Clinical trial NCT04419506
Conditions: Idiopathic Pulmonary Fibrosis
Sponsor: Boehringer Ingelheim
Start date: 2020-07-28; Completion date: 2021-10-15
Enrollment: 147 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study is open to adults with idiopathic pulmonary fibrosis (IPF) who are at least 40 years old. People taking standard medicines for IPF, including antifibrotic medicines, can continue taking them throughout the study.

The purpose of the study is to find out whether a medicine called BI 1015550 can slow down the worsening of lung function. Participants are in the study for about 4 months. During this time, they visit the study site about 7 times. At the beginning, they visit the study site every 2 weeks.

After 1 month of treatment, they visit the study site every 4 weeks.

The participants are put into 2 groups by chance. 1 group gets BI 1015550. The other group gets placebo. Placebo tablets look like BI 1015550 tablets but contain no medicine. The participants take BI 1015550 or placebo tablets twice a day.

The participants have lung function tests at study visits. The results of the lung function tests are compared between the BI 1015550 group and the placebo group. The doctors also regularly check the general health of the participants.

Detailed description:

Arms: arm 1: Idiopathic pulmonary fibrosis (IPF) patients on stable antifibrotic treatment with nintedanib or pirfenidone at baseline were administered placebo matching BI 1015550 taken orally as film-coated tablets (matching the respective BI 1015550 tablets) twice daily, in the morning and in the evening for 12 weeks. During the 12-weeks of administration of BI 1015550 patients stayed on their stable background therapy of nintedanib or prifenidone. arm 2: Idiopathic pulmonary fibrosis (IPF) patients on stable antifibrotic treatment with nintedanib or pirfenidone at baseline were administered 18 milligram (mg) BI 1015550 taken orally as film-coated tablets (1x 6mg tablet, 1x 12 mg tablet) twice daily (36 mg daily), in the morning and in the evening for 12 weeks. During the 12-weeks of administration of BI 1015550 patients stayed on their stable background therapy of nintedanib or prifenidone. arm 3: Idiopathic pulmonary fibrosis (IPF) patients not on stable antifibrotic treatment at baseline were administered placebo matching BI 1015550 taken orally as film-coated tablets (matching the respective BI 1015550 tablets) twice daily, in the morning and in the evening for 12 weeks. arm 4: Idiopathic pulmonary fibrosis (IPF) patients not on stable antifibrotic treatment at baseline were administered 18 milligram (mg) BI 1015550 taken orally as film-coated tablets (1x 6mg tablet, 1x 12 mg tablet) twice daily (36 mg daily), in the morning and in the evening for 12 weeks.
Interventions: intervention 1: BI 1015550 intervention 2: Placebo
Intervention descriptions: intervention 1: 18 milligram (mg) BI 1015550 taken orally as film-coated tablets (1x 6mg tablet, 1x 12 mg tablet) twice daily (36 mg daily), in the morning and in the evening for 12 weeks. intervention 2: placebo matching BI 1015550 taken orally as film-coated tablets (matching the respective BI 1015550 tablets) twice daily, in the morning and in the evening for 12 weeks.

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:
c29492723-04
EudraCT No.
EU Trial No.
2019-004167-45
BI Trial No.
1305-0013
BI Investigational
Medicinal Product
BI 1015550
Title
A randomised, double-blind, placebo-controlled parallel group  
study in IPF patients over 12 weeks evaluating efficacy, safety and
tolerability of BI 1015550 taken orally.
Lay Title
A study to test how taking BI 1015550 for 12 weeks affects lung 
function in people with idiopathic pulmonary fibrosis (IPF).
Clinical Phase
II
Clinical Trial 
Leader
Tel: 
Fax: 
Email: 
Coordinating 
Investigator
Phone: 
Fax : 
Version and Date
Version: 4.0
Date: 09 Sep 2020
Page 1 of 118
Proprietary confidential information.
! 2020 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
17 Feb 2020
Revision date
09 Sep 2020
BI trial number
1305-0013
Title of trial
A randomised, double-blind, placebo-controlled parallel group study
in IPF patients over 12 weeks evaluating efficacy, safety and
tolerability of BI 1015550 taken orally.
Coordinating 
Investigator
Phone: 
Fax :
Trial site(s)
Multi-centre trial conducted in approximately 20 countries
Clinical phase
II
Trial rationale
The purpose of this trial is to demonstrate proof of concept of clinical 
activity of BI 1015550 on the change of Forced Vital Capacity (FVC)
between baseline and 12 weeks.
New treatments are needed that further reduce the decline in FVC, 
positively affect symptoms and improve quality of life in patients 
with Idiopathic Pulmonary Fibrosis.
This trial will investigate BI 1015550 to be used in this patient 
population either as stand-alone treatment or in addition to local 
standard of care (SoC), which may or may not include currently 
approved antifibrotic treatments (nintedanib or pirfenidone). FVC
change from baseline will be used to generate sufficient evidence of 
efficacy in the subpopulation on no background antifibrotic treatment, 
to inform the phase III program.
Trial objective(s)
To investigate the efficacy of BI 1015550 18 mg b.i.d compared to 
placebo based on the change from baseline in FVC.
To investigate the safety and tolerability of BI 1015550 in overall trial 
population.
Trial endpoints
The primary endpoint is the change from baseline in FVC at 12 weeks
(in mL).
The secondary endpoint is the Percentage of patients (%) N with 
Treatment Emergent Adverse Events (TEAE).
Trial design
Double-blind, placebo controlled, parallel design of 2 groups over 12 
weeks.
Total number of 
patients randomised
Approx. 150 (min 120)
Number of patients on 
Approx. 100 in BI 1015550 18 mg b.i.d. group


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each treatment
Approx. 50 in placebo group
Diagnosis
IPF patients either treated with antifibrotic treatment or not.
Main in- and exclusion 
criteria
Inclusion criteria :
∀Patients aged ≥40 years.
∀IPF diagnosis confirmed by central review.
∀FVC≥ 45%.
∀DLCO≥25% and<80%.
∀Either stable treatment with antifibrotics for at least 8 weeks 
prior to Visit 1 or not treated with antifibrotics for at least 8
weeks prior to Visit 1.
Exclusion criteria : 
∀Relevant airways obstruction (pre-bronchodilator FEV1/FVC 
< 0.7) at Visit 1.
∀Acute IPF exacerbation within 4 months prior to screening 
and/or during the screening period.
∀Lower respiratory tract infection requiring antibiotics within 4 
weeks prior to Visit 1 and/or during the screening period.
∀Any suicidal behaviour in the past 2 years.
∀Any suicidal ideation of type 4 or 5 on the C-SSRS in the past 
3 months or at Visit 1.
∀Baseline condition or medical history of vasculitis.
∀
Confirmed infection with SARS-CoV-2 within 4 weeks prior to 
visit 1 or during screening period.
Test product(s)
BI 1015550
dose
18 mg b.i.d (36 mg daily)
mode of 
administration
Oral
Comparator product(s)
Placebo
dose
Matching
mode of
administration
Oral
Duration of treatment
12 weeks
Statistical methods
The purpose of this trial is to demonstrate proof of concept of clinical 
activity of BI 1015550 on the primary endpoint. For the proof of 
concept an evaluation of a minimum relevant additional benefit of 
BI 1015550 compared to placebo is conducted. Hereby, the posterior 
probability of the difference in change from baseline in FVC between 
BI 1015550 and placebo will be evaluated for different boundary 
values.
The primary endpoint change from baseline in FVC at week 12 will 
be evaluated separately in the patient group with antifibrotic treatment 
and in the patient group with no antifibrotic treatment.
To account for the repeated nature of the data and the covariates in 


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the model, MMRM analysis will be carried out for change from 
baseline of FVC after 12 weeks of treatment in each patient group.
The adjusted mean change from baseline (and the related standard 
error) will be calculated for each group and will be used for the 
Bayesian borrowing approach.
The analysis will include the fixed, categorical effect of treatment at 
each visit, and the fixed continuous effects of baseline FVC at each 
visit. Visit will be treated as the repeated measure with an 
unstructured covariance structure used to model the within-patient 
measurements.


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FLOW CHART
Trial Periods
Screening 
Randomised Treatment 
Follow 
Up**
Visits
1
2 
3
4
5
6 – End of 
Treatment
7 - End 
of Trial
Weeks
D 1*
2
4
8
12
EoT + 1 
week
Days
-301
1
15
29
57
85
EoT + 
7d
Time window for visits
-14/+23 
days
±3
days
±7
days
±7
days
-7/+4
days
+3 days
Informed consent2
X
Demographics
X
Medical history
X
Physical examination
X
X
X
X
X
X
X
Vital signs***
X
X
X
X
X
X
X
Weight
X
X
X
X
X
X
X
Height
X
Safety laboratory tests3
X
X
X
X
X
X
X
12 lead-ECG4
X
X
X
X
Review of in-/exclusion criteria
X
X
Randomisation
X
Dispense trial drugs
X
X
X
Administer trial drugs
X
X
X
X
X
Return trial drugs
X
X
X
X
X
Spirometry (FEV1, FVC)6
X
X
X
X
X
X
C-SSRS7
X
X
X
X
X
X
X
 
 
X
X
X
HRCT9
X
DLCO6
X
X
X
X
 
X
 
X
Optional 24hr Cough assessment 
substudy12
X
X
IRT call/notification
X
X
X
X
X
All AEs/SAEs/AESIs****
X
X
X
X
X
X
X
Compliance check 
X
X
X
X
Concomitant therapy
X
X
X
X
X
X
X
Completion of patient participation 
X
1.
Visit 1 (screening) is expected to be conducted in the 30 days prior to Visit 2 (randomisation), considering the time for 
HRCT central review. This period may be extended up to 44 days in case of administrative issue (eg result from HRCT 
central reading not available). If Visit 2 cannot be performed in this extended timeframe, the patient will have to be 
screen failed.


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2.
Before or at the latest at Visit 1. Informed consent (IC) needs to be signed before any procedure related to the trial is 
performed, including HRCT review. All adverse events (AEs) and concomitant therapies (CTs) from the day of signing 
informed consent have to be recorded.
3.
Safety laboratory parameters will be evaluated at each visit, pre dose. This will include blood and urine collection.
4.
All ECGs will be performed pre dose.
5.
 
 
6.
Order of lung function measurements: 1. Spirometry followed by patients rest; 2. DLCO. Measurements have to be 
performed at the same time each visit ± 90 min (reference time at Visit 2).
7.
At Visit 1, the C-SSRS version to be used is the screening one. At all other Visits, starting at Visit 2, the version of C-
SSRS to be used is the version “since last Visit”.
8.
 
 
9.
Review of high resolution computer tomography (HRCT). Central review: a historical HRCT not older than 12 months 
should be sent; only if the patient does not have a HRCT within 12 months at Visit 1, or the available HRCT does not 
meet the required image acquisition specifications and patient meets all other inclusion and no exclusion criteria, 
screening HRCT can be performed as part of the study. To perform an HRCT within the trial, all local regulatory 
requirements to perform an HRCT has to be met. In Germany, no HRCT will be performed as a trial procedure, only 
historical HRCT will be submitted.
10.
 
 
 
 
 
 
12. For the 24hr cough assesmentsubstudy, the patients will have to sign a separate informed consent at Visit 2.
(*)
Day of Randomisation / Day of first intake of randomised medication.
(**)
Patients who discontinue trial treatment prematurely should still follow the trial schedule, if possible, please see 
section 3.3.4.
(***)
Measurements of vital signs should precede blood sampling 
(****)
After the EoTrial visit (=individual patient’s end of the trial) the investigator should report only any cancers of new 
histology and exacerbations of existing cancer, trial treatment related SAEs and trial treatment related AESIs of which the 
investigator may become aware of and only via the BI SAE form, please see section.5.2.6.2.1.


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TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS .....................................................................2
FLOW CHART........................................................................................................................5
TABLE OF CONTENTS ........................................................................................................7
ABBREVIATIONS................................................................................................................11
1.
INTRODUCTION...............................................................................................14
1.1
MEDICAL BACKGROUND.............................................................................14
1.2
DRUG PROFILE................................................................................................14
Mode of action.....................................................................................................14
1.2.1
Key pharmacokinetic characteristics................................................................14
1.2.2
Drug interactions.................................................................................................15
1.2.3
Residual Effect Period ........................................................................................16
1.2.4
Data from non-clinical studies ...........................................................................16
1.2.5
Data from clinical studies...................................................................................18
1.2.6
1.3
RATIONALE FOR PERFORMING THE TRIAL.........................................18
1.4
BENEFIT - RISK ASSESSMENT.....................................................................19
Benefits.................................................................................................................19
1.4.1
Risks .....................................................................................................................20
1.4.2
Discussion.............................................................................................................23
1.4.3
2.
TRIAL OBJECTIVES AND ENDPOINTS......................................................25
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS........25
Main objectives....................................................................................................25
2.1.1
Primary endpoints...............................................................................................25
2.1.2
Secondary endpoint.............................................................................................25
2.1.3
2.2.2.2
Safety endpoints....................................................................................................26
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...........................................................................................27
3.3
SELECTION OF TRIAL POPULATION .......................................................28
Main diagnosis for trial entry ............................................................................29
3.3.1
Inclusion criteria .................................................................................................29
3.3.2
Exclusion criteria ................................................................................................30
3.3.3
Withdrawal of patients from treatment or assessments..................................31
3.3.4
3.3.4.1
Discontinuation of trial treatment .........................................................................32


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3.3.4.2
Withdrawal of consent to trial participation .........................................................32
3.3.4.3
Discontinuation of the trial by the sponsor...........................................................33
4.
TREATMENTS...................................................................................................34
4.1
INVESTIGATIONAL TREATMENTS ...........................................................34
Identity of the Investigational Medicinal Products..........................................34
4.1.1
Selection of doses in the trial and dose modifications......................................35
4.1.2
Method of assigning patients to treatment groups...........................................36
4.1.3
Drug assignment and administration of doses for each patient......................37
4.1.4
Blinding and procedures for unblinding...........................................................38
4.1.5
4.1.5.1
Blinding.................................................................................................................38
4.1.5.2
Unblinding and breaking the code ........................................................................38
Packaging, labelling, and re-supply...................................................................38
4.1.6
Storage conditions...............................................................................................38
4.1.7
Drug accountability.............................................................................................39
4.1.8
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS ................................................................................................39
Other treatments and emergency procedures..................................................39
4.2.1
Restrictions ..........................................................................................................40
4.2.2
4.2.2.1
Restrictions regarding concomitant treatment ......................................................40
4.2.2.2
Restrictions on diet and life style..........................................................................41
4.2.2.3
Contraception requirements..................................................................................41
4.3
TREATMENT COMPLIANCE........................................................................41
5.
ASSESSMENTS..................................................................................................42
5.1
ASSESSMENT OF EFFICACY........................................................................42
FVC ......................................................................................................................42
5.1.1
DLCO...................................................................................................................42
5.1.2
5.2
ASSESSMENT OF SAFETY.............................................................................44
Physical examination ..........................................................................................44
5.2.1
Vital signs.............................................................................................................44
5.2.2
Safety laboratory parameters ............................................................................44
5.2.3
Electrocardiogram Recording ...........................................................................46
5.2.4
Suicidal risk assessed by the C-SSRS................................................................47
5.2.5
Assessment of adverse events.............................................................................48
5.2.6
5.2.6.1
Definitions of AEs ................................................................................................48
5.2.6.2
Adverse event collection and reporting ................................................................51


