Myers JL, et al. Diagnosis of Idiopathic 
Pulmonary Fibrosis An Official ATS/ERS/JRS/ALAT Clinical Practice 
Guideline. American Journal of Respiratory and Critical Care Medicine 198 
(5), e44-e68 (2018). 


 
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R19-1104 
Olson A, Hartmann N, Schlenker-Herceg R, Wallace L. Prevalence of 
progressive fibrosing interstitial lung disease. ERS 2018. Eur Respir J. 2018; 
52(Suppl 62): PA3030 (Abstract). 
R19-1170 
Ban C, Yan W, Xie B, Zhu M, Liu Y, Zhang S, et al. Spectrum of interstitial 
lung disease in China from 2000 to 2012. Eur Respir J 52, 1701554 (2018). 
R19-2980 
Shi X, Liu H, Zhan S, Wang Z, Wang L, Dong C, et al. Rare diseases in 
China: analysis of 2014 - 2015 hospitalization summary reports for 281 rare 
diseases from 96 tertiary hospitals. Orphanet J Rare Dis 14, 160 (2019). 
R96-0690 
Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum 
creatinine. Nephron 1976. 16(1):31-41. 
 
9.2 
UNPUBLISHED REFERENCES  
c01783972 
Most recent version: Investigator`s Brochure. Nintedanib (BIBF 1120). 
c02153150-02 
 
Clinical overview. Treatment of Idiopathic Pulmonary Fibrosis (IPF) and 
To Slow Disease Progression. 7 Apr 2014. 
c22686034-01 
Clinical Trial Report – SENSCIS®: A double-blind, randomised, 
placebo-controlled trial evaluating efficacy and safety of oral nintedanib 
treatment for at least 52 weeks in patients with ‘Systemic Sclerosis-
associated Interstitial Lung Disease’ (SSc-ILD). 18 February 2019 
c26471552-02 
Clinical Trial Report – INBUILD®: A double-blind, randomized, 
placebo-controlled trial evaluating the efficacy and safety of nintedanib 
over 52 weeks in patients with Progressive Fibrosing Interstitial Lung 
Disease (Chronic Fibrosing ILDs with a Progressive Phenotype). 15 
August 2019 
n00239669 
. Evaluation of Nintedanib in preclinical models of systemic 
aclerosis. 
n00247887 
Evaluation of the therapeutic 
efficacy of nintedanib in a model of rheumatoid arthritis-associated 
interstitial lung disease. 
U02-1109 
. Analysis of potency and selectivity of the vascular 
endothelial growth factor receptor-2 inhibitor BIBF 1120. 19 Feb 2002. 
U02-1310 
. Analysis of Specificity of The Vascular Endothelial Growth 
Factor Receptor-2 Inhibitor BIBF 1120 On Selected Kinases. 29 Apr 
2002. 
U06-1451 
. Dose-dependent effects of BIBF 1120 ES on bleomycin-induced 
lung fibrosis in rats. 6 Jun 2006. 
U06-1479 
. Effect of 50 mg/kg BIBF 1120 ES on bleomycin-induced lung 
fibrosis in rats using a delayed treatment model. 19 Jun 2006. 


 
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U12-2437-01 
. Effect of nintedanib (BIBF 1120) on bleomycin induced lung 
inflammation and fibrosis. 19 Oct 2012. 
U12-2066-01 
. Effect of nintedanib (BIBF 1120) on silica induced lung 
inflammation and fibrosis. 31 Jul 2012. 
 


 
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10. 
APPENDICES  
10.1 
FVC LUNG FUNCTION CRITERIA  
FVC 
Predicted normal values will be calculated according to Global Lung Initiative (GLI) [R15- 
0845, R15-2073] at the site level, using the Spirosphere®. FVC percent predicted is a key 
inclusion criterion and a further endpoint using the following demographic information: race, 
age, gender and height. 
10.2 
CREATININE CLEARANCE  
Creatinine clearance calculation is done according to Cockroft and Gault [R96-0690]. 
• 
Creatinine clearance = (140 - age) x (Weight in kg) x (0.85 if female) / (72 x serum 
creatinine in mg/dL) 
10.3 
EQUIVALENT DOSES OF CORTICOSTEROIDS  
Table 10.3: 1 Equivalent Doses of Corticosteroids  
Drug 
Equivalent dose (mg) 
Conversion factor 
Prednisone 
5 
x 1 
Prednisolone 
5 
x 1 
Triamcinolone 
4 
x 1.25 
6-Methylprednisolone 
4 
x 1.25 
Dexamethasone 
1 
x 5 
Betamethasone 
0.75 
x 6.7 
16-Methylprednisolone 
6 
x 0.8 
Fluocortolon 
5 
x 1 
Cloprednol 
3,75-5 
x 1.0-1.5 
Deflazacort 
6 
x 0.8 
Cortisol (hydrocortisone) 
20 
x 0.25 
Cortisone 
25 
x 0.20 
 


 
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10.5 
PHARMACOKINETIC METHODS AND ANALYSES  
Not applicable. 
10.6 
TIME SCHEDULE FOR PHARMACOKINETIC (PK) BLOOD 
SAMPLING  
Not applicable. 
10.7 
TRIAL BIOMARKER PLAN  
Not applicable. 


 
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11. 
DESCRIPTION OF GLOBAL AMENDMENT(S)  
11.1 
GLOBAL AMENDMENT 1  
Date of amendment 
 
22 Feb 2021 
EudraCT number 
EU number 
 
Not applicable 
BI Trial number 
 
1199-0434 
BI Investigational 
Medicinal Product(s) 
 
Nintedanib 
Title of protocol 
 
A double blind, randomized, placebo-controlled trial 
evaluating the efficacy and safety of nintedanib over 52 
weeks in Chinese patients with Chronic Fibrosing ILDs 
with a Progressive Phenotype 
Global Amendment due to urgent safety reasons 
 
Global Amendment 
X 
 
Section to be changed 
 
Home page and 2nd page 
Description of change 
 
Deleted Principal Investigator < for single-centre trial 
or > and < for multi-centre trial if applicable >  
Rationale for change 
 
To delete the excess. 
Section to be changed 
 
Trial objective(s) of Clinical trial protocol synopsis and 
section 2.1.1 Main objectives 
Description of change 
 
Deleted and safety 
Rationale for change 
 
Safety is not a main objective and it is only a further 
objective. 
Section to be changed 
 
Mitigation strategy of Table 1.4.2:1 Overview over trial 
related risks 
Description of change 
 
Added and early management, guideline to liver 
enzyme elevations 
Rationale for change 
 
The guideline on management of liver enzymes is also a 
risk mitigation strategy for DILI. 
Section to be changed 
 
4.2.2.4 Contraception requirements 
Description of change 
 
Corrected a mistake from “or 28 days before treatment 
initiation” to “and 28 days before treatment initiation”. 
Rationale for change 
 
Typo correction. 
11.2 
GLOBAL AMENDMENT 2  
Date of amendment 
 
28 Jun 2021 
EudraCT number 
EU number 
 
Not applicable 
BI Trial number 
 
1199-0434 
BI Investigational 
Medicinal Product(s) 
 
Nintedanib 


 
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Title of protocol 
 
A double blind, randomized, placebo-controlled trial 
evaluating the efficacy and safety of nintedanib over 52 
weeks in Chinese patients with Chronic Fibrosing ILDs 
with a Progressive Phenotype 
Global Amendment due to urgent safety 
reasons 
 
Global Amendment 
X 
 
Section to be changed 
 
The whole protocol  
Description of change 
 
Changed from lab to laboratory 
Rationale for change 
 
To keep wording consistency throughout the protocol 
Section to be changed 
 
Clinical Trial Protocol Synopsis: trial design 
Description of change 
 
Added “approximately” before “two thirds of patients 
with UIP-like HRCT fibrotic patterns, one third of 
patients with other fibrotic patterns.” 
 