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5.5
BIOBANKING ....................................................................................................55
Methods and timing of sample collection..........................................................55
5.5.1
5.6
OTHER ASSESSMENTS...................................................................................55
24 hr Cough measurement (substudy at dedicated sites only)........................55
5.6.1
5.7
APPROPRIATENESS OF MEASUREMENTS..............................................55
6.
INVESTIGATIONAL PLAN.............................................................................57
6.1
VISIT SCHEDULE.............................................................................................57
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS .................57
Screening period..................................................................................................58
6.2.1
Treatment period ................................................................................................59
6.2.2
Follow-up period and trial completion..............................................................61
6.2.3
Optional substudy ...............................................................................................62
6.2.4
7.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE
...............................................................................................................................63
7.1
NULL AND ALTERNATIVE HYPOTHESES ...............................................63
7.2
PLANNED ANALYSES.....................................................................................63
General considerations .......................................................................................63
7.2.1
Primary endpoint analyses.................................................................................64
7.2.2
7.2.2.1
Prior derivation .....................................................................................................65
Secondary endpoint analyses .............................................................................67
7.2.3
Safety analyses.....................................................................................................68
7.2.5
 
Interim Analyses .................................................................................................69
7.2.7
7.3
HANDLING OF MISSING DATA ...................................................................69
7.4
RANDOMISATION ...........................................................................................69
7.5
DETERMINATION OF SAMPLE SIZE .........................................................69
8.
INFORMED CONSENT, TRIAL RECORDS, DATA PROTECTION, 
PUBLICATION POLICY, AND ADMINISTRATIVE STRUCTURE ........73
8.1
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED 
CONSENT ...........................................................................................................73
8.2
DATA QUALITY ASSURANCE ......................................................................74
8.3
RECORDS...........................................................................................................74
Source documents ...............................................................................................74
8.3.1
Direct access to source data and documents.....................................................75
8.3.2
Storage period of records ...................................................................................76
8.3.3
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS ..................................76
8.5
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY........76


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Collection, storage and future use of biological samples and corresponding 
8.5.1
data.......................................................................................................................76
8.6
TRIAL MILESTONES.......................................................................................77
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL ...................................77
9.
REFERENCES....................................................................................................79
9.1
PUBLISHED REFERENCES............................................................................79
9.2
UNPUBLISHED REFERENCES......................................................................81
10.
APPENDICES.....................................................................................................82
10.2
COLUMBIA SUICIDAL SEVERITY RATING SCALE (C-SSRS) .............97
10.3
DLCO.................................................................................................................103
 
10.5
ELIGIBILITY CONFIRMATION OF IPF DIAGNOSIS............................105
10.6
CREATININE CLEARANCE.........................................................................106
10.7
EQUIVALENT DOSES OF CORTICOSTEROIDS.....................................107
10.8
RESTRICTED MEDICATIONS TABLES....................................................107
Strong CYP3A4 inhibitors ...............................................................................107
10.8.1
Restricted PDE inhibitors ................................................................................108
10.8.2
10.9
PRIOR CALCULATION.................................................................................110
11.
DESCRIPTION OF GLOBAL AMENDMENT(S) .......................................114
11.1
GLOBAL AMENDMENT 1 ............................................................................114
11.2
GLOBAL AMENDMENT 2 ............................................................................114
11.3
GLOBAL AMENDMENT 3 ............................................................................116


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ABBREVIATIONS
AE
Adverse Event
AESI
Adverse Event of Special Interest
ALCOA
Attributable, Legible, Contemporaneous, Original, Accurate 
ALT
Alanine Aminotransferase
AST
Aspartate Aminotransferase
AUC
Area under the Curve
b.i.d.
bis in die (twice daily dosing)
BI
Boehringer Ingelheim
BMI
Body Mass Index
CA
Competent Authority
Cmax
Maximum Concentration
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration
CNS
Central Nervous System
COPD
Chronic Obstructive Pulmonary Disease
CRA
Clinical Research Associate
CRO
Contract Research Organisation
C-SSRS
Columbia-Suicide Severity Rating Scale
CTP
Clinical Trial Protocol
CYP
Cytochrome P450
DILI
Drug Induced Liver Injury
DLCO
Diffusion capacity of the lung for carbon monoxide
DMC
Data Monitoring Committee
DNA
DesoxyriboNucleic Acid
EC
Ethics Committee
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
eDC
Electronic Data Capture
eGFR
Estimated Glomerular Filtration Rate
EoT
End of Treatment
EoTrial
End of Trial
ESR
Erythrocyte Sedimentation Rate


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ES
Entered Set
EudraCT
European Clinical Trials Database
FAS
Full Analysis Set
FEV1
Forced Expiratory Volume in one second
FSH
Follicle Stimulating Hormone
FVC
Forced Vital Capacity
GCP
Good Clinical Practice
GI
Gastro Intestinal
GMP
Good Manufacturing Practice
HA
Health Authority
HR
Heart Rate
HRCT
High Resolution Computed Tomography Scan
HV
Healthy Volunteers
IB
Investigator’s Brochure
IC50
half maximal Inhibitory Concentration
ICH
International Council on Harmonisation
IEC
Independent Ethics Committee
ILD
Interstitial Lung Disease
IMP
Investigational Medicinal Product
iPD
Important Protocol Deviation
IPF
Idiopathic Pulmonary Fibrosis
IRB
Institutional Review Board
IRT
Interactive Response Technology
ISF
Investigator Site File
IUD
Intrauterine Device
IUS
Intrauterine Hormone-Releasing System
LPLT
Last Patient Last Treatment
MedDRA
Medical Dictionary for Drug Regulatory Activities
MMRM
Mixed effect Model Repeat Measurement
MRD
Multiple Rising Dose
mRNA
Messenger RiboNucleic Acid


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OPU
Operative Unit
PDE
Phosphodiesterase
PI/IC
Patient Information/Informed Consent
PoC
Proof of Concept
PPS
Per Protocol Set
RA
Regulatory Authority
REP
Residual Effect Period
RMP
Risk Management Program
RNA
RiboNucleic Acid
RS
Randomised Set
SAE
Serious Adverse Event
SmPC
Summary of Product Characteristics
SoC
Standard of Care
SOP
Standard Operating Procedure
SRD
Single Rising Dose
SUSAR
Suspected Unexpected Serious Adverse Reactions
tmax
Timepoint of Maximum Plasma Concentration
TEAE
Treatment Emergent Adverse Events
TK
Toxicokinetic
TNF
Tumor Necrosis Factor
TS
Treated Set
TSAP
Trial Statististical Analysis Plan
ULN
Upper Level of Normal
UIP
usual interstitial pneumonia
WHO
World Health Organisation
WOCBP
Woman of childbearing potential


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1.
INTRODUCTION
BI 1015550 is a selective inhibitor of the Phosphodiesterase 4 B (PDE4 B) with broad anti-
inflammatory and anti-fibrotic activities. It is under development for the treatment of 
idiopathic pulmonary fibrosis (IPF).
1.1
MEDICAL BACKGROUND
IPF is a progressive, fibrosing interstitial lung disease (ILD) characterized by decline in lung 
function and worsening dyspnea [R18-2794]. IPF carries a poor prognosis, with a median 
post-diagnosis survival in untreated patients of approximately 3 years [R18-1413].
IPF occurs worldwide. The prevalence of the disease appears to be increasing, although it is 
unclear whether this reflects increased recognition or a true increase in incidence. The 
incidence of IPF appears to be higher in North America and Europe (3 to 9 cases per 100,000 
person-years) than in South America and East Asia (fewer than 4 cases per 100,000 person-
years) [R17-4284]. In the United States, the prevalence of IPF has been reported to range 
from 10 to 60 cases per 100,000 [R16-1737], [R18-0408], [R14-2284]. Increasing rates of 
hospital admissions and deaths due to IPF also suggest an increasing burden of disease [R17-
4284], [R14-4266], [P13-05880].
Nintedanib and pirfenidone are the only drugs registered for the treatment of IPF and 
recommended in the recent ATS/ERS/JRS/ALAT Clinical Practice Guideline for the 
Treatment of Idiopathic Pulmonary Fibrosis [R18-2794]. Despite the availability of these 
drugs, the medical need remains high in this devastating disease.
 
 
 
 
 
 
 
 
 
 


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1.3
RATIONALE FOR PERFORMING THE TRIAL
This phase II trial will investigate the efficacy of BI 1015550 18 mg b.i.d. by comparing the 
change from baseline in FVC after 12 week of treatment compared to placebo. This trial will 
also evaluate the safety of BI 1015550 over 12 weeks compared to placebo where antifibrotic 
background treatment is introduced for the first time in the BI 1015550 clinical programme.
BI 1015550 will be evaluated as a stand-alone in patients on no background antifibrotic 
treatment and in addition to antifibrotic treatments, i.e. this trial will include patients with or 
without approved and available antifibrotic treatment (nintedanib or pirfenidone) at baseline
and during the study. 
As per the 1305-0012 Phase Ic study, the 12 weeks treatment duration is being adequately 
supported by the 13 weeks toxicology data.
Overall, the Proof of Concept (PoC) of this trial is primarily based on the efficacy results of 
the treatment group not on antifibrotics. PoC and safety of the overall study population of this 
trial will be used to inform the phase III program.
New treatments are needed that further reduce the decline in FVC, positively affect 
symptoms and improve quality of life in patients with IPF.
Overall, due to the in vitro/in vivo activity of BI 1015550 both in anti inflammatory and anti-
fibrotic assays/models, BI1015550 is hypothesized to have complementary activity (on 
myofibroblast transformation) to current antifibrotic therapies in IPF and a synergistic effect 


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in combination with nintedanib on fibroblast proliferation if BI 1015550 is shown to be safe 
and well tolerated when combined with approved antifibrotics.
Please refer to section 1.4.1 for further details.
In order to be able to address future scientific questions, patients will be asked to voluntarily 
donate biospecimens for banking (please see 
). If the patient agrees, banked 
section 5.5
samples may be used for future biomarker research and drug development projects, e.g. to 
identify patients that are more likely to benefit from a treatment or experience an adverse 
event (AE), or to gain a mechanistic or genetic understanding of drug effects and thereby 
better match patients with therapies.
1.4
BENEFIT - RISK ASSESSMENT
Benefits
1.4.1
Preclinical experiments have shown that BI 1015550 affects the fibrotic pathway and the 
effects may be complementary and/or synergistic to those of nintedanib. Based on this, it is 
postulated that BI 1015550 may provide therapeutic benefit to patients with IPF or other 
progressive fibrosing ILDs but this has not yet been determined clinically [c02094779].
Due to the limited short treatment duration in this study, only patients on no background 
antifibrotic treatment may have an improvement of FVC versus baseline. Nevertheless, 
patients’ participation in this 12 weeks trial in IPF patients with or without background 
antifibrotic therapy treated with BI 1015550, 18 mg b.i.d. is of utmost importance to 
investigate the safety, tolerability, efficacy 
 of BI 1015550 when administered
alone or on background antifibrotic treatment prior to progressing to longer term treatment 
Phase III to show an effect on FVC decline in the overall IPF population.
Two PDE4 inhibitors are marketed with indications of psoriasis and chronic obstructive 
pulmonary disease (COPD). Studies conducted in non-human primates with both marketed 
compounds suggest that primates are less sensitive than rats to PDE4i-associated toxicity. No 
adverse vascular changes in humans have been reported.
Overall, BI 1015550 is expected to be safe and well tolerated with an improved tolerability 
compared to other marketed PDE4 inhibitors due to lower affinity for PDE4 D.


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Risks
1.4.2
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 BI 1015550
Pharmacokinetic 
interaction with strong 
CYP3A4 inhibitors 
CYP450 3A4 is regarded as the major 
enzyme responsible for BI 1015550 
metabolism in human hepatocytes. 
CYP3A is predicted to contribute to 
~70% of the hepatic metabolism of 
BI 1015550.
In a drug drug interaction trial, the 
strong CYP 3A4 inhibitor 
(itraconazole) increased the exposure 
to BI 1015550 by 1.3-fold (Cmax) 
and 2.2-fold AUC. 
Potent CYP3A inhibitors are 
restricted medication.
Safety in addition of 
marketed antifibrotic 
treatments
At the start of this 12 weeks treatment 
trial, no safety data will be available 
on BI 1015550 given in addition to 
marketed antifibrotics.
DMC will be in place to 
assess the entire safety data 
on an ongoing basis.
Vasculitis 
Vasculopathy is an established 
toxicity of PDE4 inhibitors in rats. 
Vasculitis has been shown in both the 
rats and minipigs following oral 
administration of BI 1015550 and it 
has been the basis of the NOAEL (No 
Observable Adverse Effect Level) 
definition. 
Vasculitis is listed as an important 
potential risk in the RMP for the 
marketed PDE4- inhibitors apremilast 
and roflumilast. 
In marketed PDE4 inhibitors, 
vasculitis has not been identified as 
an adverse drug reaction in humans.
Baseline condition or 
medical history of vasculitis 
is an exclusion criterion. 
Patient’s withdrawal  in case 
of any vasculitis adverse 
event considered drug related 
or not.
Increased awareness and 
expedite reporting (AESI).
Gastrointestinal
disorders (e.g.
diarrhoea, nausea,
vomiting, abdominal
pain)
Vomiting and diarrhea are important 
dose-limiting side effects of marketed 
oral PDE-4 inhibitors. 
Gastrointestinal disorders are very 
common or common side effect of the 
approved antifibrotics.
Increased awareness of 
symptoms.
Careful monitoring of 
hydration in patients with 
diarrhoea is recommended.
Management strategies as 
described in approved labels 
have to be followed.


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Table 1.4.2: 1 Overview over trial related risks (cont’d)
Possible or known risks
of clinical relevance for 
this trial
Summary of data, rationale for the 
risk
Mitigation strategy
Treatment 
interruption/discontinuation 
is left at the investigator’s 
discretion.
Reproductive toxicity
Specific studies to evaluate the 
potential for BI 1015550 to affect 
male and female fertility and 
developmental toxicity have not yet 
been conducted.
Women of childbearing 
potential are excluded from 
the trial.
Contraception requirements 
for men able to father a 
child.
Weight decrease in 
underweight patients 
(BMI < 18.5 kg/m2)
For the marketed PDE4-inhibitors 
apremilast and roflumilast weight loss 
in underweighted patients is 
identified as an important risk.
Body weight evaluated at 
each visit.
Patients who have a BMI 
<18.5 kg/m2 at visit 2, and 
subsequently experience 
unexplained and clinically 
significant weight loss 
(>10%) will be discontinued 
from trial treatment.
Suicidality
Two of the currently marketed PDE4 
inhibitors are associated with 
increased risk of depression with 
some patients reporting suicidal 
ideation and attempts and also 
reported cases of completed suicide.
Any suicidal behaviour in 
the past 2 years and any 
suicidal ideation of type 4 or 
5 on the Columbia-Suicide 
Severity Ranking Score (C-
SSRS) in the past 3 months 
or at Visit 1 are exclusion 
criteria.
Prospective suicidality 
monitoring, will be 
performed throughout this
trial using the C-SSRS.
Patient’s withdrawal criteria 
in case of suicidal 
behaviouror any suicidal 
ideation of type 4 or 5 in the 
C-SSRS.