Deleted “s” from “one third of patients with other fibrotic 
patterns”. 
Rationale for change 
 
To make the text more precise. 
 
Typo correction. 
Section to be changed 
 
Flow Chart 
Description of change 
 
Deleted of treatment and 0 from Flow Chart, kept weeks 
and added D1. 
Rationale for change 
 
According to BI standard process, Day 1 is usually the 
day of the first randomised treatment administration. Day 
0 should not be used to describe the trial schedule.  
Section to be changed 
 
Flow Chart, section 3.1 Overall trial design,  section 6.2.1 
Screening period(s) and section 6.2.4 Dose reduction visit 
/ dose increase visit 
Description of change 
 
Deleted call/ from IRT call/notification in the Flow 
Chart. 
 
Changed from Interactive phone/web Response System 
(IRT) to Interactive web Response System (IRT) in 
section 3.1. 
 
Changed from Site personnel will perform a screening 
call in IRT to ensure in-time trial medication shipment 
to Site personnel will perform a screening registration 
in IRT to ensure in-time trial medication shipment in 
section 6.2.1. 
 
Changed from IRT call for reduction or increase of the 
dose and trial medication dispensation to IRT 


 
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registration for reduction or increase of the dose and 
trial medication dispensation in section 6.2.4. 
Rationale for change 
 
The IRT is not using phone anymore. 
Section to be changed 
 
Flow Chart, section 6.2.2 Treatment period(s) and section 
4.1.4 Drug assignment and administration of doses for 
each patient 
Description of change 
 
Added Release patient diary and Review and collect 
patient diary into the Flow Chart. 
 
Added Patient diary release and Patient diary will be 
collected & reviewed and/or dispensed according to 
Flow Chart into section 6.2.2. 
 
Added A patient diary will be used to record the daily 
intake of the trial medication into section 4.1.4. 
Rationale for change 
 
Patient diary will be dispensed to collect the use of drug 
when the patient at home.  
Section to be changed 
 
Section 1.2 Drug profile and  Section 9.2 unpublished 
references 
 
Description of change 
 
Removed “-14” from index [c01783972-14] of section 
1.2 and section 9.2 and changed to Most recent version: 
Investigator`s Brochure. Nintedanib (BIBF 1120) in 
section 9.2. 
Rationale for change 
 
As the most recent IB version has extension 18. 
Section to be changed 
 
Section 1.3 
Description of change 
 
Added “l” into “conditionally” 
Rationale for change 
 
Typo correction 
Section to be changed 
 
Table 1.4.2:1 Overview over trial related risks 
Description of change 
 
Added the following guidance related to COVID-19 
vaccination: 
Rationale for change 
 
Updated based on the current situation of COVID-19 
Section to be changed 
 
Section 3.2 Discussion of trial design, including the 
choice of control group(s)   
Description of change 
 
Deleted 12 months treatment duration for primary 
assessment of benefit-risk of nintedanib in Chronic 
Fibrosing ILDs with a Progressive Phenotype. 
Rationale for change 
 
To delete the excess. 
Section to be changed 
 
Section 3.3.3 Exclusion criteria: article 26 


 
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Description of change 
 
Added footnote ** for article 26: Testing for SARS-CoV-
2 is not the part of this trial. If required this needs to be 
done per local requirements or investigator’s assessment. 
Rationale for change 
 
To clarify SARS-CoV-2 testing clearly 
Section to be changed 
 
Section 3.3.3 Exclusion criteria: footnote * 
Description of change 
 
Deleted include hysterectomy, bilateral salpingectomy 
and bilateral oophorectomy 
Rationale for change 
 
To delete the excess. 
Section to be changed 
 
Table 4.1.4: 1 Dosage and treatment schedule 
Description of change 
 
Added “n” into “morning” 
Rationale for change 
 
Typo correction. 
Section to be changed 
 
Corrected a mistake for Table 4.2.1.1: 1 Management of 
diarrhoea (considered related to trial medication) 
Description of change 
 
Added Diarrhoea with increase of ≥7 stools per day over 
baseline1; stool incontinence,  
or life threatening consequences. 
Rationale for change 
 
A mistake correction. 
Section to be changed 
 
Table 4.2.1.2: 1 Recommendations for managing liver 
enzyme elevations 
Description of change 
 
Added Close observation4 
Rationale for change 
 
Close observation is still required for patient safety. 
Section to be changed 
 
Section 5.2.4 Electrocardiogram 
Description of change 
 
Deleted 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. 
Rationale for change 
 
To delete the excess. 
Section to be changed 
 
5.2.6.1.4 Adverse events of special interest 
Description of change 
 
Added Adverse events relating to gastrointestinal 
perforation and hepatic injury will be considered AESIs. 
Rationale for change 
 
According to nintedanib previous trials, gastrointestinal 
perforation is also thought as AESIs. 
Section to be changed 
 
5.2.6.2.2 AE reporting to the sponsor and timelines 
Description of change 
 
To delete “via fax” 
Rationale for change 
 
The AE reporting method is not limited to fax 
Section to be changed 
 
Section 6.1 Visit schedule 
Description of change 
 
Changed from The maximum duration is expected to be 
434 days to The maximum duration is expected to be 
437 days. 
Rationale for change 
 
A mistake correction. 
Section to be changed 
 
Section 6.1 Visit schedule 
Description of change 
 
Deleted of the participating country 
Rationale for change 
 
The trial is only conducted in China. 
Section to be changed 
 
Section 6.2.1 Screening period(s) and the footnotes of 
Flow Chart  


 
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Description of change 
 
Deleted Patients will be asked to give informed consent 
about COVID-19 from section 6.2.1 and added Patients 
will be asked to give informed consent about COVID-19 
if necessary into the footnotes of Flow Chart. 
Rationale for change 
 
The outbreak is well under control in China. The site can 
assess whether or not ICF about COVID-19 needs to be 
signed based on the actual situation, so this ICF signature 
is not a general rule at Visit 1. 
Section to be changed 
 