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Table 1.4.2: 1 Overview over trial related risks (cont’d)
Possible or known risks 
of clinical relevance for 
this trial
Summary of data, rationale for the 
risk
Mitigation strategy
Drug-induced liver 
injury (DILI)
Rare but severe event, standard topic 
of interest for products in 
development thus under constant 
surveillance by sponsors and 
regulators.
Timely detection, evaluation, 
and follow-up of laboratory 
alterations in selected liver 
laboratory parameters to 
ensure patients´ safety.
Increased awareness and 
expedite reporting  (AESI).
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.
HRCT
The more radiation is received over 
the course of a life, the greater risk of 
having cancerous tumors or of 
inducing changes in genes. The 
changes in genes possibly could 
cause abnormalities or disease in 
future offspring. The radiation in this 
trial is not expected to greatly 
increase these risks, but the exact 
increase in such risks is not known.
HRCT only required in case 
no historical one (less than 
12 months) is available or in 
case of insufficient quality.
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.


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Table 1.4.2: 1 Overview over trial related risks (cont’d)
Possible or known risks 
of clinical relevance for 
this trial
Summary of data, rationale for the 
risk
Mitigation strategy
Lung function 
measurements 
(Spirometry and DLCO)
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;
-
training from vendor to 
conduct correct 
manoeuvre.
Other risks
Administration of 
Placebo
If the patient is randomised to receive 
a placebo, the patient´s condition 
could get worse during the course of 
the trial.
The placebo treatment until 
Week 12 is deemed 
acceptable from an ethical 
perspective.
SARS CoV-2 infection
Based on the pharmacological 
mechanism and existing non-
clinical and clinical data there is 
no indication that treatment with 
BI 1015550 may increase the risk 
of severe clinical courses of 
SARS-COV-2 infection. 
However, patients with IPF may 
be at risk of severe clinical 
courses due to the underlying 
chronic progressing lung fibrosis, 
associated co-morbidities and 
potential use of 
immunosuppressive co-
medications.
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 (see 
section 3.3.3). In addition, 
during the course of the 
trial, treatment with BI 
1015550 will be 
discontinued in case of a 
confirmed SARS-CoV-2 
infection (refer to section 
3.3.4.1)
Discussion
1.4.3
Treatment with BI 1015550 has the potential to provide significant benefit to patients with
IPF by ultimately slowing lung function decline, improving burdensome symptoms and 
quality of life over a long term period.


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The purpose of this 12 week Phase II trial is to investigate the efficacy and safety of BI 
1015550 and provide  proof of concept of clinical activity for further progression to Phase III.
The available results of completed Phase I and Phase I C trials in HVs and IPF patients 
respectively,show a favorable safety profile  at single doses tested up to 48 mg in HVs and at 
up to 18 mg b.i.d in multiple doses tested for up to 12 weeks in IPF patients.
In this trial, the dose of 18 mg b.i.d. administered orally for 12 weeks is considered 
appropriate from both a preclinical (i.e supported by the 13 weeks toxicology data) and 
clinical point of view, consequent to the benign safety profile to date.


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2.
TRIAL OBJECTIVES AND ENDPOINTS
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS
Main objectives
2.1.1
-
To investigate the efficacy of BI 1015550 compared to placebo based on the change 
from baseline in Forced Vital Capacity (FVC).
-
To investigate safety and tolerability of BI 1015550 in the overall trial population.  
Primary endpoints
2.1.2
The primary endpoint is the change from baseline in FVC at 12 weeks (in mL).
Secondary endpoint
2.1.3
The percentage N (%) of patients with Treatment Emergent Adverse Events (TEAE).


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2.2.2.2
Safety endpoints
Safety and tolerability
Further criteria of interest to evaluate the safety and tolerability of BI 1015550:
∀Change in C-SSRS (Columbia Suicidal Severity Rating Scale) over time.
∀Change from baseline in weight over time.


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN 
This phase II trial is a double-blind, placebo-controlled comparison of BI 1015550 18 mg 
b.i.d over 12 weeks in patients treated with antifibrotic treatment or not treated with
antifibrotic treatment at baseline.
Patients randomised into the trial will be treated for 12 weeks. The patients will be included 
in the trial and during the screening period (up to 44 days), the eligibility criteria will be 
assessed. After this period, the eligible patients will be randomised in the trial in a 2:1 ratio 
(BI 1015550 18 mg b.i.d/ placebo b.i.d).
Patients will be proposed an optional substudy (restricted to some sites/countries). To 
participate, patient will be proposed to sign a dedicated informed consent. More details about 
this substudy can be found in section 5.6.
After the patients have terminated their treatment period, they will enter a 1-week follow-up 
period. Follow up visit will be the End of Trial.
In case of early treatment discontinuation, the patient is expected to follow the trial schedule 
as per protocol.
Figure 3.1:1
1305-0013 Study Design Overview
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP
At the time of writing the protocol of this trial, the 1305-0012 trial has assessed the safety of 
BI 1015550 18 mg b.i.d over 4 to 12 weeks in 15 IPF patients not on antifibrotic treatment.
This trial is a placebo-controlled randomised trial to provide the most robust results and is 
thus considered the most appropriate design. However, whilst in situations where effective 
therapies are available and a placebo-controlled trial could be considered not to be ethical, 
there is currently no approved pharmacotherapy that can finally stop the FVC decline and the 
Screening
Follow
Up
6
12
0
2
4
4
2
3
8
5
Placebo (approx. 50 pat)
BI 1015550 18 mg bid (approx.100 pat)
Week
Visit
1
Randomised 2:1
7
13


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impact on Quality of Life and premature death in these patients. In addition, none of the 
currently available treatments has shown a consistent effect on cough and dyspnea, the most 
debilitating symptoms in these patients.
A total minimum of 60 patients per group (with or without antifibrotic treatment) are 
included in this study with up to 150 patients in total with an unequal allocation ratio (1:2) 
selected for the placebo and the BI 1015550 treatment group. The usage of an unequal 
allocation ratio is explained by the incorporation of historical data from the nintedanib 
development program in IPF (via Bayesian borrowing). This approach leads to a better 
precision, while reducing the number of required patients on placebo at the same time and 
increasing the number of patients treated on BI 1015550 for the safety assessment.
A 12 weeks treatment duration is sufficient to observe differences in FVC change from 
baseline versus placebo in the patient group not on background antifibrotics. The duration is 
considered too short to assess changes from baseline in FVC versus placebo in the patient 
group on antifibrotic treatment. 12 weeks of treatment will be informative on safety and
tolerability in both treatment groups.
This is a PoC trial and the 18mg bid dose is tested in order to show PoC as this was the 
highest tested dose in 1305.12.
Details of the statistical approach including a sample size justification are given in Section 7.
FVC has been choosen as primary endpoint as this is the only clinical endpoint approved by 
authories to assess disease status and progression.
A DMC will assess safety and tolerability during the course of the trial by performing a check 
of the entire safety data on an ongoing basis.
3.3
SELECTION OF TRIAL POPULATION
A sufficient number of male and female patients with a confirmed diagnosis of IPF will be 
screened in order to ensure the randomisation of approximately 150 patients.
This trial will include IPF patients treated with SoC which includes antifibrotic treatment 
with nintedanib or pirfenidone or no background antifibrotic treatment. At least 60 patients 
on antifibrotic background treatment and 60 patients not on antifibrotic treatment will be 
included in the trial. If necessary, recruitment of one group will be stopped in order to 
achieve this. The randomisation of patients will be stratified according their antifibrotic 
treatment background status at baseline.
Only male patients and postmenopausal or surgically sterilised female patients will be 
included into the study because hitherto no data on reproductive toxicology are available.
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 


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patients for this trial. Patients in screening at this time will be allowed to continue to 
randomisation if eligible.
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.
Patients who do not meet all inclusion criteria or meet one or more exclusion criteria should
not be randomized into the trial.
If a patient was randomized in error (did not meet all inclusion criteria or met one or more
exclusion criteria on the day of randomization), the sponsor should be contacted immediately
to reach a decision on treatment discontinuation or continuous trial participation based on
individual benefit-risk assessment.
Main diagnosis for trial entry
3.3.1
Patients diagnosed with IPF and who comply with eligibility requirements may qualify for 
participation in the trial.
Please refer to section 8.3.1 (Source Documents) for the documentation requirements 
pertaining to the in- and exclusion criteria.
Inclusion criteria
3.3.2
1. Patients aged ≥40 years when signing the informed consent.
2. Diagnosis : for detailed specifications see also Appendix 10.5)
a.
IPF based on 2018 ATS/ERS/JRS/ALAT Guideline [R18-2794] as confirmed 
by the investigator based on chest HRCT scan taken within 12 months of Visit 
1 and if available surgical lung biopsy.
and
b. UIP or probable UIP HRCT pattern consistent with the clinical diagnosis of 
IPF, as confirmed by central review prior to Visit 2*
*if indeterminate HRCT finding IPF may be confirmed locally by (historical) biopsy
3. Stable for at least 8 weeks prior to Visit 1. Patients have to be either :
∀not on therapy with nintedanib or pirfenidone for at least 8 weeks prior to Visit 
1 (combination of nintedanib plus pirfenidone not allowed), or
∀on stable* therapy with nintedanib or pirfenidone for at least 8 weeks prior to 
Visit 1 and planning to stay stable on this background therapy after 
randomisation.
[*stable therapy is defined as the individually and general tolerated regimen of either pirfenidone 
or nintedanib]
4. Forced Vital Capacity (FVC) ≥45% of predicted normal at Visit 1
5. DLCO (corrected for haemoglobin [Hb] [Visit 1]) ≥ 25% to < 80% of predicted 
normal at Visit 1.


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6. Signed and dated written informed consent in accordance with ICH-GCP and local 
legislation prior to admission to the trial.
Exclusion criteria
3.3.3
1. Relevant airways obstruction (pre-bronchodilator FEV1/FVC < 0.7) at Visit 1.
2. In the opinion of the Investigator, other clinically significant pulmonary abnormalities.
3. Acute IPF exacerbation within 4 months prior to screening and/or during the screening 
period (investigator-determined).
4. Lower respiratory tract infection requiring antibiotics within 4 weeks prior to Visit 1  
and/or during the screening period.
5. Major surgery (major according to the investigator’s assessment) performed within 3 
months prior to Visit 1 or planned during the course of the trial. (Being on a transplant list 
is allowed).
6. Any documented active or suspected malignancy or history of malignancy within 5 years 
prior to Visit 1, except appropriately treated basal cell carcinoma of the skin, “under 
surveillance” prostate cancer or in situ carcinoma of uterine cervix.
7. Evidence of active infection (chronic or acute) based on clinical exam or laboratory 
findings (see table 5.2.3 :1) at Visit 1 or at Visit 2.
8. Any suicidal behaviour in the past 2 years (i.e. actual attempt, interrupted attempt, 
aborted attempt, or preparatory acts or behavior).
9. Any suicidal ideation of type 4 or 5 on the C-SSRS in the past 3 months or at Visit 1 (i.e. 
active suicidal thought with method and intent but without specific plan; or active suicidal 
thought with method, intent and plan).
10. Baseline condition or medical history of vasculitis.
11. AST or ALT > 1.5 x ULN or total Bilirubin > 1.5 x ULN at Visit 1.
12. eGFR (Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] formula or 
Japanese version of CKD-EPI for Japanese patients) ≤45 ml/min/1.73 m2 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 randomisation. 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].
13. Patients with underlying chronic liver disease (Child Pugh A, B or C hepatic impairment).
14. Cardiovascular diseases, any of the following:
a. Severe hypertension (uncontrolled under treatment ≥160/100 mmHg at multiple 
occasions) within 3 months of Visit 1
b. Myocardial infarction within 6 months of Visit 1
c. Unstable cardiac angina within 6 months of Visit 1
15. History of thrombotic event (including stroke and transient ischemic attack) within 6
months of Visit 1.
16. Surgery of the GI tract 
 (except 
appendectomy or simple hernia repair).
17. Patients who must or wish to continue the intake of restricted medications (see section 
4.2.2.1 and appendix 10.8) eg. strong CYP3A4 inhibitor, prednisone >15mg/day or any 
drug considered likely to interfere with the safe conduct of the trial


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18. Patients not expected to comply with the protocol requirements or not expected to 
complete the trial as scheduled.
19. Previous randomisation in this trial.
20. Currently enrolled in another investigational device or drug trial, or less than 30 days 
since ending another investigational device or drug trial(s), or receiving other 
investigational treatment(s).
21. In the opinion of the Investigator, active alcohol or drug abuse.
22. Inability to refrain from smoking on trial days.
23. Male patients who do not agree to minimize the risk of female partners becoming
pregnant from first dosing day until 3 months after the study completion. Acceptable 
methods of contraception comprises barrier contraception and a medically accepted 
contraceptive method for the female partner (intra-uterine device with spermicide, 
hormonal contraceptive used for at least two months prior), true sexual abstinence (when 
this is in line with the preferred and usual lifestyle of the patient), or surgically sterilized, 
including vasectomy.
24. Women who are not surgically sterilised or who are not postmenopausal, defined as at 
least 1 year of spontaneous amenorrhea (in questionable cases a blood sample with 
simultaneous levels of Follicle-stimulating hormone (FSH) above 40 U/L and estradiol
below 30 ng/L is confirmatory).
25. History of allergy or hypersensitivity or contraindications to the class of drugs under 
study including known hypersensitivity to the drug or its excipients.
26. Patients with a significant disease or condition other than IPF which in the opinion of 
theinvestigator, may put the patient at risk because of participation, interfere with study 
procedures, or cause concern regarding the patient’s ability to participate in the study or 
any medical condition which could lead to a life expectancy <12months
27. The patient has a confirmed  infection with SARS-CoV-2 within the 4 weeks prior to Visit 1 
and/or during the screening period.  
Withdrawal of patients from treatment or assessments
3.3.4
Patients may discontinue trial treatment or withdraw consent to trial participation as a whole
(“withdrawal of consent”) with very different implications; please see sections 3.3.4.1 and 
3.3.4.2 below.
Every effort should be made to keep the patients in the trial: if possible on treatment, or at 
least to collect important trial data.
Measures to control the withdrawal rate include careful patient selection, appropriate 
explanation of the trial requirements and procedures prior to trial enrolment, as well as the
explanation of the consequences of withdrawal. 
The decision to discontinue trial treatment or withdraw consent to trial participation and the 
reason must be documented in the patient files and CRF. If applicable, consider the 
requirements for Adverse Event collection reporting (please see sections 5.2.6.2.1 and 
5.2.6.2.2).


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3.3.4.1
Discontinuation of trial treatment
An individual patient will discontinue trial treatment if:
∀The patient wants to discontinue trial treatment, without the need to justify the decision.
∀The patient has repeatedly shown to be non-compliant with important trial procedures 
and, in the opinion of both, the investigator and sponsor representative, is not willing or 
able to adhere to the trial requirements in the future.
∀The patient experiences unacceptable adverse events in the opinion of the investigator.
∀The patient fulfills the AESI definition of hepatic injury (see section 5.2.6.1.6).
∀The patient experiences an infection with SARS-CoV-2. 
∀The patient needs to take concomitant medication that interferes with the investigational 
medicinal product or other trial treatment (see section 4.2.2).
∀The patient can no longer receive trial treatment for medical reasons (such as surgery, 
adverse events, other diseases, or pregnancy). The patient exhibits serious suicidality, in 
the clinical judgment of the investigator or according to the following criteria:
- any suicidal behavior (i.e. actual attempt, interrupted attempt, aborted attempt,
or preparatory acts or behaviour)
- any suicidal ideation of type 4 or 5 in the C-SSRS (i.e. active suicidal thought
with intent but without specific plan, or active suicidal thought with plan and intent)
∀The patient shows any vasculitis adverse event considered drug related or not.
∀For patients with a BMI<18,5 kg/m2 at Visit 2 only : unexplained and clinically 
significant (>10%) weight loss. 
∀The patient shows clinically relevant changes in ECG requiring intervention.
∀The patient shows a QTc>500 ms in ECG.
In case of a temporary reason, trial treatment should be restarted if medically justified, please 
see section 4.1.4.
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 the trial treatment is discontinued, the patients remain in the trial if possible and should still 
follow the trial schedule as outlined in the Flow Chart and section 6.2.3. Follow up Visit can 
be skipped in case the following Visit after the end of treatment is planned at least 7 days 
after the last drug intake.
3.3.4.2
Withdrawal of consent to trial participation
Patients may withdraw their consent to trial participation at any time without the need to 
justify the decision.
If a patient wants to withdraw consent, the investigator should be involved in the discussion 
with the patient and explain the difference between trial treatment discontinuation and 
withdrawal of consent to trial participation, as well as explain the options for continued 
follow-up after trial treatment discontinuation, please see section 3.3.4.1 above.


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3.3.4.3
Discontinuation of the trial by the sponsor
Boehringer Ingelheim reserves the right to discontinue the trial overall or at a particular trial
site at any time for the following reasons:
1. Failure to meet expected enrolment goals overall or at a particular trial site.
2. New efficacy or safety information invalidating the earlier positive benefit-risk-
assessment, please see section 3.3.4.1.
3. Deviations from GCP, the trial protocol, or the contract impairing the appropriate conduct 
of the trial.
Further follow up of patients affected will occur as described in section 3.3.4.1.
The investigator / the trial site will be reimbursed for reasonable expenses incurred in case of 
trial termination (except in case of the third reason).


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4.
TREATMENTS
4.1
INVESTIGATIONAL TREATMENTS
The investigational product has been manufactured by BI Pharma GmbH & Co. KG or a 
qualified vendor (placebo).
Identity of the Investigational Medicinal Products
4.1.1
The characteristics of the test product are given below:
Table 4.1.1:1 BI 1015550 6 mg
Substance:
BI 1015550
Pharmaceutical formulation:
film-coated tablets
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
6 mg 
Posology:
b.i.d
Mode of administration:
Oral
Table 4.1.1:2 Placebo matching BI 1015550 6 mg
Substance:
Placebo matching in size, weight, colour and shape 
to 6 mg tablet of BI 1015550
Pharmaceutical formulation:
film-coated tablets
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
n.a
Posology:
b.i.d
Method and route of administration:
Oral


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Table 4.1.1: 3
BI 1015550 12 mg
Substance:
BI 1015550
Pharmaceutical formulation:
film-coated tablets
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
12 mg
Posology:
b.i.d
Method and route of administration:
Oral
Table 4.1.1: 4 Placebo matching BI 1015550 12 mg
Substance:
Placebo matching in size, weight, colour and shape 
to 12mg tablet of BI 1015550
Pharmaceutical formulation:
film-coated tablets
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
n.a
Posology:
b.i.d
Method and route of administration:
Oral
Selection of doses in the trial and dose modifications
4.1.2
Doses equal and above 12 mg b.i.d of BI 1015550 are assumed to be effective doses based on 
pre-clinical in vitro data from human IPF fibroblast proliferation and fibroblast-to-
myofibroblast transition experiments.
These experiments showed IC50‘s of 210 – 250 nM for mono and 23–110 nM for synergistic 
action with nintedanib. Also, the clinical total coverage (at steady state) is equal or above the 
fibroblast IC50‘s, using doses equal or above 12 mg b.i.d (actual and modelled data, 
assuming that total concentrations of BI 1015550 are driving the desired effect).
This assumption is supported by clinical indirect target engagement ex vivo (LPS 
(Lipopolyssacharide)-stimulated TNF(tumor Necrosis factor)-α and IFN (interferon)-γ
release), which may not be directly linked to an anti-fibrotic action, but can be linked to an 
anti-inflammatory action on macrophages and T cells in IPF. A substantial and significant 


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indirect target engagement was shown in 1305-0011 phase I trial using 12 mg b.i.d dose and 
36 mg and 48 mg single doses.
Nintedanib, pirfenidone and BI 1015550 are effective in animal models of bleomycin induced 
lung fibrosis. Comparison of efficacious exposure levels in animals for the two marketed 
anti-fibrotics with the reached clinical exposure indicates an approx. 5-fold higher necessary 
exposure in the animal bleomycin studies.
Assuming that this 5-fold pre-clinical over-prediction is also relevant for BI 1015550 this 
leads to a predicted human efficacious dose of BI 1015550 in IPF of 12–15 mg b.i.d.
Taking together, therefore the maximum dose of 18 mg b.i.d is expected to be a therapeutic 
dose. This dose was tested in trial 1305-0012 in 15 IPF patients not on background 
antifibrotic treatment, administered for 4 to 12 weeks which was supported by the 13 weeks 
rat and minipig toxicology data.
In 1305-0012 trial, the preliminary results show geometric mean Cmax,ss and AUCτ,ss values of 
460 nM and 3720 nM∙h reached respectively for BI 1015550 within the 18 mg dose group 
with good safety and tolerability of BI 1015550 18 mg b.i.d. in 15 IPF patients not on 
background antifibrotic treatment.
In this Phase II trial (1305-0013), the exposure in IPF patients at the planned dose of 18 mg 
b.i.d is expected: 
a) to fall within range of the estimated therapeutic range and 
b) to be below the pre-defined maximal acceptable human systemic exposure limit as 
defined in trial 1305-0012 on the basis of the 13 weeks rat toxicology data.
In addition, based on the current knowledge on BI 1015550 preclinical evaluation no 
significant DDI interactions neither between BI 1015550 and nintedanib, nor between BI 
1015550 and pirfenidone are expected.
Method of assigning patients to treatment groups
4.1.3
After the assessment of all in- and exclusion criteria by the investigator and/or his/her staff, 
each eligible patient will be randomised to treatment groups according to a randomisation
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 randomisation will be stratified according the background status of the patient (either 
treated or not treated with antifibrotic treatment).
Each patient fulfilling all in- and exclusion criteria will be randomised via IRT at Visit 2 to 
one of the 2 following arms in a 2:1 ratio:
∀BI 1015550 18 mg b.i.d
∀Placebo b.i.d


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Drug assignment and administration of doses for each patient
4.1.4
The patient will be treated starting at Visit 2 for 12 weeks (until Visit 6).
Table 4.1.4: 1
Dosage and treatment schedule
Treatment arm
BI 1015550
6 mg tablet
Placebo matching 6 
mg tablet
BI 1015550
12 mg tablet
Placebo matching 
12 mg tablet
To be taken twice daily, in the morning and in the evening
18 mg
1
1
Placebo
1
1
Based on the treatment allocated at randomisation, the IRT system will be used to dispense 
the appropriate medication kits at each visit.
Medication is packaged in wallet containing 4 times 4 blisters stripes of 7 tablets each, each
containing 28 film-coated tablets so 112 films-coated tablets per wallet to cover 4 weeks 
treatment. To ensure patients receive adequate supply of study medication, kits will be 
dispensed at clinic 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
Number of 
IMP kits 
dispensed
1+1*
1
1
*: the second kit dispensed at Visit 2 is a reserve kit to cover the time windows at each visit. It will be 
brought back at each visit by the patient to calculate the compliance and then returned to the patient
unless it is empty. When less than 7 tablets left in the kit or when expiry date approaches, the site 
should perform an additional IRT call to allocate a new kit as reserve.
The patients should swallow the trial medication (“sun” column for the morning, “moon” 
column for the evening intake) together with a glass of water (~250 mL), and should observe 
a dose interval of 12 hours. 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 investigational product should only be dispensed to participating patients according to 
the protocol by authorised personnel as documented in the ISF.
During the COVID-19 pandemic, physical visits to the sites 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 the trial treatment and trial medication may be 


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shipped to the patient’s home if acceptable according to local law and regulations (for more 
details see section 6.2.2).
Blinding and procedures for unblinding
4.1.5
4.1.5.1
Blinding
Patients, investigators, central reviewers, and everyone involved in trial conduct or analysis
(except bioanalytics and possibly DMC members) or with any other interest in this double-
blind trial will remain blinded with regard to the randomised treatment assignments until after 
database lock.
The access to the randomisation code will be kept restricted until its release for analysis.
The randomisation codes will be provided to bioanalytics to allow samples from placebo 
patients to be excluded from the analyses of pharmacokinetic (PK) samples. Bioanalytics will 
not disclose the randomisation code, which patients have been tested or the results of their 
measurements until the trial is officially unblinded.
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.
Due to the requirements to report Suspected Unexpected Serious Adverse Reactions 
(SUSARs), it may be necessary for a representative from BI’s Pharmacovigilance group to 
access the randomisation code for individual patients during trial conduct. The access to the 
code will only be given to authorised Pharmacovigilance representatives for processing in the 
PV database system and not be shared further. 
Packaging, labelling, and re-supply
4.1.6
The investigational medicinal products will be provided by BI or a designated CRO. They 
will be packaged and labelled in accordance with the principles of Good Manufacturing 
Practice (GMP).
Re-supply to the sites will be managed via an IRT system, which will also monitor expiry 
dates of supplies available at the sites.
For details of packaging and the description of the label, refer to the ISF.
Storage conditions
4.1.7
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.


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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.
Drug accountability
4.1.8
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, HA / RA approval.
∀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,
∀Availability of FDA Form 1572 (if applicable).
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 
appointed CRO, the investigator or designee must verify that all unused or partially used drug 
supplies have been returned by the clinical trial patient and that no remaining supplies are in
the investigator’s possession.
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS
Other treatments and emergency procedures
4.2.1
There are no special emergency procedures to be followed.
Temporary treatment interruption for up to one week is allowed to manage adverse events
(such as GI events, need to take restricted medication etc…) will be documented on the 
respective eCRF page.
A maximum total duration of interruptions of 2 weeks is allowed.


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Restrictions
4.2.2
4.2.2.1
Restrictions regarding concomitant treatment
All concomitant or rescue therapies will be recorded (including time of intake on study days) 
on the appropriate eCRF page.
Marketed antifibrotic treatment (nintedanib or pirfenidone) is allowed at baseline when 
stabilised according to eligibility criteria and is expected to be stable throughout the trial.
Temporary antifibrotics interruption/dose reduction are left at the discretion of the investi 
gator eg to manage gastrointestinal effects.
Table 4.2.2.1:1
Restricted medication 
Medication
Prior to 
Study
Screening 
Period
Treatment 
period
Follow up 
period 
Potent CYP3A 
inhibitors
Permitted
Not 
permitted
Not permitted
Permitted
Nintedanib/Pirfeni
done if stable at 
Visit 1 (refer to 
inclusion 3)
Permitted
Permitted
Permitted
Permitted
Nintedanib/Pirfeni
done for patients 
not on antifibrotic 
treatment at Visit 1
Not 
permitted1
Not 
permitted
Not permitted
Permitted
PDE inhibitors2
Not 
permitted2
Not 
permitted
Not permitted
Not 
permitted
Prednisone>15mg/
day or equivalent
Permitted
Not 
permitted3
Not permitted4
Permitted
Footnotes to restricted medication Table 4.2.2.1:1
1. Not permitted during the 8 weeks prior to screening visit (Visit 1)
2. This covers non selective PDE inhibitors as well as PDE1, PDE3, PDE4 and PDE10 
inhibitors. Not permitted 30 days prior to randomisation (Visit 2).
3. Not permitted during the 2 weeks prior to randomisation (Visit 2).
4. Prednisone >15mg/day or equivalent can be prescribed during the treatment period in 
case of acute exacerbation as described in section 5.2.6.1.5. Table of equivalent doses 
of corticosteroids can be found in Table 10.7: 1
Lists of potent CYP3A inhibitors and PDE inhibitors can be found in Appendix 10.8.


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4.2.2.2
Restrictions on diet and life style
Patients should refrain from consuming Methylxanthine-containing drinks or foods (such as 
coffee, tea, cola, energy drinks, and chocolate) in the 24 h preceding each on site visit.
Patients should also refrain drinking grapefruit juice during the course of the trial.
4.2.2.3
Contraception requirements
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 : 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 (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 [approved in Japan], intravaginal [unapproved in Japan], 
transdermal[unapproved in Japan]).
∀Progestogen-only hormonal birth control that prevents ovulation (oral, injectable, 
implantable) [unapproved in Japan].
∀Intrauterine device (IUD) or intrauterine hormone-releasing system (IUS).
∀Bilateral tubal occlusion.
Or:
Patients must abstain from male-female sex. This is defined as being in line with the 
preferred and usual lifestyle of the patient. Periodic abstinence e.g. calendar, ovulation, 
symptothermal, post-ovulation methods; declaration of abstinence for the duration of 
exposure to study drug; and withdrawal are not acceptable.
4.3
TREATMENT COMPLIANCE
Patients are requested to bring all remaining trial medication including empty package 
material with them when attending visits.
Based on 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
FVC
5.1.1
FVC and FEV1 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.
Efforts should be made, to schedule the spirometric measurements at approximately the same 
time of the day at each visit ± 90 min , 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. 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 will be conducted while the patient is in a seated position. . It is preferable that 
the same trained individual performs the PFTs for a given patient. The best of three efforts 
will be defined as the highest FEV1 and the highest FVC each obtained on any of three blows 
meeting the ATS/ERS criteria (with a maximum of eight attempts). Spirometry results 
captured by spirometers provided by the sponsor will be electronically transmitted and 
confirmed by central reading.
DLCO
5.1.2
The site will use its own equipment to assess carbon monoxide diffusion capacity during the 
single breath diffusion test and conduct all measurements with the same equipment. Single 
breath diffusion test will be carried out according to the ATS/ERS guidelines [R06-2002].
Before the test the maneuvers should be demonstrated and the patient carefully instructed. 
The mean value between at least two acceptable tests should be reported. Please refer to 
appendix 10.3 for additional information.
For each patient, spirometry testing and DLCO should always start at approximately the same 
time of day. DLCO should always been performed after spirometry.
 
 
 
 


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5.2
ASSESSMENT OF SAFETY
Physical examination
5.2.1
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. All abnormal findings at baseline will be recorded on the 
Baseline Condition eCRF page. New abnormal findings or worsening of baseline conditions 
detected at the subsequent physical examinations, if judged clinically relevant, will be 
recorded as adverse events on the appropriate eCRF page.
Measurement of height will be performed at the time point specified in the Flow Chart.
Body weight will also be evaluated at each visit. It should be measured with the patient 
wearing indoor clothing and no shoes. For each individual patient, weight should be 
measured consistently in the morning at all visits after emptying the bladder.
The results must be included in the source documents available at the site. 
Vital signs
5.2.2
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.
Safety laboratory parameters
5.2.3
Safety laboratory parameters to be assessed are listed in Table 5.2.3.1. For the sampling time 
points please see the Flow Chart.
Analyses of most parameters will be performed by a central laboratory, the respective 
reference ranges will be provided in the ISF. ESR will be performed on-site using supplies 
provided by the central laboratory. The value for ESR will be reported directly by the site in 
the eCRF. 
Patients do not have to be fasted for the blood sampling. 
Instructions regarding sample collection, sample handling/ processing and sample shipping 
are provided in the Laboratory Manual in the ISF. 
The central laboratory will send reports to the investigator. It is the responsibility of the 
investigator to evaluate the laboratory reports. Clinically relevant abnormal findings as 
judged by the investigator will be reported as adverse events (please refer to section 5.2.6).
In case the criteria for hepatic injury are fulfilled, a number of additional measures will be 
performed (please see section 5.2.6.1 and the DILI Checklist provided in the eDC system.
The amount of blood taken from the patient concerned will be increased due to this additional 
sampling.
The central laboratory will transfer the results of the analysis to the sponsor.