Description of change 
 
Rationale for change 
 
 
11.3 
GLOBAL AMENDMENT 3  
Date of amendment 
 
31 May 2022 
EudraCT number 
EU number 
 
Not applicable 
BI Trial number 
 
1199-0434 
BI Investigational 
Medicinal Product(s) 
 
Nintedanib 
Title of protocol 
 
A double blind, randomized, placebo-controlled trial 
evaluating the efficacy and safety of nintedanib over 52 
weeks in Chinese patients with Chronic Fibrosing ILDs 
with a Progressive Phenotype 
Global Amendment due to urgent safety 
reasons 
 
Global Amendment 
X 
 
Section to be changed 
 
3.3.4 imaging criteria 
Description of change 
 
Added section 3.3.4 imaging criteria as below: 
Patients with original physician diagnosis of different 
fibrosing ILDs, e.g. CTD-ILD, chronic fibrosing HP, 
iNSIP, unclassifiable IIP and environmental/ 
occupational fibrosing lung disease will be included if 
they meet the protocol criteria for PF-ILD. While the 
clinical ILD diagnosis will not be verified, central review 
of the screening HRCT images will ensure that relevant 


 
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lung fibrosis is present and the HRCT pattern is not 
indicative of other causes of progression. 
 
At screening the recent (not older than 12 months at 
screening) HRCT image of the patient will be evaluated; 
previous HRCT images will not be collected or reviewed. 
Hence inclusion based on increasing extent of fibrotic 
changes on chest imaging within 24 months will reflect 
the investigator’s judgement. 
 
Eligible patients will have fibrosing lung disease on 
HRCT, defined as reticular abnormality with traction 
bronchiectasis with or without honeycombing with 
disease extent of >10%. 
 
The following co-existing features will be accepted: 
• 
Ground glass opacity 
• 
Upper lung or peribronchovascular predominance 
• 
Mosaic attenuation 
• 
Air trapping 
• 
Centrilobular nodules 
 
The following co-existing features will not be allowed: 
• 
Widespread consolidation 
• 
Progressive massive fibrosis 
 
In addition, determination of the HRCT pattern will also 
be done by central review and will be used for 
randomization stratification. The study will be enriched 
for patients meeting either criteria A, B and C, criteria A 
and C, or criteria B and C as described below. These 
patients will be referred to as “patients with HRCT with 
UIP-like fibrotic pattern only”. 
Patients with PF-ILD who do not meet these criteria will 
be referred to as “patients with other HRCT fibrotic 
patterns”. 
A=Definite honeycomb lung destruction with basal 
and peripheral predominance 
B=Presence of reticular abnormality AND traction 
bronchiectasis consistent with fibrosis 
with basal and peripheral predominance 
C=Atypical features are ABSENT, specifically: 
nodules and consolidation. Ground glass opacity, if 
present, is less extensive than reticular opacity 
pattern 
 


 
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Specifications for the HRCT acquisition will be provided 
in the ISF. Screening HRCT can be performed as part of 
the study in case the available HRCT does not meet the 
required image acquisition specifications. 
 
Rationale for change 
 
HRCT imaging requirements are clearly provided for the 
investigator as a reference. 
Section to be changed 
 
5.1.1 FVC 
Description of change 
 
Added “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.” 
Rationale for change 
 
To make the text more precise. 
Section to be changed 
 
5.2.3 Safety laboratory parameters 
Description of change 
 
Added the below content: 
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; -, +, ++, +++) 
Local Urine dipstick pregnancy test in all women of 
childbearing potential. If urine test is not acceptable to 
local authorities, a blood test must be done at a local 
laboratory. 
 
The samples and pregnancy tests 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. 
 
Creatinine clearance will be calculated based on serum 
creatinine according to Cockcroft and 
Gault (R96-0690, Appendix 10.2). 
 


 
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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 4.2.1.2 for monitoring elevations and Section 
3.3.5 for withdrawal criteria. 
 
Laboratory analysis will be done using central laboratory 
services. Venous whole blood will be collected in 
appropriate syringes provided by the Sponsor through the 
assigned central laboratory. 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. 
 
Rationale for change 
 
To refine and supplement relevant information 
Section to be changed 
 
6.1 VISIT SCHEDULE 
Description of change 
 
Added the below description: 
Except for visit 1, visit 2 and EOT visit, in the event of 
force majeure or other disrupting circumstances the 
other visits may have to be performed at the patient’s 
home after alignment with sponsor, remotely (by 
phone) or as a combination of home and remote visits. 
At these visits, the following assessments can be 
performed at the 
Patient’s home or remotely: 
• 
Concomitant therapy 
• 
Pregnancy testing (urine) if need 
• 
review results if some assessments can be done at 
local hospital except for FVC, please refer to Flow 
Chart for more details. 
• 
all AEs / SAEs / AESIs 
• 
IRT call after completing the above assessment, 
include the test results review from local laboratory 
• 
Dispense trial medication  
• 
compliance check 
 
Trial medication will not be collected at visits 
performed remotely. Instead, the medication should be 
collected when the patient next visits the site, or when a 
visit is performed at the patient’s home (see below). 


 
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The following assessments can be performed at the 
patient’s home: 
• 
vital signs 
• 
physical examination if possible 
• 
resting 12-lead ECG (using a portable ECG 
machine) if possible 
• 
safety laboratory sampling and review of results if 
possible 
• 
collect trial medication 
 
If safety laboratory sampling via the central laboratory 
is not possible from the investigational site (and is 
instead performed at the patient’s home or local 
hospital), analyses can be performed at a local 
laboratory. The results of the safety laboratory tests 
must be transferred to the Investigator who must 
ensure a medical review and document any clinically 
relevant safety issues as AEs. For a list of “minimum 
required safety laboratory parameters” refer to Section 
5.2.3 and Table 5.2.3: 1. 
 
When scheduling such visits every effort should be 
made to ensure a continuous supply of trial medication 
for the patient, whilst also taking into account that the 
next kit(s) of trial medication may need to be shipped 
from the site to the patient’s home and, that medical 
pre-requisites should be performed and confirmed prior 
to shipment of new supplies. 
 
The investigators should ensure as much as possible 
that FVC assessment can be finished on site for every 
visit. 
 
All deviations from the original schedule of 
assessments as defined in the Flow Chart will be 
documented and the implications considered for the 
analysis of the trial data. 
 
Rationale for change 
 
Updated based on the current situation of COVID-19 
Section to be changed 
 
9.1 PUBLISHED REFERENCES 
Description of change 
 
Added “R96-0690 
Cockcroft DW, Gault MH. 
Prediction of creatinine clearance from serum creatinine. 
Nephron 1976. 16(1):31-41.” 
 