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Table 5.2.3:1 
Safety laboratory tests
Functional lab group
Test name 
Haematology
Haematocrit
Haemoglobin
Red blood cell count (RBC)
Reticulocyte count
White blood cell count (WBC)
Platelet count
Erythrocyte sedimentation rate (ESR)
Automatic WBC differential 
(relative and absolute)
Neutrophils, eosinophils, basophils, monocytes, lymphocytes
Manual differential WBC (if automatic
differential WBC is abnormal)
Polymorphnuclear neutrophils (segs), band neutrophils (stabs), 
eosinophils, basophils, monocytes, lymphocytes 
Coagulation
Activated partial thromboplastin time (aPTT)
Prothrombin time (Quick’s test and INR)
Fibrinogen
Enzymes
Aspartate transaminase (AST/GOT)
Alanine transaminase (ALT/GPT)
Alkaline phosphatase (AP)
Gamma-glutamyl transferase (GGT)
Creatine kinase (CK)
CK-MB, only if CK is elevated 
Lactate dehydrogenase (LDH)
Lipase
Amylase
Hormones
Thyroid stimulating hormone (TSH)
fT3, fT4
Substrates
Plasma glucose
Creatinine 
Total bilirubin 
Direct and indirect bilirubin
Total protein
High sensitivity C-Reactive Protein (hs CRP)
Brain Natriuretic Peptide (BNP)
Uric acid 
Total cholesterol 
Triglycerides
Albumin
Electrolytes
Sodium
Potassium
Chloride
Calcium
Inorganic phosphate
Urine analysis
(semi-quantitative measurements; -, +, 
++, +++)
pH
Glucose
Erythrocytes
Leukocytes
Protein 
Nitrite 


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eGFR will be analysed and calculated by the central laboratory at the same timepoints as 
other safety laboratory parameters (see in the Flow Chart).
eGFR will be calculated by using the CKD-EPI formula (see Section 10.6) and using the 
Jaffe assay for serum creatinine measurement, IDMS standardized.
Electrocardiogram Recording
5.2.4
Twelve-lead resting ECGs (I, II, III, aVR, aVL, aVF, V1 - V6) will be recorded using a 
computerised electrocardiograph which will be provided to the sites, at the time points given 
in the Flow Chart.
In order to achieve a stable heart rate (HR) at rest and to assure high quality recordings at 
comparable resting phases, all ECGs will be recorded for 10-sec duration after the patients 
have rested for at least 10 min in a supine position. The site personnel will be instructed to 
assure a relaxed and quiet environment so that all patients are at complete rest during the 
recordings. ECG assessment will always precede all other study procedures (except PRO 
completion) of the same time point (except blood drawing from an intravenous cannula 
which is already in place) to avoid compromising the ECG quality.
Electrode placement will be performed according to the method of Wilson, Goldberger and 
Einthoven or limb leads modified by Mason and Likar (hips and shoulders instead of ankles 
and wrists). 
ECGs will be recorded as single ECGs as indicated in the Flow Chart.
ECGs may be repeated for quality reasons for instance due to alternating current artefacts, 
muscle movements, or electrode dislocation. The repeat ECGs are assigned to the respective 
scheduled time point.
Additional (unscheduled) ECGs may be recorded for safety reasons. These ECGs are 
assigned to the prior scheduled time point in the sponsor’s database. 
Data transfer
All ECGs will be transferred electronically to the central ECG lab for storage and evaluation.
In case of repeat ECGs due to quality reasons, all ECGs will be transferred to the central 
ECG lab who will select the correct one for analysis. 
Unscheduled ECGs (for safety reasons) will be transferred to the central ECG lab but will not 
be included into the statistical analysis of interval lengths.
Evaluation
a) Central ECG lab
Central ECG lab evaluation will be performed for the pre dose ECGs.
This will include the determination of cardiac QRS-axis as assessed by the ECG 
machine’s algorithm as well as the intervals RR, PR, QRS and QT measured semi-
automatically.
Heart rate (HR) and the QT interval corrected for HR (QTc e.g. QTcF and QTcB) will be 
determined by the sponsor (see TSAP for details).


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All semi-automatic interval measurements in one petient will be performed on the same 
lead. The intervals will be measured from four cardiac cycles (beats) in lead II. If lead II 
shows a flat T wave or is not measurable for any reason, lead V5 will be used, or if that 
lead is not measurable, then lead I will be used. The lead actually used will be reported in 
the Clinical Trial Report.
For automatic interval measurements no lead will be provided.
For blinding arrangements see section 4.1.5.1. No more than two blinded readers will 
evaluate all ECGs of the study. ECGs from a particular patient should be evaluated by a 
single reader. For quality assurance and control of the measurements, all ECGs of a 
patient will be subsequently reviewed by the ECG technician supervisor or his/her 
designee to assess the overall variance of the measured intervals and, to detect accidental 
switching of leads and/or false patient assignments of the ECGs. After quality control, the 
fiducial point markings will be reviewed by the cardiologist assigned to the study.
Evaluation of ECGs will comply with the ICH E14 guidance document and supplements 
[R07-4722, R16-0366] as well as the FDA requirements for annotated digital ECGs [R09-
4830].
b) Trial site
All ECGs will be evaluated by the investigator or a designee.
For the inclusion or exclusion (see section 3.3) of a patient and for the assessment of 
cardiac safety during the study, the QT and QTc values generated by the ECG machines 
or their manual corrections by the investigators will be used. In doubtful cases, ECGs 
may be sent upfront for centralised evaluation. In this case, these centrally measured 
results would overrule any other results obtained.
Abnormal findings, irrespective of whether they originate from central or local evaluation, 
will be reported as AEs (during the trial) or baseline conditions (at screening) if judged 
clinically relevant by the investigator. Any ECG abnormalities will be monitored carefully 
and, if necessary, the patient will be removed from the trial and will receive the appropriate 
medical treatment.
Suicidal risk assessed by the C-SSRS
5.2.5
For the marketed PDE4-inhibitors apremilast [R17-1539];[R17-1540] and
roflumilast [R17-1542] an increased risk of suicidality has been described. Therefore
prospective suicidality monitoring, will be performed throughout this trial using the
Columbia Suicidal Severity Rating scale (C-SSRS).
The C-SSRS is a semi-structured, investigator-rated interview, developed by clinical experts 
in cooperation with the FDA, assessing both suicidal behavior and suicidal ideation. It does 
not give a global score, but provides some categorical and some severity information 
specifically for behavior and ideation.
The C-SSRS has been widely used in large multinational clinical trials. The C-SSRS will
be administered at the screening visit (using the ‘screening’ version) with the aim to exclude 
patients suicidal ideation type 4 to5 within the preceding 3 months or at Visit 1 or any 


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suicidal behaviour in the past 2 years. The life time history of suicidal ideation and behavior 
will also be recorded.
After the screening/baseline visit the assessment ‘since last visit’ will be performed at each 
clinic visit (‘since last visit’ version).
For details on how C-SSRS will be assessed, refer to 
2.
appendix 10.
C-SSRS results will be reported in terms of AEs as described in Section 5.2.6.1.4.
Assessment of adverse events
5.2.6
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.
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 


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room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do 
not result in hospitalisation or development of dependency or abuse. 
For Japan only: the following events will be handled as “deemed serious for any other 
reason”. AEs which possibly lead to disability will be reported as SAEs.
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
Suicidal Risk assessed by the C-SSRS
All C-SSRS reports of suicidal ideation type 4 and 5 and all reports of suicidal behavior must 
be reported as separate SAEs by the investigator.
For ‘self-injurious behavior, no suicidal intent’(type 11) standard AE/SAE reporting rules are 
to be applied.
For each negative report (Suicidal ideation type 1, 2 or 3) after the start of the trial, the 
investigator is to decide based on clinical judgement whether it represents an adverse event 
(AE) as defined in the protocol, and if it is considered an AE then it must be reported 
accordingly.
5.2.6.1.5
Acute IPF exacerbations
The most recent definition of acute IPF exacerbation will be used [P16-06899]. The AEs will 
not be adjudicated. 
Acute exacerbation will be defined as an acute, clinically significant, respiratory deterioration 
characterized by evidence of new widespread alveolar abnormality with all of the following:
∀Acute worsening or development of dyspnea typically less than one month 
duration.
∀Computed tomography with new bilateral ground-glass opacity and/or 
consolidation superimposed on a background pattern consistent with IPF.
∀Deterioration not fully explained by cardiac failure or fluid overload.
This event must be reported “acute exacerbation of disease under investigation”.


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Events that are clinically considered to meet the definition of acute IPF exacerbation but fail 
to meet diagnostic criteria due to missing CT data must be reported as “suspected acute 
exacerbations of disease under investigation” (as long as this assessment persists).
5.2.6.1.6
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.
The following are considered as AESIs:
Hepatic injury
A hepatic injury is defined by the following alterations of hepatic laboratory parameters: 
∀an elevation of AST (Aspartate Aminotransferase) and/or ALT (Alanine 
Aminotransferase) ≥3 fold ULN combined with an elevation of total bilirubin ≥2 fold 
ULN measured in the same blood draw sample, or
∀aminotransferase (ALT, and/or AST) elevations ≥10 fold ULN.
These lab findings constitute a hepatic injury alert and the patients showing these lab 
abnormalities need to be followed up according to the “DILI checklist” provided via eDC.
In case of clinical symptoms of hepatic injury (icterus, unexplained encephalopathy, 
unexplained coagulopathy, right upper quadrant abdominal pain, etc.) without lab results 
(ALT, AST, total bilirubin) available, the investigator should make sure these parameters are 
analysed, if necessary in an unscheduled blood test. Should the results meet the criteria of 
hepatic injury alert, the procedures described in the DILI checklist should be followed.
Vasculitis events 
In this trial protocol vasculitis is defined as any event term included in the MedDRA SMQ 
Vasculitis (broad). This includes clinical and pathological features related to primary or 
secondary vasculitis syndromes and involving any type, size, and location of blood vessels.
5.2.6.1.7
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.
5.2.6.1.8
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-


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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.
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 


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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.
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 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.
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.


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5.6
OTHER ASSESSMENTS
One optional substudy can be proposed to the patients in case the site where he/she 
participates takes part of it. 
Participating in this substudy is totally voluntary. Not participating in will not affect the 
participation to the main study.
24 hr Cough measurement (substudy at dedicated sites only)
5.6.1
Subjects with a VAS severity ≥25 mm (on a scale of 100 mm) will be eligible for this sub-
study
Objective cough count measurements will be collected over a 24-hour period via a device 
worn by the patient at Visit 2 and Visit 6 respectively as indicated in the Flow Chart.
The device will be removed by the patient and brought back by the patient to the site at the 
next Visit.
The records will be analysed quantitatively by isolating the cough records and change from 
baseline in cough frequency over 24 hours, during night-time and awake will be described.
Detailed instructions for the 24hr Cough measurement will be provided in the ISF.
Results may be included into the clinical trial report or reported separately.
5.7
APPROPRIATENESS OF MEASUREMENTS
All measurements conducted for primary and secondary endpoints are using standard 
methods. Refer to Section 3.2 for the discussion of the choice of FVC as primary endpoint. 


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6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
The acceptable time windows for visits are given in the Flow Chart.
Study measurements and assessments scheduled to occur ‘before’ trial medication 
administration on Day 1 are to be performed and completed within a 2 h-period prior to the 
trial drug administration 
).
If several measurements including venepuncture are scheduled for the same time, 
venepuncture should be the last of the measurements due to its inconvenience to the patient 
and possible influence on physiological parameters.
 
 
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.
In exceptional cases, if standard visits at the trial sites are impossible because of COVID-19 
related safety risks, visits 3, 4, 5 and 7 may be performed at the patients’s home or remotely
via telephone and/or internet means of communication.
The visits may also be performed as a combination of home and remote visits.
All home/remote visits need to be discussed with and approved by the sponsor`s trial team. 
Local regulatory and legal requirements of the participating country 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.
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
The following sequence of procedures at each visit (where applicable) is recommended:
Timing at Visit Days
Procedures
Pre-dose
∀
 
∀
Blood sampling including predose 
 
Serum/Plasma and DNA sampling.
∀
ECG 
∀
FVC 
∀
DLCO 
∀
Time record of pre-dose blood collection.


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∀
IRT call
∀
Pre-dose or 
Post-dose
∀
∀
Physical examination including vital signs and body weight [at 
baseline only: demographics, medical history including pre-existing 
conditions]
∀
AE and concomitant therapy collection, smoking status [at baseline 
only: treatment history]
∀
C-SSRS questionnaire.
∀
∀
Treatment dispense and administration of trial drug 
 
∀
 
Screening period
6.2.1
Screening Period
After having been informed about the trial, all patients will be required to give written 
informed consent in accordance with ICH-GCP and local legislation prior to enrolment in the 
study. 
After informed consent is obtained, inclusion and exclusion criteria should be checked 
according to Flow Chart.
At selected sites performing Digital lung Auscultation substudy, patients should be invited 
during the informed consent process to participate in the respective substudy.
At selected sites performing 24hr Cough Measurement substudy, patients should be invited 
during the informed consent process to participate in the respective substudy.
Patients will be asked to give informed consent to the DNA, Plasma and Serum banking 
samples (please note: the banking samples must not be taken prior to Visit 2). Participation is 
voluntary and is not a prerequisite for participation in the trial.
 
 
For information regarding laboratory tests, ECG, vital signs, body weight and physical 
examination, refer to sections 5.2.1 to section 5.2.4.
For information on spirometry (FEV1 and FVC) and DLCO refer to section 5.1.1, 5.1.2 and 
3.
appendix 10.


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An historical HRCT can be used to determine eligibility, providing the scan was performed 
within the past 12 months prior to screening. If historical scan is not available, or an available 
scan fails to meet the required image acquisition specification, an HRCT may be performed 
after consent to determine eligibility. All HRCT scans will be sent to a central vendor for 
review and confirmation of IPF diagnosis, prior to randomisation. Confirmation of diagnosis 
must be available prior to visit 2. HRCT should not be repeated for eligibility if previous scan 
was taken within the past 3 months. To perform an HRCT within the trial, all local regulatory 
requirements to perform an HRCT have to be met.
If required, the HRCT scan should be performed as close to screening date as possible, 
preferably once eligibility is confirmed based on other parameters, to avoid unnecessary 
scans for patients who are found ineligible based on other criteria. 
Screening period may be extended for administrative reasons. Approval should be obtained 
from the sponsor who will also determine if any tests specified in the protocol must be 
repeated before the randomisation visit (Visit 2).
Treatment period
6.2.2
All patients who fullfill all inclusion criteria and none of the exclusion criteria, including 
positive HRCT review, will be randomised at Visit 2 via IRT in one of the two treatment 
arms.
At the beginning of each visit during treatment phase, investigator and site personnel should 
check the well-being of the patient as well as prepare all requirements for conduct of the 
visits that are necessary.
 
 
For information regarding laboratory tests, ECG, vital signs, body weight and physical 
examination, refer to sections 5.2.3 to section 5.2.4
Each patient will receive the first dose of BI 1015550 or placebo the morning of Visit 2 (Day 
1). Patients will take BI 1015550 18 mg (or placebo) twice daily (b.i.d) from Day 1 onwards. 
Trial medication will be taken orally. At clinic visits, trial medication will be taken under 
direct supervision of the investigator or 
 designee.
The patient will have to bring back all IMP kits, used and unused  at each on site visit, 
including Visit 3.
The patient will have to come back home with the IMP kit dispense at the corresponding visit 
in addition to the reserve kit dispense at Visit 2. 
The investigator has to check the expiry date of the reserve kit and replace it in case it expires 
before the next on site visit.
FVC has to be measured at the same time each visit ± 90 min (reference time at Visit 2).
DLCO should be done after FVC measurements. If it is done timely close to FVC 
measurement, patients should have the possibility to rest in between.


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Patients not treated with antifibrotics at Visit 1 are not allowed to start an antifibrotic 
treatment during the treatment period.
 
Visit 6 will be the End of Treatment visit. The last drug intake will occur on site during the 
visit. All IMPs kits will have to be brought back to the site at Visit 6.
Due to COVID-19 pandemic restrictions, the trial conduct may need to be adjusted and 
remote visits may be performed for Visits 3, 4, 5 and/or 7 if necessary.  
If a patient is not able to come to the site for a trial visit, a remote visit (by phone or visio 
conference application) should be performed instead. At minimum, the following assessment 
should be done: adverse events (AE, SAE, AESIs), C-SSRS, concomitant therapy, safety 
laboratory testing, trial medication compliance check. Patients can report and/or send 
photos of trial medication kit used to their site staff, if needed and possible.
If blood sampling for central lab at the trial site is not possible, safety lab analyses can be 
performed at a local lab. The results of the lab tests must be transferred to the investigator 
who ensures medical review and documents a clinically relevant safety issue as an adverse 
event. Minimum required safety lab parameters are listed in Table 6.2.2.1. 
If home visits are possible (preferable option), some assessments can be done at the patient’s 
home (e.g. collection of blood and urine samples to be sent to the central lab, vital signs).
Applicable to Visits 4, 5: If a patient is not able to come as planned but the investigator
considers it favorable and safe for the patient to continue on trial medication, the trial
medication can be shipped from site directly to the patient (if acceptable according to local
laws and regulations (see section 4.1.4). In this case, patients must consent to providing 
contact details for shipping purposes and should retain all unused IMP and packaging and 
return it when they are able to return to the site. Investigators should conduct phone visits 
first to discuss adverse events, concomitant therapies, C-SSRS, assess trial medication
compliance and have reviewed (local) safety laboratory results.


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Table 6.2.2:1 
Minimum Required Safety Lab Parameters
Functional lab group
Test name 
Haematology
Haematocrit
Haemoglobin
Red blood cell count (RBC)
Reticulocyte count
White blood cell count (WBC)
Platelet count
Erythrocyte sedimentation rate (ESR)
Coagulation
Activated partial thromboplastin time (aPTT)
Prothrombin time (Quick’s test and INR)
Fibrinogen
Enzymes
Aspartate transaminase (AST/GOT)
Alanine transaminase (ALT/GPT)
Alkaline phosphatase (AP)
Gamma-glutamyl transferase (GGT)
Creatine kinase (CK)
CK-MB, only if CK is elevated 
Lactate dehydrogenase (LDH)
Lipase
Substrates
Amylase
Creatinine 
Total bilirubin 
Total protein
High sensitivity C-Reactive Protein (hs CRP)
Albumin
Electrolytes
Sodium
Potassium
Chloride
Calcium
Inorganic phosphate
Urine analysis
(semi-quantitative measurements; -, +, 
++, +++)
pH
Glucose
Erythrocytes
Leukocytes
Protein 
Nitrite
Follow-up period and trial completion
6.2.3
A follow up period of a minimum of 7 days (+3 days) will be required. All patients will 
complete an end of trial visit. For AE assessment, laboratory tests, recording of ECG and 
vital signs, and physical examination during the end of trial period, see sections 5.2.2 to 5.2.4.
All abnormal values (including laboratory parameters) that are judged clinically relevant by 
the investigator will be monitored using the appropriate tests until a return to a medically 
acceptable level is achieved. All (S)AEs persisting after individual patient’s end of trial must 


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be followed up until they have resolved, have been assessed as “chronic” or “stable” , or no 
further information can be obtained.
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”). 
Optional substudy
6.2.4
Patients at dedicated substudy sites will be invited to optionally participate in the exploratory 
24hr cough assessment test and will give their consent by a separate patient information / 
informed consent (PI / IC).
Participation in the substudy is voluntary and not a prerequisite for participation in the main 
trial. Participation in the main trial must not be affected if a patient withdraws from substudy 
participation.
Scheduling of optional substudy procedures is specified in the Flow Chart.
Substudy information for respective sites will be provided in the ISF.


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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
The primary endpoint is the change from baseline in FVC at week 12. This endpoint will be 
evaluated separately per strata, in the patient group with antifibrotic treatment and in the 
patient group with no antifibrotic treatment. The purpose of this trial is to demonstrate proof 
of concept of clinical activity of BI 1015550 on the primary endpoint. For the proof of 
concept an evaluation of a minimum relevant additional benefit of BI 1015550 compared to 
placebo is conducted. Hereby, the posterior probability of the difference in change from 
baseline in FVC between BI 1015550 and placebo will be evaluated for different boundary 
values Δ.
Historical information for the placebo group (separately for patients treated with antifibrotic 
treatment and patients not treated with antifibrotic treatment) will be taken into account via 
the usage of a Bayesian approach with informative priors. The results in both patient groups 
will then be combined to assess if proof of concept could be shown. 
7.1
NULL AND ALTERNATIVE HYPOTHESES
No hypothesis testing will be performed in the confirmatory sense. All the analyses will be 
performed in an exploratory fashion to better understand the efficacy and safety profile of 
BI 1015550.
The primary analysis on the primary endpoint will be based on a Bayesian borrowing
approach.
7.2
PLANNED ANALYSES
General considerations
7.2.1
The following analysis sets will be defined for statistical analyses:
Entered Set (ES): This patient set includes all patients who signed informed consent. The ES 
will be used for the analysis of protocol deviations.
Randomised Set (RS): This patient set includes all entered and randomised patients. The RS 
will be used for the analyses of patient disposition.
Treated Set (TS): This patient set includes all patients who received at least one dose of study 
drug. The TS is used for safety analyses as well as demographics and baseline characteristics.
Full Analysis Set (FAS): This patient set includes all patients in the TS who had a baseline 
and at least one post-baseline measurement available for FVC, FEV1 or DLCO. Patients in 
FAS are analyzed based on the trial medication they have actually received. The FAS is the 
main analysis set for the analysis of efficacy.
Per protocol set (PPS): includes all patients from the FAS without important protocol 
deviations (IPD) leading to exclusion from PPS. The PPS is used for efficacy analyses.


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Data from patients who are screened but not randomised will be listed but not included in any
summary statistics or inferential statistics. Specifications of important protocol deviations 
leading to exclusion will be provided in the trial Integrated Quality and Risk Management 
Plan (IQRMP) and all decisions concerning IPDs will be made before un-blinding.
Further Analysis Sets will be defined in the TSAP, if needed.
Primary endpoint analyses
7.2.2
Planned analyses for primary endpoint
The main analysis for the primary endpoint will be conducted separately for patients not on 
antifibrotic treatment and for patients on antifibrotic treatment at baseline, where baseline is 
defined as data collected at visit 2 prior to administration of first dose of study medication, or 
screening data if visit 2 data are missing.
To account for the repeated nature of the data and the covariates in the model, MMRM 
analysis will be carried out for change from baseline of FVC after 12 weeks of treatment 
The adjusted mean change from baseline (and the related standard error) will be calculated 
for each group and will be used for the Bayesian borrowing approach [R16-0278], [R16-
0281].
In order to evaluate the treatment effects, historical data from the nintedanib development 
program in IPF will be included for the placebo groups in each stratum and posterior 
probabilities for the treatment difference of BI 1015550 vs. placebo with respect to the 
primary endpoint will be estimated. The median of the posterior probability (and 95% 
credible intervals) will be calculated.
The analysis will include the fixed, categorical effect of treatment at each visit, and the fixed 
continuous effects of baseline FVC at each visit. Visit will be treated as the repeated measure 
with an unstructured covariance structure used to model the within-patient measurements.
Procedures to follow if the analysis fails to converge will be described in the TSAP.
 
 
 
 
 
 


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at visit 
 
 
 
 
 
 
The primary analysis will be performed on the FAS. The primary estimand of interest is the 
treatment effect assuming all patients took randomized treatment for the duration of the trial
using a hypothetical approach, i.e. trial drug is taken as directed. The primary analysis of the 
primary endpoint will include all data collected while on treatment. Any data collected at the 
follow up will not be included in the primary analysis. The resulting missing data will be 
assumed to be missing at random (MAR). Patients will be analysed according to the stratum 
to which they belong (regardless of any mis-assignment to treatment based on identification 
of the wrong stratum), as such an error occurs before randomisation and is therefore 
consistent with regulatory guidance.
 
 
 
7.2.2.1
Prior derivation
For both placebo groups (on antifibrotics and not on antifibrotics), an informative prior will 
be used based on historical data from the nintedanib development program in IPF. 
The derivation of the informative prior is based on a meta-analytic predictive (MAP) prior 
approach, where a vaguely informative mixture component is added to the prior to obtain a 
prior which is robust against prior-data conflicts. 


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For the comparison of the BI 1015550 treatment with placebo, the posterior probability of the 
difference in change from baseline in FVC between BI 1015550 and placebo will be 
evaluated. This evaluation will be done based on the posterior probability P( BI – PBO > Δ
ml | Data) > x using predefined thresholds Δ and x.
For the primary endpoints defined in Section 2.1.2 the used estimated placebo corrected 
adjusted means and standard deviations for the prior calculation are given in Table 7.2.2.1: 1
below.
Table 7.2.2.1: 1 Estimated placebo corrected adjusted means and standard deviations
Study*
Placebo group of patients not on 
antifibrotic treatment
Placebo group of patients on 
antifibrotic treatment
N
adj. mean change from 
baseline at week 12 (SE)
N
adj. mean change from 
baseline at week 12 (SE)
1199_0032
204
-71.45 (12.53)
307
-20.13 (10.22)
1199_0034
216
-87.89 (12.23)
327
-33.10 (9.97)
1199_187P1
53
-31.79 (24.33)
53
12.97 (24.33)
1199_227
230
-72.93 (12.53)
116
-1.98 (17.48)
1199_30
85
-81.54 (24.00)
84
0.09 (24.10)
1199_222
NA
NA
51
-29.77 (25.95)
1199_0036
NA
NA
135
-25.65 (15.82)
*Based on unpublished data. Trials were reanalysed using the analysis model planned for the 
primary analysis
The estimates from Table 7.2.2.1: 1 were used to generate informative priors for the two 
placebo groups (patients on antifibrotic treatment at baseline and patients not on antifibrotic 
treatment at baseline) based on a meta-analytic predictive (MAP) prior approach, where a 
vaguely informative mixture component is added to the prior to obtain a prior which is robust 
against prior-data conflicts [R16-0281]. Thus, the prior is a mixture of informative and non-
informative beta priors and the weight of the non-informative beta prior is 50%. This prior is 
further downweighted by increasing the SD of all components by the same factor (to allow 
for the new data to have a sufficient weight). Therefore, the actual prior considered for the 
placebo group of patients not on antifibrotic treatment at baseline is (mixture normal 
distributed prior with 3 informative and 1 vaguely informative components):
 !,"#$ ~ 0.28N(−74.0, 16.1) + 0.19(−71.1, 42.2) + 0.03(−70.2, 97.8)
+ 0.5(−73.0, 315.7)
Likewise for the placebo group of patients on antifibrotic treatment at baseline the prior is 
given as
 !,#$ ~ 0.27N(−20.0, 16.2) + 0.20(−17.0, 39.8) + 0.03(−15.4, 87.7)
+ 0.5(−19.0, 385.7)


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For the BI 1015550 treatment groups with and without antifibrotic treatment at baseline 
vaguely-informative priors are generated. These two priors do not consist of a mixture of 
priors:
 01,"023 ~ N(−73.0, 315.7)
  01,023 ~ N(−19.0, 385.7)
Details for the prior calculation can be found in Appendix 10.9.
The actual prior may be updated based on additional historical information being available 
before the trial starts. The final prior will be documented in the TSAP. All analyses based on 
informative priors will be repeated with vaguely informative priors as well to ensure 
comparability with a frequentist setting.
 
.
Secondary endpoint analyses
7.2.3
The analysis of the secondary endpoint percentage N (%) of patients with Treatment 
Emergent Adverse Events (TEAE) will be described in Section 7.2.5.


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Safety analyses
7.2.5
Adverse events will be coded using the Medical Dictionary for Drug Regulatory Activities
(MedDRA). Standard BI summary tables and listings will be produced. All adverse events 
with an onset between start of treatment and end of the REP, a period of 7 days after the last 
dose of trial medication, will be assigned to the on-treatment period for evaluation.
All treated patients will be included in the safety analysis. In general, safety analyses will be 
descriptive in nature and will be based on BI standards. No hypothesis testing is planned.
Statistical analysis and reporting of adverse events will be conducted separately for the 
patients on antifibrotic treatment and the patients not on antifibrotic treatment and combined 
for the two strata.
The analysis and reporting of adverse events will concentrate on treatment-emergent adverse 
events, i.e. all adverse events occurring between start of treatment and end of the REP.
Adverse events that start before first drug intake and deteriorate under treatment will also be 
considered as ‘treatment-emergent’.
Frequency, severity, and causal relationship of adverse events will be tabulated by system 
organ class and preferred term after coding according to the current version of the Medical 
Dictionary for Drug Regulatory Activities (MedDRA) at database lock.
Laboratory data will be analysed both quantitatively as well as qualitatively. The latter will 
be done via comparison of laboratory data to their reference ranges. Values outside the 
reference range as well as values defined as clinically relevant will be summarised. Treatment 
groups will be compared descriptively with regard to distribution parameters as well as with 
regard to frequency and percentage of patients with abnormal values or clinically relevant 
abnormal values.
Vital signs, physical examinations, or other safety-relevant data observed at screening, 
baseline, during the course of the trial and at the end-of-trial evaluation will be assessed with 
regard to possible changes compared to findings before start of treatment.
Further details will be provided in the TSAP.
Other Analyses
7.2.6
7.2.6.1 Pharmacokinetic methods
In the Clinical Trial Report, plasma concentrations of BI 1015550 will be tabulated with
descriptive statistics. In case of a positive outcome of the trial, i.e. when further studies are 
initiated and the project proceeds to a next phase, a population pharmacokinetic analysis will 
be performed on BI 1015550 plasma concentrations. 
A separate Population PK Analysis Plan will be written, and results will be reported
separately.


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Interim Analyses
7.2.7
No interim analysis is planned but a Data Monitoring Committee (DMC) will be in place 
with tasks as described in section 8.7.
7.3
HANDLING OF MISSING DATA
In the primary analysis of all continuous endpoints, 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". This means e.g. patients with missing data would have behaved 
similarly to patients with observed data.
Missing or incomplete AE dates will be imputed according to BI standards. 
Handling of missing data for secondary endpoints as well as for sensitivity analysis will be 
described in the TSAP.
The handling of missing data for the Population PK Analysis is described in a separate
PopPK Analysis Plan.
7.4
RANDOMISATION
Patients will be randomised to one of the treatment arms in a 2:1 ratio (BI 1015550 18 mg / 
placebo, all b.i.d), with approximately 100 patients in the BI dose group and approximately 
50 patients in the placebo group (total maximum 150 patients). Randomisation will be 
stratified by antifibrotic treatment (patients treated with antifibrotic treatment vs patients not 
treated with antifibrotic treatment at baseline).
The Randomisation of patients to the treatment groups will be performed via an interactive 
response technology (IRT). This system will also include caps for use of antifibrotic 
treatment to ensure a certain balance required for the evaluation of the study objectives. In 
particular a minimum number of 60 patients treated with antifibrotic treatment and a 
minimum number of 60 patients not treated with antifibrotic treatment will be recruited.
BI will arrange for the randomisation and the packaging and labelling of trial medication. The 
randomisation list will be generated using a validated system, which involves a pseudo-
random number generator so that the resulting treatment will be both reproducible and non-
predictable. The block size will be documented in the Clinical Trial Report. Access to the 
codes will be controlled and documented.
7.5
DETERMINATION OF SAMPLE SIZE
This is an exploratory trial and is planned to include at least 60 patients in the group with 
antifibrotic treatment and at least 60 in the patient group with no antifibrotic treatment, from 
a total of approximately 150 patients with a 1:2 ratio between placebo and BI 1015550.
Calculations below are based on the minimum of 120 patients.