Rationale for change 
 
Added a published reference. 
Section to be changed 
 
10.2 CREATININE CLEARANCE 


 
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Description of change 
 
Deleted Table 10.2:1 Equivalent Doses of Corticosteroids 
and added: 
Creatinine clearance calculation is done according to 
Cockroft and Gault [R96-0690]. 
• 
Creatinine clearance = (140 - age) x (Weight in 
kg) x (0.85 if female) / (72 x serum creatinine in mg/dL) 
Rationale for change 
 
An error was corrected in order to be consistent with article 
3 of the Exclusion Criteria 
11.4 
GLOBAL AMENDMENT 4  
Date of amendment 
 
18 Sep 2023 
EudraCT number 
EU number 
 
Not applicable 
BI Trial number 
 
1199-0434 
BI Investigational 
Medicinal Product(s) 
 
Nintedanib 
Title of protocol 
 
A double blind, randomized, placebo-controlled trial 
evaluating the efficacy and safety of nintedanib over 52 
weeks in Chinese patients with Chronic Fibrosing ILDs 
with a Progressive Phenotype 
Global Amendment due to urgent safety 
reasons 
 
Global Amendment 
X 
 
Section to be changed 
 
Title Page: Clinical Trial Leader 
Description of change 
 
• 
The name of Clinical Trial Leader “
” was 
changed into “
 
• 
The address of Clinical Trial Lead was changed to 
• 
The phone number of Clinical Trial Leader was 
changed to 
” 
Rationale for change 
 
CTL handover 
Section to be changed 
 
Flow Chart Footnote 10 
Description of change 
 
Updated the text as following (See text in bold): 
 
• 
Footnote10: Conclusion of trial participation is 
only applicable for subjects who withdraw consent 
for all subjects who complete all treatment visits. 
Rationale for change 
 
Conclusion of participation needs to be checked at the 
follow up visit for all subjects who complete all treatment 
visits.  
These revisions have been clarified in the Protocol 
Administrative Letter (date: on 28 June 2023). 


 
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Section to be changed 
 
Section 4.1.4 Drug assignment and administration of 
doses for each patient 
Description of change 
 
Updated the text as following (See text in bold): 
 
• 
The patients should take the trial medication with 
food, swallow whole with water, and should not be 
chewed or crushed because of a bitter taste, and 
should observe a dose interval of 12 hours as far as 
possible. Effort should be made to ensure that drug 
administration occurs at the same time every day 
+/- 30 min (between 06:00 and 11:00 in the 
morning, and between 18:00 and 23:00 in the 
evening). A forgotten dose should be skipped if 
the time window to the next dose is less than 8 
hours. The next dose should be taken as 
scheduled. The recommended maximum daily 
dose of 300 mg should not be exceeded. 
 
• 
The dose may be reduced to 100 mg bid due to AE 
after the investigator assessment. The investigator 
can dispense new medication kits with 100mg to 
the patient via IRT system. 
 
• 
If a dose is missed, administration should resume at 
the next scheduled time point at the recommended 
dose. If a dose is missed the patient should not take 
an additional dose. The recommended maximum 
daily dose of 300 mg should not be exceeded.  
Rationale for change 
 
Texts were added to avoid potential side effects of 
accumulating exposure to the drug if the interval between 
morning dose and evening dose becomes too short. 
Clarification about the actions if the time window to the 
next dose is less than 8 hours. 
These revisions have been clarified in the Protocol 
Administrative Letter (date: on 28 July 2022). 
Section to be changed 
 
Section 5.2.3 Safety laboratory parameters 
Description of change 
 
Updated the text as following (See text in bold): 
 
• 
eGFR will be analysed and calculated by the central 
laboratory at the same timepoints as other safety 
laboratory parameters (see in the Flow Chart). 
 
• 
Creatinine clearance will be calculated based on 
serum creatinine according to Cockcroft and Gault 
(R96-0690, Appendix 10.2). 
 


 
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…….Venous whole blood will be collected through the 
assigned central laboratory in appropriate syringes 
provided by the Sponsor through the assigned central 
laboratory.  
Rationale for change 
 
For clarification and consistency. 
This revision has been clarified in the Protocol 
Administrative Letter (date: on 25 Apr 2023). 
Section to be changed 
 
Section 6.2.2 Treatment period(s) 
Description of change 
 
Updated the text as following (See text in bold): 
 
General rules 
…Drug intake at visit days Visit 7 should always be 
performed at site and after blood and urine sample 
collection and pregnancy test. 
Rationale for change 
 
Clarification 
Section to be changed 
 
Section 6.2.3 Follow-up period and trial completion 
Description of change 
 
Updated the text as following (See text in bold): 
 
A Follow-up Visit has to be scheduled 7 days after End 
of Treatment Visit for all patients. This Follow-up Visit 
is the safety follow-up after treatment discontinuation. 
• Physical examination including vital signs. 
• Adverse events and concomitant therapy will be 
assessment since last visit. 
• Local dipstick pregnancy test (if applicable). 
• Spirometry (FVC) in the allowed time window will 
be performed. 
• Acute ILD exacerbations will be recorded. 
 
Patient’s participation will be concluded for patients 
who withdraw consent and do not attend future visits 
all subjects who complete all treatment visits. 
 
Trial completion 
The trial completion eCRF page has to be filled-in when 
the patient has terminated the trial. 
The end of the trial for the individual patient is: 
• For patients who complete all study visits, end of 
trial is EOT follow-up (FU) visit (after the end of 
treatment visit (EOT)).  
• For patients who withdraw consent 
- 
at time of trial medication discontinuation, end of trial 
is an EOT visit followed by a follow-up visit. 


 
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- 
after EOT was already completed, then the patient 
should have a final visit based on their scheduled 
study visit. 
• For patients who discontinue trial medication 
prematurely during the study period and complete 
an End of Treatment (EOT) visit and a Follow-up 
(FU) visit 1 week later, end of trial is visit at Week 
52. 
• For patients who withdraw consent, end of trial is 
the date of consent withdrawn 
 
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 52 weeks after his/her randomization, at the 
time of data cut-off for the primary analysis and at the 
end of the trial for patients who have withdrawn consent. 
 
Rationale for change 
 
To keep consistent with the change of footnote 10. “A 
Follow-up Visit has to be scheduled 7 days after End of 
Treatment Visit for all patients”, the trial completion 
description for patients completed all study visits is 
corrected. Correct the end of trial description for patients 
who withdraw consent. 
These revisions (except the revision of vital status 
information) have been clarified in the Protocol 
Administrative Letter (date: on 28 June 2023). 
 

SAP_001.pdf: 
ABCD
 
 
 
BI-VQD-12681-S-G_50-415_AD-01 (5.0) 
TRIAL STATISTICAL ANALYSIS PLAN 
TITLE PAGE 
Document No.: 
c40328414-01 
BI Trial No.: 
1199-0434 
Title: 
A double blind, randomized, placebo-controlled trial evaluating 
the efficacy and safety of nintedanib over 52 weeks in Chinese 
patients with Chronic Fibrosing ILDs with a Progressive 
Phenotype 
revised protocol version 5.0 [c34975667-06] 
Investigational 
Product(s): 
Ofev®, Nintedanib 
Responsible trial 
statistician(s): 
Date of statistical 
analysis plan: 
07 JUN 2024 SIGNED 
Version: 
1.0 
Page 1 of 33 
Proprietary confidential information 
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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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BI-VQD-12681-S-G_50-415_AD-01 (5.0) 
1. 
TABLE OF CONTENTS 
TITLE PAGE ........................................................................................................................... 1 
1. 
TABLE OF CONTENTS...................................................................................... 2 
LIST OF TABLES ................................................................................................................... 4 
2. 
LIST OF ABBREVIATIONS .............................................................................. 5 
3. 
INTRODUCTION ................................................................................................. 6 
4. 
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY ...................... 7 
4.1 
CLARIFICATION ................................................................................................ 7 
5. 
ENDPOINTS(S) .................................................................................................... 8 
5.1 
PRIMARY ENDPOINT(S) .................................................................................. 8 
5.2 
SECONDARY ENDPOINT(S) ............................................................................ 8 
6. 
GENERAL ANALYSIS DEFINITIONS .......................................................... 10 
6.1 
TREATMENT(S) ................................................................................................ 10 
6.2 
IMPORTANT PROTOCOL DEVIATIONS.................................................... 10 
6.3 
INTERCURRENT EVENTS ............................................................................. 10 
6.4 
SUBJECT SETS ANALYSED ........................................................................... 11 
 
 
6.7 
BASELINE, TIME WINDOWS AND CALCULATED VISITS ................... 12 
7. 
PLANNED ANALYSIS ...................................................................................... 14 
7.1 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS ......... 14 
7.2 
CONCOMITANT DISEASES AND MEDICATION ..................................... 14 
7.3 
TREATMENT COMPLIANCE ........................................................................ 15 
7.4 
PRIMARY OBJECTIVE ANALYSIS .............................................................. 15 
7.4.1 
Main analysis ....................................................................................................... 15 
7.4.3 
Supplementary analysis ...................................................................................... 19 


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Date: 07 JUN 2024, Version 1.0 
 
BI-VQD-12681-S-G_50-415_AD-01 (5.0) 
7.5 
SECONDARY OBJECTIVE ANALYSIS ........................................................ 19 
7.7 
EXTENT OF EXPOSURE ................................................................................. 21 
7.8 
SAFETY ANALYSIS .......................................................................................... 22 
7.8.1 
Adverse events ..................................................................................................... 22 
7.8.2 
Laboratory data .................................................................................................. 23 
7.8.3 
Vital signs ............................................................................................................. 24 
7.8.4 
ECG ...................................................................................................................... 24 
7.9 
OTHER ANALYSIS ........................................................................................... 24 
8. 
TIMEPOINT OF RELEASE OF TREATMENT INFORMATION ............. 25 
9. 
REFERENCES .................................................................................................... 26 
11. 
HISTORY TABLE .............................................................................................. 33 
 
 


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BI-VQD-12681-S-G_50-415_AD-01 (5.0) 
LIST OF TABLES 
Table 6.3: 1 
Intercurrent events and handling strategies ...................................................... 11 
Table 6.4: 1 
Subject sets analyzed ........................................................................................ 11 
Table 11: 1 
History table ..................................................................................................... 33 
 
 
 


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BI-VQD-12681-S-G_50-415_AD-01 (5.0) 
2. 
LIST OF ABBREVIATIONS  
Term 
Definition / description 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
BI 
Boehringer Ingelheim 
CI 
Confidence Interval 
CTR 
Clinical Trial Report 
DBL 
Database Lock 
eCRF 
Electronic Case Report Form 
FVC 
Forced Vital Capacity 
HRCT 
High-Resolution Computer Tomography 
ICH 
International Conference on Harmonization 
ILD 
Interstitial Lung Disease 
IPF 
Idiopathic Pulmonary Fibrosis 
MedDRA 
Medical Dictionary for Regulatory Activities 
SD 
Standard Deviation 
UIP 
Usual Interstitial Pneumonia 
TSAP 
Trial Statistical Analysis Plan 
ULN 
Upper Limit of Normal 
 
 
 


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BI-VQD-12681-S-G_50-415_AD-01 (5.0) 
3. INTRODUCTION 
As per ICH E9 (9.1), 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, randomization. 
The objective of the current trial is to generate additional data on the efficacy of 150 mg bid 
nintedanib in Chinese patients with Chronic Fibrosing ILDs with a Progressive Phenotype 
compared to placebo over 52 weeks. The primary endpoint is defined in the same way as in 
the INBUILD trial (1199-0247). The efficacy of reduction in lung function decline will be 
measured by the annual rate of decline in FVC for nintedanib compared to placebo over 52 
weeks. 
Unless otherwise noted, SAS® Version 9.4 and R Version 4.0.1 (or higher) will be used for 
all analyses. 
 
 


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BI-VQD-12681-S-G_50-415_AD-01 (5.0) 
4. CHANGES IN THE PLANNED ANALYSIS OF THE STUDY 
4.1 CLARIFICATION 
• 
Comparing with the INBUILD trial (1199-0247), the duration of treatment of this study 
is only 52 weeks. The primary endpoint will include data collected up to last treatment 
visit, instead of day 373. 
• 
The main analysis for primary efficacy endpoint of this study will be based on the treated 
set (according to randomized treatment), using all available data from baseline (excluded) 
up to week 52 visit. For patients who prematurely discontinued study treatment, data 
collected at follow-up visit and visits after treatment discontinuation will be included in 
the analysis. 
• 
Due to the possible occurrence of mis-stratifications during the randomization process, 
the HRCT pattern as reported in the eCRF will be used in all analyses. 
• 
Three patients were randomized by mistake, whose HRCT pattern was recorded 
incorrectly in the Interactive Response Technology (IRT) system. Two patients were 
randomized under “other HRCT fibrotic patterns” and the other one was randomized 
under “HRCT with UIP-like fibrotic pattern only”. They will be counted in the 
subpopulation of patients as collected in the eCRF in all analyses within the CTR. 
 
 


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5. 
ENDPOINTS(S) 
5.1 PRIMARY ENDPOINT(S) 
The primary efficacy endpoint is the annual rate of decline in Forced Vital Capacity (FVC) 
over 52 weeks expressed in mL. The analysis will be based on FVC values obtained at all 
post-baseline visits over 52 weeks. Handling of missing data is described in Section 6.6. 
5.2 SECONDARY ENDPOINT(S) 
Not applicable since there is no secondary endpoint. 