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The sample size for the patient group not treated with antifibrotic treatment is based on the 
following evaluations of the posterior probabilities (see also Table 7.5:2). Hereby also the 
posterior probabilities of the patient group on antifibrotic treatment are taken into account.
However, the expected treatment effect of BI 1015550 vs. Placebo in addition to antifibrotic 
treatment is expected to be low after 12 weeks of treatment as the expected decline in FVC is 
only 20mL at 12 weeks. Therefore, the main driver for the decision probabilities presented 
below is the group without antifibrotic treatment at baseline.
The sample size of this trial is based on evaluation of the observed treatment effects in
patients with and without antifibrotic treatment at baseline. In order to evaluate the treatment 
effects, historical data from the nintedanib development program in IPF will be included for 
the placebo groups in each stratum and posterior probabilities P( BI – PBO > 50mL | Data) 
for the treatment difference of BI 1015550 vs. placebo with respect to the primary endpoint 
will be estimated. The median of the posterior probability will be used for the assessment and 
described as observed treatment effect in the following. A stepwise approach will be used to 
assess the observed treatment effects within the strata:
1. Treatment effect within the stratum without antifibrotic treatment only:
The observed treatment effect will be compared to a certain minimum treatment effect 
ΔnAF (e.g. 50mL) in the group without antifibrotic treatment (independent of the 
observed treatment effect in the group with antifibrotic treatment)
2. Treatment effect within the stratum without antifibrotic treatment and with 
antifibrotic treatment:
In a second step, if the treatment effect observed in the group without antifibrotic 
treatment is lower than ΔnAF, but higher than another threshold ΔCnAF <= ΔnAF (e.g. 
35mL), then  the group with antifibrotic treatment will be taken into account and the 
observed treatment effect in the patient group with antifibrotic treatment will be 
compared to a certain minimum treatment effect ΔCAF (e.g. 30mL) ,see Table 7.5: 1
below for a clear definition of what a minimum effect based on the two patient groups 
means.
Table 7.5: 1
Minimum effect of BI 1015550 based on the two patients groups with 
and without antifibrotic treatment 
Change from baseline in FVC [ml] 
at week 12 in patients not on 
antifibrotic treatment
Change from baseline in 
FVC [ml] at week 12 in 
patients on antifibrotic 
treatment
Not on antifibrotics 
criterion
≥50 mL
-
Combined criterion
≥ 35 mL
≥30 mL


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The assumed sample sizes for BI 1015550 18 mg b.i.d and placebo group (in both strata on
antifibrotic treatment and without antifibrotic treatment) are 40 and 20, respectively, and 
historical information for the placebo groups (with an effective sample size of approximately 
20 for each stratum) is included via Bayesian borrowing. 
For example, if there is a true treatment difference of 70 mL in change from baseline in the 
not on antifibrotics group (assuming a disease progression of approx. -73mL over 12 weeks 
in the placebo group and a standard deviation of 200 mL in both groups) , and a true 
treatment difference of 20 mL in change from baseline in the antifibrotics group (assuming a 
disease progression of approx. -19mL over 12 weeks in the antifibrotics control group and a 
standard deviation of 200 mL in both groups), the probability is 75% to observe a treatment 
effect of > 50 mL in the not on antifibrotics group or >35 mL in the not on antifibrotics group 
combined with a treatment effect of > 30 mL in the antifibrotics group (based on the two 
criteria specified in Table 5.2.3: 1). If there is actually no true treatment difference in both 
groups, such sample size provides a chance of 89% to observe either a treatment effect of 
<35 mL in the not on antifibrotics group or <50 mL in the not on antifibrotics group 
combined with a treatment effect of <30 mL in the antifibrotics group.
The sample size calculation is conducted for several data scenarios using different effect sizes. 
The results are given in Table 7.5: 2 for a randomisation ratio of 1:2.
Table 7.5: 2
Outcome probabilities for each scenario under different settings (including 
historical information via information prior for the Pbo group) assuming a 
SD of 200 ml and 20+H/40 patients on PBO/BI 1015550
Assumed 
effect
Sizes
N in each 
stratum 
P(Outcome +#)
P(Outcome -#)
P(Outcome +/-)
Without
antifibrotics/ 
With 
antifibrotics
With/Without 
antifibrotics 
(Pbo/BI)
70mL/20mL
20+H/40
75%
11%
14%
60mL/15mL
20+H/40
65%
17%
18%
10mL/ 0mL
20+H/40
16%
60%
24%
0mL/ 0mL
20+H/40
11%
66%
23%
Numbers are each based on 10000 simulated trials for each scenario.
# Outcome +=not on antifibrotics or combined criterion are fulfilled, i.e,
∀Observed treatment effect for the not on antifibrotics group δnAF ≥50mL OR
∀Observed treatment effect for the not on antifibrotics group δnAF ≥35mL and 
observed treatment effect for the antifibrotics group δAF ≥30mL
  Outcome -= Neither of the following two conditions is fulfilled, 
∀Observed treatment effect for the not on antifibrotics group δnAF ≥35mL
∀Observed treatment effect for the antifibrotics group δAF ≥30mL   
  Outcome +/-: 
∀Observed treatment effect for the not on antifibrotics group 35mL ≤ δnAF < 50mL and 
observed treatment effect for the antifibrotics group δAF <30mL OR 


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∀Observed treatment effect for the not on antifibrotics group δnAF < 35mL and observed 
treatment effect for the antifibrotics group δAF ≥ 30mL.
+H=including historical information via informative prior (with an effective sample size of 
approximately 20).
Calculations were based on R version 3.6.1 using the RBest package.


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8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY, AND
ADMINISTRATIVE STRUCTURE
The trial will be carried out in compliance with the protocol, the ethical principles laid down 
in the Declaration of Helsinki, in accordance with the ICH Harmonized Guideline for Good 
Clinical Practice (GCP), relevant BI Standard Operating Procedures (SOPs), the EU directive 
2001/20/EC / EU regulation 536/2014, the Japanese GCP regulations (Ministry of Health and 
Welfare Ordinance No. 28, March 27, 1997) 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.
If study conduct may need to be adjusted during the COVID-19 pandemic (see Section 4.1.4
and Section 6.2), the patient must be made aware of any modifications and provide their
agreement to the modifications prior to them being implemented.
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.
Source documents
8.3.1
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 on-
site (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 


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other data pertinent to the investigation on each trial patient. Source data as well as reported 
data should follow the “ALCOA principles” and be attributable, legible, contemporaneous, 
original and accurate. Changes to the data should be traceable (audit trail).
Data reported on the CRF must be consistent with the source data or the discrepancies must 
be explained.
The current medical history of the patient may not be sufficient to confirm eligibility for the 
trial and the investigator may need to request previous medical histories and evidence of any 
diagnostic tests. In this case, the investigator must make at least one documented attempt to 
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. Before sending or uploading those copies, the investigator must ensure that 
all patient identifiers (e.g. patient’s name, initials, address, phone number, social security 
number) have properly been removed or redacted from any copy of the patients’ source 
documents.
If the patient is not compliant with the protocol, any corrective action e.g. re-training must be 
documented in the patient file.
For the 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)
∀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)
∀Patient related outcome worksheet completed by the patient and reviewed by the site.
∀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.
Direct access to source data and documents
8.3.2
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 


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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 
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.
Storage period of records
8.3.3
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.
Collection, storage and future use of biological samples and corresponding 
8.5.1
data 
Measures are in place to comply with the applicable rules for the collection, biobanking and 
future use of biological samples and clinical data, in particular
∀Sample and data usage has to be in accordance with the separate biobanking informed 
consent
∀The BI-internal facilities storing biological samples from clinical trial participants as 
well as the external banking facility are qualified for the storage of biological samples 
collected in clinical trials
∀An appropriate sample and data management system, incl. audit trail for clinical data 
and samples to identify and destroy such samples according to ICF is in place
∀A fit for the purpose documentation (biomarker proposal, analysis plan and report) 
ensures compliant usage
∀A fit for purpose approach will be used for assay/equipment validation depending on 
the intended use of the biomarker data


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∀Samples and/or data may be transferred to third parties and other countries as 
specified in the biobanking ICF
8.6
TRIAL MILESTONES
The start of the trial is defined as the date when the first patient in the whole trial signs 
informed consent.
The end of the trial is defined as the date of the last visit of the last patient in the whole trial
(“Last Patient Completed”).
The “Last Patient Last Treatment” (LPLT) date is defined as the date on which the last 
patient in the whole trial is administered the last dose of trial treatment (as scheduled per 
protocol or prematurely). Individual investigators will be notified of SUSARs occurring with 
the trial medication until 30 days after LPLT at their site. Early termination of the trial is 
defined as the premature termination of the trial due to any reason before the end of the trial
as specified in this protocol.
Temporary halt of the trial is defined as any unplanned interruption of the trial by the 
sponsor with the intention to resume it.
Suspension of the trial is defined as an interruption of the trial based on a Health Authority 
request.
The IEC / competent authority in each participating EU member state will be notified about 
the trial milestones according to the respective laws.
A final report of the clinical trial data will be written only after all patients have completed 
the trial in all countries (EU or non-EU) to incorporate and consider all data in the report.
The sponsor will submit to the EU database a summary of the final trial results within one 
year from the end of a clinical trial as a whole, regardless of the country of the last patient
(EU or non-EU).
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL
The trial is sponsored by Boehringer Ingelheim (BI).
A Coordinating Investigator is responsible to coordinate investigators at the different sites 
participating in this trial. Tasks and responsibilities are defined in a contract. 
A DMC will be established. Members of the DMC are independent of BI, they are physicians 
experienced in the treatment of the disease under investigation and a statistician. 
The DMC will evaluate the entire safety data and will meet on an ongoing basis during the 
course of the trial. The DMC can receive urgent significant safety concerns for immediate 
evaluation. While DMC members may be unblinded, measures are in place to ensure the 
blinding for everyone else involved in the trial. Regular DMC meetings will be held at 
specified intervals. The DMC will recommend continuation, modification or termination of 
the trial as detailed in the DMC charter. DMC recommendations as well as the final BI 
decision will be reported to the appropriate Regulatory Authorities (RAs)/Health Authorities 
(HAs), IRBs/ECs, and to investigators as requested by local law. The tasks and 
responsibilities of the DMC are specified in a charter.
Relevant documentation on the participating (Principal) Investigators (e.g. their curricula 
vitae) will be filed in the ISF.


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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 of participating 
countries.
The organisation of the trial in the participating countries will be performed by the respective 
local or regional BI-organisation (Operating Unit, OPU) in accordance with applicable 
regulations and BI SOPs, or by a Contract Research Organisation (CRO) with which the 
responsibilities and tasks will have been agreed and a written contract filed before initiation 
of the clinical trial.
Data Management and Statistical Evaluation will be done by BI according to BI SOPs.
Bioanalysis of BI 1015550 is done by sponsor or a delegated laboratory.
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, a central ECG review 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, Coates A, 
Crapo R, Enright P, Grinten CPM van der, Gustafsson P, Jensen R, Johnson 
DC, MacIntyre N, McKay R, Navajas D, Pedersen OF, Pellegrino R, Viegi 
G, Wanger J Standardisation of spirometry. Eur Respir J 26 (2), 319 - 338 
(2005)
P13-05880
Hassan Z, Muzaimi M, Navaratnam V, Yusoff NHM, Suhaimi FW,
Vadivelu R, Vicknasingam BK, Amato D, Hoersten S von, Ismail NIW,
Jayabalan N, Hazim AI, Mansor SM, Muller CP From Kratom to
mitragynine and its derivatives: physiological and behavioural effects
related to use, abuse, and addiction. Neurosci Biobehav Rev 37 (2), 138 -
151 (2013)
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 194 (3), 265 - 275 (2016)
R06-2002
Macintyre N, Crapo RO, Viegi G, Johnson DC, Grinten CPM van der, 
Brusasco V, Burgos F, Casaburi R, Coates A, Enright P, Gustafsson P, 
Hankinson J, Jensen R, McKay R, Miller MR, Navajas D, Pedersen OF, 
Pellegrino R, Wanger J
Standardisation of the single-breath determination of carbon monoxide 
uptake in the lung.
Eur Respir J 26 (4), 720 - 735 (2005)
R06-0533
Birring SS, Prudon B, Carr AJ, Singh SJ, Morgan MDL, Pavord ID
Development of a symptom specific health status measure for patients with 
chronic cough: Leicester Cough Questionnaire (LCQ).
Thorax 58 (4), 339 - 343 (2003)
R07-4722
Guidance for industry: E14 clinical evaluation of QT/QTc interval 
prolongation and proarrhythmic potential for non-antiarrhythmic drugs.
Rockville: U.S. Department of Health and Human Services, Food and Drug 
Administration, Center for Drug Evaluation and Research (CDER), Center 
for Biologics Evaluation and Research (CBER) (2005)
R09-4830
Brown BD, Badilini F
HL7 aECG implementation guide (March 21, 2005).
R10-1424
Pinheiro J, Bornkamp B, Bretz F. Design and analysis of dose-finding
studies combining multiple comparisons and modeling procedures. J
Biopharm Stat. 2006. 16(5): 639-656.
R14-1197
Lehmacher W, Wassmer G. Adaptive sample size calculations in group


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sequential trials. Biometrics 1999; 55:1286–1290 R14-2334 Bretz, F. , 
Koenig, F. , Brannath, W. , Glimm, E. and Posch, M. (2009),Adaptive 
designs for confirmatory clinical trials. Statist. Med., 28: 1181-1217. 
doi:10.1002/sim.3538
R15-2001
Bornkamp B, Pinheiro J, Bretz F. Package ‘DoseFinding’. Comprehensive 
R Archive Network. 19 February 2015.
R14-2284
Raghu G, Chen SY, Yeh WS, Maroni B, Li Q, Lee YC, Collard HR
Idiopathic pulmonary fibrosis in US Medicare beneficiaries aged 65 years 
and older: incidence, prevalence, and survival, 2001 - 11. Lancet Respir 
Med 2, 566 - 572 (2014)
R14-4266
Hutchinson JP, McKeever TM, Fogarty AW, Navaratnam V, Hubbard RB 
Increasing global mortality from idiopathic pulmonary fibrosis in the 21st 
century. Ann Am Thorac Soc 11 (8), 1176 - 1185 (2014)
R15-2010
Ferraz MB, Quaresma MR, Aquino LRL, Atra E, Tugwell P, Goldsmith 
CH
Reliability of pain scales in the assessment of literate and illiterate patients 
with rheumatoid arthritis. J Rheumatol 17 (8), 1022 - 1024 (1990)
R16-0278
Neuenschwander B, Capkun-Niggli G, Branson M, Spiegelhalter DJ. 
Summarizing historical information on controls in clinical trials. Clin 
Trials 7(1), 5 - 18 (2010)
R16-0281
Schmidli H, Gsteiger S, Roychoudhury S, O'Hagan A, Spiegelhalter D,
Neuenschwander B. Robust meta-analytic-predictive priors in clinical trials 
with historical control information. Biometrics 70, 1023 - 1032 (2014)
R16-0366
E14 Implementation Working Group
ICH E14 guideline: the clinical evaluation of QT/QTc interval 
prolongation and proarrhythmic potential for non-antiarrhythmic drugs: 
questions & answers (R3) (current version dated 10 December 2015).
Geneva: International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use (2015)
R16-1737
Esposito DB, Lanes S, Donneyong M, Holick CN, Lasky JA, Lederer D,
Nathan SD, O'Quinn S, Parker J, Tran TN Idiopathic pulmonary fibrosis in 
United States automated claims: incidence, prevalence, and algorithm
validation. Am J Respir Crit Care Med 192 (10), 1200 - 1207 (2015)
R17-1427
Otezla 10 mg, 20 mg, 30 mg film-coated tablets, Otezla 30 mg film-coated 
tablets (Celgene) (summary for product characteristics, manufacturer 
responsible for batch release, conditions or restrictions regarding supply 
and use, other conditions and requirements of the marketing authorisation, 
conditions or restrictions with regard to the safe and effective use of the 
medicinal product, labelling and package leaflet (first published 
16/02/2015).
R17-1539
Otezla 30mg tablets (Celgene) (summary of product characteristics updated 
05-Jan-2017).