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6. GENERAL ANALYSIS DEFINITIONS 
6.1 TREATMENT(S) 
For the definition of treatment administered during the trial, see Section 4 of CTP. 
• Screening: From informed consent to randomization 
• Treatment period: From first trial drug intake to last trial drug intake 
• Residual effect period / Safety follow-up: From the last trial drug intake plus 1 day to 
last trial drug intake plus 7 days 
• Off-treatment period: From start date of trial drug interruption to re-start of trial drug 
All analyses will be based on the planned treatment groups (Nintedanib 150 mg bid vs. 
Placebo) as randomized by IRT. The subjects will be analyzed according to the stratum to 
which they actually belong to, regardless of any stratification error at randomization. 
6.2 IMPORTANT PROTOCOL DEVIATIONS 
Potentially important protocol deviations (iPDs) will be handled according to BI standards 
(9.5). The number and proportion of patients with iPDs will be presented for completeness 
purposes and to demonstrate the adherence to the CTP. Handling of iPDs in analysis is 
included in the DV domain specifications and stored within the TMF. 
6.3 INTERCURRENT EVENTS 
Intercurrent events and handling strategies with respect to the primary efficacy endpoint are 
described in Table 6.3:1. 
For the main analysis, intercurrent events such as premature treatment discontinuation and 
restricted medication use will be handled by applying treatment policy strategy, i.e., all 
available data collected up to week 52 visit will be included in the analysis. 
Death will be handled by applying while-alive strategy, i.e., data collected while patient is 
alive will be included in analysis. 
The use of Pirfenidone and Nintedanib (non-IMP prescribed by investigator) are prohibited 
during the trial and considered as important protocol violations. In the supplementary 
analysis, prohibited medication and restricted medication will be handled by applying while-
on-treatment strategy, i.e., data collected after the initiation of prohibited or restricted 
medication will not be included in the analysis. 
Further details of intercurrent event handling strategies will be described in Section 7. 
 
 
 
 


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Table 6.3: 1 
Intercurrent events and handling strategies 
Intercurrent event 
Main analysis strategy 
Supplementary 
strategy 
Treatment discontinuation 
Treatment policy 
While-on-treatment 
Initiation of restricted medication  
Treatment policy 
While-on-treatment 
Initiation of prohibited medication Treatment policy 
While-on-treatment 
Death 
While-alive 
While-alive 
6.4 SUBJECT SETS ANALYSED 
Patient sets analyzed are defined as: 
• Screened set (SCS): 
This subject set includes all subjects who signed informed consent. 
• Randomized set (RS): 
This subject set includes all randomized subjects, whether treated or not. 
• Treated set (TS): 
This subject set includes all subjects who were dispensed study medication and were 
documented to have taken at least one dose of investigational treatment. 
Table 6.4: 1 
Subject sets analyzed 
 
Subject set 
Class of analysis 
Screened set 
Randomized set 
Treated set 
Primary endpoint 
 
 
X 
Further endpoint  
 
 
X 
Safety and treatment exposure  
 
 
X 
Demographic & baseline 
characteristics 
 
 
X 
Disposition 
 
X 
 
Reason for non-randomization 
X 
 
 
6.5 SUBGROUPS 
Subgroup analysis is not planned. 


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6.6 HANDLING OF MISSING DATA AND OUTLIERS 
In general, missing data will not be imputed. Exceptions and further details will be described 
in Section 7. 
For continuous efficacy endpoints, missing data will be handled by the Random Slope and 
Intercept (RSI) model and Mixed Models for Repeated Measures (MMRM), assuming a 
missing at random mechanism. 
For binary endpoints, missing data will be considered as worst-case outcome in the main 
analysis, e.g., no response. 
Missing or incomplete AE and CM dates are imputed according to BI standards (9.2). 
6.7 BASELINE, TIME WINDOWS AND CALCULATED VISITS 
As a general rule, the last assessment / measurement observed prior to the start of trial 
medication will be assigned to baseline. Note that for some trial procedures (e.g., body 
weight, vital signs, laboratory tests), this may be the value measured on the same day as trial 
medication started. In these cases, it will be assumed that the measurements were taken prior 
to the intake of any study medication (if the measurement time was not captured). If no 
further data available, this can also be the last screening assessment. 
Visit windowing will be performed as described in Table 6.7: 1, Table 6.7: 2 and Table 6.7: 3. 
In order to assign data to the relevant study visit based on the actual day of the assessment, 
data will be analysed using the re-calculated visits in statistical tables. However, in listings, 
all visits performed will be displayed (even if outside time-window), along with the re-
calculated visit. 


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If after windowing of visits at baseline, the last value prior to first drug intake will be taken 
into account. If after windowing of post-baseline visits, two or more visits fall in the same 
interval, then the measurement closest to the planned visit will be taken into account. In case 
two measurements are equidistant from the planned visit, then the last one will be used in 
analysis. 
 
 


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7. PLANNED ANALYSIS 
The labelling and display format of statistical parameters will follow BI standards (9.3). For 
End-Of-Text tables, the set of summary statistics are: N / Mean / SD / Min / Median / Max. In 
case extreme data outside of the expected range are observed, quartiles and percentiles will be 
presented additionally. 
Tabulations of frequencies for categorical data will include all categories depicted in the 
eCRF 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 patients in the 
respective patient set whether they have non-missing values or not). The category missing 
will be displayed only if there are actually missing values. 
Unless otherwise noted, all analyses will be conducted on the treated set (TS). 
7.1 DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
Descriptive statistics will be provided for disposition, demographics, baseline disease 
characteristics, presented by treatment groups and overall total. 
Disposition table will include the number of patients randomized and treated. The number and 
percentage of patients who completed and prematurely discontinued study treatment will be 
summarized by treatment groups, the reasons for treatment discontinuation will be shown. 
Similarly, the number and percentage of patients who completed and prematurely 
discontinued observation period will also be summarized by treatment groups, the reason for 
study discontinuation will be shown. Where percentages are shown, the denominator will be 
the number of patients treated in each treatment group. 
In addition, the reason for non-randomization will be summarized based on the screened set.  
Demographics such as Age, Sex, Race, Ethnicity, Weight (kg), Height (cm) and BMI will be 
summarized by treatment groups. 
Trial indication characteristics including original underlying ILD diagnoses and baseline 
disease extent as collected in eCRF will be summarized by treatment group. In addition, the 
underlying ILD diagnosis grouping will be summarized by treatment group, the grouping will 
be determined by medical review and documented prior to DBL. 
7.2 CONCOMITANT DISEASES AND MEDICATION 
Concomitant diseases and concomitant medications will be descriptively summarized by 
treatment groups and overall total. 
Concomitant diseases will be coded according to the most recent version of MedDRA. 
Concomitant medications will be coded according to the most recent version of the World 
Health Organization – Drug Dictionary (WHO-DD). 
A medication will be considered concomitant to treatment if it: 
• is ongoing at the start of trial medication intake. 


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• starts within the treatment period (see Section 6.1 for a definition of study phases). 
Concomitant medication use will be summarized with frequency and percentage of subjects 
by ATC3 class and preferred name, grouped by randomized treatment.  
On-treatment restricted medication and prohibited medication will be summarized by 
treatment groups, definitions of restricted and prohibited medications are depicted in CTP 
Section 4.2.2., prohibited medication will be documented in the iPD specification. 
7.3 TREATMENT COMPLIANCE 
The overall compliance (%) will be summarized by treatment groups and overall total. If the 
number of capsules actually taken is missing for an expected visit, the overall compliance is 
not calculated. 
Compliance will be calculated over 52 weeks as: 
Compliance [%] =
𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁 𝑜𝑜𝑜𝑜 𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐 𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎 𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡
𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁𝑁 𝑜𝑜𝑜𝑜 𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐 𝑠𝑠ℎ𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜 ℎ𝑎𝑎𝑎𝑎𝑎𝑎 𝑏𝑏𝑏𝑏𝑏𝑏𝑏𝑏 𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡× 100 
The number of capsules which should have been taken over the 52-week treatment period will 
be calculated as: 
Number of capsules = (date of last drug intake – date of first drug intake + 1) × 2 
In case of dose reduction to 100 mg bid, the calculation of compliance remains the same. The 
duration of treatment interruptions due to AE will be subtracted from the studied treatment 
duration when calculating number of capsules should have been taken.  
Compliance will be categorised into classes: <50%, ≥50% - <80%, ≥80% - ≤ 120%, > 120%. 
Compliance category will be summarized by treatment groups and overall total. 
7.4 PRIMARY OBJECTIVE ANALYSIS 
7.4.1 Main analysis  
The primary efficacy endpoint is the annual rate of decline in Forced Vital Capacity (FVC; 
expressed in mL) over 52 weeks. The main analysis will be based on the TS (according to 
randomized treatment), using all available data from baseline (excluded) up to week 52 visit. 
For patients who prematurely discontinued study treatment, data collected at follow-up visit 
and visits after treatment discontinuation will be included in the analysis. For patients who 
had multiple FVC measurements on the same day, the last measurement will be used in the 
analysis. Intercurrent event handling strategies for main analysis are described in Section 6.3. 
The main analysis uses a restricted maximum likelihood (REML) based approach with a 
random slope and intercept model. The analysis will include the fixed, categorical effects of 
treatment, HRCT pattern at baseline, fixed continuous effects of time and baseline FVC as 
well as the treatment-by-time and baseline-by-time interactions. Random effects will be 
included for patient response for both time and intercept. The HRCT pattern at baseline 
collected in eCRF will be used in the analysis. 
The statistical model can be written as follows: 
𝑦𝑦𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖= (a𝑖𝑖+ ϑ𝑚𝑚+ 𝛽𝛽0𝑆𝑆𝑖𝑖+ 𝜏𝜏𝑘𝑘) + (g𝑖𝑖+ 𝛽𝛽𝑠𝑠𝑆𝑆𝑖𝑖+ 𝜑𝜑𝑘𝑘)t𝑖𝑖𝑖𝑖+ 𝑒𝑒𝑖𝑖𝑖𝑖 


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(a𝑖𝑖, g𝑖𝑖) ~ 𝑁𝑁2 (𝟎𝟎, 𝜮𝜮)  
𝑒𝑒𝑖𝑖𝑖𝑖 
𝑖𝑖𝑖𝑖𝑖𝑖
~
 
 𝑁𝑁 (0, 𝜎𝜎2)  
The components of the model are as follows: 
yijkm 
= 
FVC for patient i with HRCT pattern m at time j receiving treatment k 
ai 
= 
random intercept effect for patient i, i=1,2,… 
ϑ𝑚𝑚 
= 
intercept coefficient of HRCT pattern m, m=1,2. (“other HRCT fibrotic 
patterns” as the class reference) 
𝛽𝛽0 
= 
intercept coefficient of baseline FVC 
𝑆𝑆𝑖𝑖 
= 
baseline FVC measurement for patient i 
𝜏𝜏𝑘𝑘 
= 
intercept coefficient of the effect of treatment k, k=1,2 
gi 
= 
random slope effect for patient i 
𝛽𝛽𝑠𝑠 
= 
slope coefficient of baseline FVC 
𝜑𝜑𝑘𝑘 
= 
slope coefficient of the effect of treatment k 
tij 
= 
time of measurement j for patient i, j= 1,2,… Ji 
eij 
= 
the random error associated with the time j of patient i. Measurement 
errors are independent and normally distributed with mean 0 and 
variance 𝜎𝜎2, and uncorrelated with ai and gi. 
𝜮𝜮 
= 
a 2x2 unstructured covariance matrix 
Within patient errors are assumed to follow a random coefficient regression model with 
random effect for intercept and slope. An unstructured variance-covariance structure will be 
used to model these random slope and intercept. The Kenward-Roger approximation will be 
used to estimate denominator degrees of freedom and adjust standard errors.  
In case of model non-convergence, methods to overcome the issue are described in Section 
10.1. The first model to converge will be used as the main analysis on the primary endpoint.  
The point estimate of treatment difference between the nintedanib and placebo group as well 
as two-sided 95% CI will be provided. No formal statistical testing will be performed. The 
primary treatment comparison of slopes will be assessed through the treatment-by-time 
interaction coefficient. 
SAS code specifications are included in Section 10.2. 


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7.4.3 Supplementary analysis 
A supplementary analysis including only on-treatment measurements of FVC (ml) will be 
analyzed. This analysis reflects the expected biologic effect of nintedanib 150 mg bid in the 
treatment of patients with PF-ILD. 
FVC collected from the first drug administration up to the last drug intake plus one day will 
be included in analysis. The same RSI model used in the main analysis will be applied (see 
Section 7.4.1). Point estimate and two-sided 95% CI of the treatment effect will be presented. 
Tables presenting the results of the supplementary analysis will be created in addition to 
graphical representations. 
7.5 
SECONDARY OBJECTIVE ANALYSIS 
This section is not applicable as no secondary endpoint has been specified in the protocol. 


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7.7 
EXTENT OF EXPOSURE 
Exposure summary will be presented over 52 weeks. The duration on treatment and dose 
intensity will be computed overall, as well as on the individual dose strengths.  
In case last drug administration date is incomplete, assume all prescribed medication at the 
last clinical visit have been taken. Impute the last drug administration date  based on the last 
clinical visit date and number of capsules dispensed, it could be the end of study date if the 
imputed last drug administration date occurs after the end of study date.  


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A summary of treatment interruptions will be created including number of patients with at 
least one interruption, number and reason of interruptions. A similar summary will be 
performed for dose changes. Reasons for dose reduction or interruption will be presented.  
Duration of exposure [months] = (date of last drug administration – date of first drug 
administration +1 day) / 30.5  
Duration of exposure in categories: ≤3 months (91 days); >3 months (91 days) to ≤ 6 months 
(182 days); > 6 months (182 days) to ≤12 months (365 days)  
Treatment interruptions will not be subtracted from the duration of exposure.  
Duration on actual dose (100 or 150 mg bid) (sum of durations on-treatment for each dose 
effectively taken): in weeks and in categories (≤ 8 weeks, > 8 weeks) 
Total dose [g]: Duration of exposure [days] * actual dose [g] 
Dose intensity [%]: amount of drug actually administered over the study (dose 100mg and 
150mg) divided by the amount of drug that would have been administered had dose 150mg 
bid been administered over all the study (from date of first administration to date of last 
administration, whether or not trial drug was prematurely discontinued). Dose intensity will 
be summarized in percent and in categories (≤ 30 %, >30% - ≤50%, >50% - ≤90%, >90% - 
<100%, 100%). 
7.8 SAFETY ANALYSIS 
All safety analyses will be performed by randomized treatment groups based on the treated 
set. 
7.8.1 Adverse events 
Unless otherwise specified, the analyses of AEs will be descriptive in nature. All analyses of 
AEs will be based on the number of subjects with AEs and NOT on the number of AEs. For 
further details on handling of missing or incomplete AE dates and summarization of AE data, 
please refer to (9.2, 9.4). 
The analysis of AEs will be based on the concept of treatment emergent adverse events 
(TEAEs). That means that all AEs occurring between first drug intake till 7 days after last 
drug intake will be assigned to the randomized treatment. All AEs occurring before first drug 
intake will be assigned to ‘screening’ and all AEs occurring after last drug intake + 7 days 
will be assigned to ‘follow-up’ (for listings only). For details on the treatment definition, see 
Section 6.1. 
According to ICH E3 (9.7), 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). An overall summary of adverse events will be presented.  
The frequency of subjects with AEs will be summarized by treatment, primary system organ 
class and PT (mention MedDRA levels to be displayed in the tables). Separate tables will be 
provided for subjects with SAEs, other significant AEs, AEs leading to permanent dose 
reduction, AEs leading to treatment discontinuation, AEs of at least moderate severity, drug-


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related AEs, drug-related SAEs, adverse events leading to death and adverse events of special 
interest (AESI). In addition, selected safety topics / user-defined AE categories (UDAECs) 
will be summarized by treatment group, these selected AE topics will be determined by 
medical review and documented prior to DBL. 
The system organ classes will be sorted by default alphabetically, PTs will be sorted by 
frequency (within SOC). 
7.8.2 Laboratory data 
The analyses of laboratory data will be descriptive in nature and based on SI units according 
to BI standards (9.6). Missing data will not be imputed. 
Summary statistics of laboratory tests by functional group over time will be presented by 
treatment groups.  
Potentially clinically significant abnormalities will be identified based on BI standard rules 
which are based on converted lab values, i.e., using SI units. Frequency tables will summarize 
the number of patients with potentially clinically significant abnormalities. In addition, lab 
shift tables will be presented. 
Patients having an abnormal lab value at baseline will be presented in a listing separately. A 
separate listing will present all patients with potentially clinically significant lab values. In 
addition, a summary table will be prepared for the values outside of the clinically significant 
reference range including frequency and percentage of patients with abnormal values for 
relevant laboratory parameter. 
A summary table of liver enzymes and bilirubin elevations over 52 weeks will also be 
provided. Liver enzyme and bilirubin elevations will be reported using the three following 
definitions:  
• ALT and/or AST ≥ 8xULN 
• ALT and/or AST ≥ 3xULN AND total bilirubin ≥ 2xULN* 
• ALT and/or AST ≥ 3xULN and unexplained INR > 1.5* 
• ALT and/or AST ≥ 3xULN and unexplained eosinophilia (>5%)* 
• ALT and/or AST ≥ 3xULN and appearance of fatigue, nausea, vomiting, right upper 
abdominal quadrant pain or tenderness, fever and/or rash 
* in the same blood draw sample. 
A graphical analysis of the ALT and total bilirubin during the on-treatment period will also be 
performed according to BI standards (9.6), the so-called eDISH plot. For cases whose total 
bilirubin, AST/ALT values meet the criteria for Hy’s Law (Maximum total bilirubin two or 
more times the ULN for the parameter, and the maximum ALT and/ or AST value three or 
more times its ULN) at any individual visit will be presented in a listing, showing the 
constituent values plus the associated alkaline phosphatase value at that time and the full 
course of available values for that case obtained during the study. 


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7.8.3 Vital signs 
Summary statistics of vital signs (systolic and diastolic blood pressure, pulse rate and weight) 
over time will be presented by treatment groups. 
The number and percentage of patients with marked changes in vital signs over 52 weeks will 
also be summarized by treatment. 
A marked increase is defined as: 
• Systolic Blood Pressure >130 mmHg and increase ≥ 25 mmHg above baseline 
• Diastolic Blood Pressure >80 mmHg and increase ≥ 10 mmHg above baseline 
• Pulse Rate >100 bpm and increase ≥ 10 bpm above baseline 
A marked decrease is defined as: 
• Systolic Blood Pressure <100 mmHg and decrease >10 mmHg below baseline 
• Diastolic Blood Pressure <60 mmHg and decrease >10 mmHg below baseline 
• Pulse Rate <60 bpm and decrease >10 bpm below baseline 
7.8.4 ECG 
ECG analysis is not planned. 
7.9 OTHER ANALYSIS 
Other analysis is not planned. 
 
 
 


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8. TIMEPOINT OF RELEASE OF TREATMENT INFORMATION 
The treatment information will be released to unblind the trial database after the last patient 
has completed their End-of-Study/Follow-up visit and all data has been entered and cleaned as 
defined in the “Data Ready to be Unblinded and/or Final Trial Closure Notification” (RUN) 
form. 
 
 
 


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9. REFERENCES 
9.1  CPMP/ICH/363/96: "Statistical Principles for Clinical Trials", ICH Guideline 
Topic E9, Note for Guidance on Statistical Principles for Clinical Trials, current 
version. 
9.2  BI-VQD-01530: “Handling of Missing and Incomplete AE Dates”, current 
version, group / owning department “Med Biostatistics & Data Sciences”, DMS 
for controlled documents. 
9.3  BI-VQD-01538: “Standards for Reporting of Clinical Trials and Project 
Summaries”, current version, group / owning department “Med Clinical 
Development & Operations”, DMS for controlled documents. 
9.4  BI-VQD-01041: “Analysis and Presentation of AE data from clinical trials”, 
current version, group / owning department “Med Biostatistics & Data Sciences”, 
DMS for controlled documents. 
9.5  BI-VQD-12045_40-413: “Identify and Manage Important Protocol Deviations 
(iPD)”, current version, group / owning department “Med Clinical Development & 
Operations”, DMS for controlled documents. 
9.6  BI-VQD-01535: “Handling, Display and Analysis of Laboratory Data”, current 
version, group / owning department “Med Biostatistics & Data Sciences”, DMS 
for controlled documents. 
9.7  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. 
9.9  Rubin, DB. Multiple Imputation for Nonresponse in Surveys. New York: John 
Wiley & Sons. 1987. [R12-2378] 
9.10 Bonella F, Maher T M, Cottin V, et al. Consistent effect of nintedanib on reducing 
FVC decline across interstitial lung diseases (ILDs)[J]. Eur Respir J, 2020, 56(64): 
739. 
9.11 Bonella F, Cottin V, Valenzuela C, et al. Meta-analysis of effect of nintedanib on 
reducing FVC decline across interstitial lung diseases[J]. Advances in Therapy, 
2022, 39(7): 3392-3402. 
 
 
 


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11. HISTORY TABLE 
Table 11: 1 
History table 
Version 
Date 
(DD-MMM-
YY) 
Author 
Sections 
changed 
Brief description of change 
1.0 
07-JUN-24 
 
None 
This is the final TSAP.