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R17-1540
Otezla 10mg, 20mg, 30mg treatment initiation pack (Celgene) (summary 
of product characteristics updated 05-Jan-2017).
R17-1542
Daxas 500 micrograms film-coated tablets (AstraZeneca) (summary of 
product characteristics updated 06-Dec-2016).
R17-4075
Lynch DA, Sverzellati N, Travis WD, Brown KK, Colby TV, Galvin JR, et 
al Diagnostic criteria for idiopathic pulmonary fibrosis: a Fleischner 
Society White Paper. Lancet Respir Med, (2017)
R17-4284
Hutchinson J, Fogarty A, Hubbard R, McKeever T Global incidence and
mortality of idiopathic pulmonary fibrosis: a systematic review. Eur Respir 
J 46 (3), 795 - 806 (2015)
R18-0408
Raghu G, Morrow E, Collins BF, Ho LAT, Hinojosa MW, Hayes JM, et al 
Laparoscopic anti-reflux surgery for idiopathic pulmonary fibrosis at a
single centre. Eur Respir J 48, 826 - 832 (2016)
R18-1413
Strongman H, Kausar I, Maher TM Incidence, prevalence, and survival of 
patients with idiopathic pulmonary fibrosis in the UK. Adv Ther, (2018)
R18-2794
Raghu G, Remy-Jardin M, Myers JL, Richeldi L, Ryerson CJ, Lederer DJ, 
et al, American Thoracic Society, European Respiratory Society, Japanese 
Respiratory Society, Latin American Thoracic Society Diagnosis of 
idiopathic pulmonary fibrosis: an official ATS/ERS/JRS/ALAT clinical 
practice guideline. Am J Respir Crit Care Med 198 (5), e44 - e68 (2018)
9.2
UNPUBLISHED REFERENCES
c24902949-
01
Final Clinical Trial Report (1305-0015) Relative bioavailability of a single 
oral dose of BI 1015550 when administered alone or in combination with 
multiple oral doses of itraconazole in healthy male subjects.  08Feb2019
c02094779
Investigator's Brochure BI 1015550 for Idiopathic Pulmonary Fibrosis. 


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10.
APPENDICES


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10.2
COLUMBIA SUICIDAL SEVERITY RATING SCALE (C-SSRS)
The C-SSRS is a brief measure which is designed to assess severity and change of suicidality
by integrating both, behavior and ideation. The C-SSRS was designed to address the need for 
a summary measure to track change in the severity of suicidality across both clinical settings
and treatment trials.
The C-SSRS interview may be administered by any type of physician, psychologist, clinical 
social worker, mental health counsel or, nurse, or coordinator with C-SSRS training. It has a 
typical duration of five minutes, and causes only a low burden on patients. At a minimum, the 
interview consists of 2 screening questions related to suicidal ideation and 4 related to 
suicidal behavior and may be expanded to up to 17 items in case of positive responses. Free 
text entries are allowed for; the investigator has to directly evaluate the scale and write a 
report.
The investigator is to review all positive and negative reports for plausibility and clinical 
relevance. Doubtful reports may be validated by a consulting psychiatrist. If there is a 
confirmed positive report of suicidal behavior or suicidal ideation type 4 or 5 after start of 
trial, the investigator is to immediately interview the patient during the clinic visit and/or is to 
consult a psychiatrist. If the positive report is confirmed, appropriate actions for the patient’s 
safety have to be initiated.
At screening, C-SSRS (screening version) will be used with the aim to exclude patients with 
suicidal ideation type 4 to5 within the preceding 3 months or at Visit 1 or any suicidal 
behaviour in the past 2 years.
Subsequently, the C-SSRS “since last visit will be performed at the time points given in the 
Flow Chart. For assessment, paper forms will be used and results will be transcribed into the 
CRF.
All positive reports during trial treatment are treatment-emergent adverse events (AEs).
The results of further medical, including psychiatric examinations,Y should be documented 
as adverse events where appropriate.
The original Columbia Suicidal Severity Rating scales used in this trial are shown as follows:
-
Visit 1 –Screening version
-
Subsequent visits- Since last visit version.


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10.3
DLCO
At Visit 1, DLCO must fulfil the following criteria:
∀Within range 25% - 80% predicted of normal; corrected for Hb
For predicted normal values, different sites may use different prediction formulas, based on 
the method used to measure DLCO. In any case, the method used must be in compliance with 
the ATS/ERS guideline on DLCO measurements [R06-2002], and the prediction formula 


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appropriate for that method. Raw data (gas mixture, equation for the prediction of normal, 
further adjustments made if so), must be traced. 
Predicted DLCO corrected for haemoglobin (Hb) expressed in g x dL-1 [R06-2002] can be 
calculated as:
Predicted DLCO corrected for Hb = Predicted DLCO x (1.7Hb/(10.22+Hb)) for males
Predicted DLCO corrected for Hb= Predicted DLCO x (1.7Hb/(9.38+Hb)) for females
For decision on inclusion/exclusion, DLCO results from visit 1 will be corrected for 
haemoglobin (value obtained at visit 1) by the site. 
For analysis of the trial data, DLCO results will be corrected for haemoglobin by central data 
management. This means that the site has to enter the DLCO results without haemoglobin 
correction, in the eCRF, at applicable visits. 
There should be at least two acceptable tests that meet the repeatability requirement of either 
being within 3 mL CO (Standard Temperature and Pressure, Dry - STPD)•min-1 •mmHg-1 
(or 1 mmol•min-1•kPa-1) of each other or within 10% of the highest value.


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10.5
ELIGIBILITY CONFIRMATION OF IPF DIAGNOSIS
Eligible are Patients with a clinical diagnosis of IPF based on the 2018 ATS/ERS/JRS/ALAT 
Clinical Practice Guideline on the diagnosis of IPF as confirmed by the investigator based on 
chest HRCT scan taken within 12 month of Visit 1 and if available surgical lung biopsy.
All chest HRCTs will be sent for central review by an experienced expert based on the recent 
ATS/ERS/JRS/ALAT guideline on the diagnosis of IPF and Fleischner Society white paper 
[R17-4075].
Patients with a centrally reviewed HRCT pattern qualifying as UIP or probable UIP are 
eligible for participation and are not required to have a surgical lung biopsy in the appropriate 
clinical context for the diagnosis of IPF.
Patients clinically suspected to have IPF with an HRCT pattern indeterminate for UIP, or 
suggesting an alternative diagnosis require historical (ie not taken for the purpose of this trial) 
surgical lung biopsy which will be reviewed locally (by the investigator/local histo-
pathologist). In these patients, specific combinations of HRCT patterns and histopathology 
patterns may still allow a diagnosis of IPF based on the 2018 ATS/ERS/JRS/ALAT Clinical 
Practice Guideline on the diagnosis of IPF. E.g. An HRCT pattern of "indeterminate for UIP"
in combination with a surgical lung biopsy with an histopathology pattern of “UIP or 
probable UIP” could qualify for inclusion.
Appropriate documentation at site for these cases is required. Copies of the original, 
histopathological assessments and resulting diagnosis are required in patient files.
IPF suspected1
Histopathology pattern
UIP
Probable UIP
Indeterminate 
for UIP
Alternative 
diagnosis
HRCT 
pattern
UIP
IPF
IPF
IPF
Non-IPF dx
Probable UIP
IPF
IPF
IPF (Likely)2
Non-IPF dx
Indeterminate 
IPF
IPF (Likely)2
Indeterminate3
Non-IPF dx
Alternative 
diagnosis
IPF(Likely)2/non-IPF 
dx
Non-IPF dx
Non-IPF dx
Non-IPF dx
dx = diagnosis; HRCT = high-resolution computed tomography; IPF = idiopathic pulmonary fibrosis; UIP = usual interstitial 
pneumonia.       
(adapted from Figure 8 in R18-2794)
Idiopathic pulmonary fibrosis diagnosis based upon HRCT and biopsy patterns.
1 “Clinically suspected of having IPF” = unexplained symptomatic or asymptomatic patterns of bilateral pulmonary fibrosis 
   on a chest radiograph or chest computed tomography, bibasilar inspiratory crackles, and age greater than 60 years.  
   (Middle-aged adults [.40 yr and ,60 yr], especially patients with risks for familial pulmonary fibrosis, can rarely present 
   with the otherwise same clinical scenario as the typical patient older than 60 years.)
2 IPF is the likely diagnosis when any of the following features are present:


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∀
Moderate-to-severe traction bronchiectasis/bronchiolectasis (defined as mild traction 
bronchiectasis/bronchiolectasis in four or more lobes including the lingual as a lobe, or moderate to severe traction 
bronchiectasis in two or more lobes) in a man over age 50 years or in a woman over age 60 years
∀
Extensive (.30%) reticulation on HRCT and an age .70 years
∀
Increased neutrophils and/or absence of lymphocytosis in BAL fluid
∀
Multidisciplinary discussion reaches a confident diagnosis of IPF.
3 Indeterminate for IPF
∀
Without an adequate biopsy is unlikely to be IPF
∀
With an adequate biopsy may be reclassified to a more specific diagnosis after multidisciplinary discussion and/or 
additional consultation.
10.6
CREATININE CLEARANCE 
Calculation Name
GFR CKD-EPI
Formula
Units
Decimal
Places
Conventional:
Black or African American formulas:
Female with a serum creatinine value of ≤0.7 mg/dL
166 x (Serum Creatinine (mg/dL) / 0.7) -0.329 x (0.993)age
Female with a serum creatinine value of >0.7 mg/dL
166 x (Serum Creatinine (mg/dL) / 0.7) -1.209 x (0.993)age
Male with a serum creatinine value of ≤0.9 mg/dL
163 x (Serum Creatinine (mg/dL) / 0.9) -0.411 x (0.993)age
Male with a serum creatinine value of >0.9 mg/dL
163 x (Serum Creatinine (mg/dL) / 0.9) -1.209 x (0.993)age
White, American Indian, Alaska Native, Asian, Native 
Hawaiian, Other Pacific Islander, Other formulas:
Female with a serum creatinine value of ≤0.7 mg/dL
144 x (Serum Creatinine (mg/dL) / 0.7) -0.329 x (0.993)age
Female with a serum creatinine value of >0.7 mg/dL
144 x (Serum Creatinine (mg/dL) / 0.7) -1.209 x (0.993)age
Male with a serum creatinine value of ≤0.9 mg/dL
141 x (Serum Creatinine (mg/dL) / 0.9) -0.411 x (0.993)age
Male with a serum creatinine value of >0.9 mg/dL
141 x (Serum Creatinine (mg/dL) / 0.9) -1.209 x (0.993)age
Creatinine in mg/dL is rounded to 2 decimal places prior to 
applying the formula.
mL/min/
1.73m²
0
SI:
Serum creatinine in μmol/L will be rounded to zero decimal 
mL/min/
1.73m²
0


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place and converted to mg/dL by multiplying by 0.01131. This 
creatinine value in mg/dL will be rounded
to 1 decimal place. This creatinine result will be used in
the GFR Conventional formulas listed above.
Limitations/Special 
Notes:
Age is truncated to a whole number prior to performing the calculation.
Japanese formula will be used for Japanese patients.
10.7
EQUIVALENT DOSES OF CORTICOSTEROIDS
Table 10.7: 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
Fluocortalon
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
10.8
RESTRICTED MEDICATIONS TABLES
Lists of medication can be found in the sections below. The lists are not exhaustive and will 
not be updated during the course of the trial.
Investigators are advised to verify product labelling /information.
Strong CYP3A4 inhibitors
10.8.1
Strong CYP 3A4 inhibitors:
∀boceprevir
∀clarithromycin
∀cobicistat
∀conivaptan


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∀diltiazem
∀idelalisib 
∀itraconazole
∀ketoconazole oral administration
∀nefazodone
∀nelfinafir
∀posaconazole
∀ritonavir
∀telaprevir
∀troleandomycin
∀voriconazole
Combinations of CYP 3A4 inhibitors:
∀danoprevir/ritonavir
∀elvitegravir/ritonavir
∀indinavir/ritonavir
∀lopinavir/ritonavir
∀paritaprevir/ritonavir/ombitasvir/dasbuvir
∀saquinavir/ritonavir
∀tipranavir/ritonavir
Restricted PDE inhibitors
10.8.2
Compound
Indication 
Non-selective
Theophylline (Theolair, Slo-Bid, Theo 
24) 
Asthma and bronchoconstriction 
Aminophylline (Phyllocontin) 
Asthma and bronchoconstriction 
Oxtriphylline (Choledyl) 
Asthma and bronchoconstriction 
Dyphylline (inhibits PDE3, 4, 7, 
adenosine 2 receptors) (Dilor, 
Lufyllin) 
Asthma and bronchoconstriction 
Pentoxifylline (inhibits PDE4, 5, 
adenosine 2 receptors) (Trental, 
Pentoxil) 
Intermittent claudication 
Ibudilast (highest affinity for PDE10A, 
4, 11, 3) (Ketas, Pinatos, Eyevinal) 
Asthma and dizziness related to cerebral 
infarction 
Allergic conjunctivitis 


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Compound
Indication 
Tofisopam (highest affinity for PDE4, 
10, 3, 2) (Emandaxin, Grandaxin) 
Anxiety 
Dipyridamole (highest affinity for 
PDE8, 1, 3, 2, adenosine deaminase 
and ENT1) (Persantine) 
Post-operative thromboembolism 
PDE1
Vinpocetine (Cavinton) 
Cerebral vascular disorders and memory 
impairment 
PDE3
Cilostazol (Pletal, Ekistol) 
Intermittent claudication 
Milrinone (Primacor, Corotrope) 
Congestive heart failure 
Amrinone (Inamrinone, Inocor) 
Congestive heart failure 
Enoximone (Perfan) 
Congestive heart failure 
Olprinone (Coretec) 
Heart failure 
Pimobendan (Acardi) 
Heart failure 
Anagrelide (also inhibits 
phospholipase A2) (Agrylin, Xagrid) 
Thrombocythaemia 
PDE4
Roflumilast (Daliresp, Daxas) 
Chronic obstructive pulmonary disease 
Apremilast (Otezla) 
Psoriasis and psoriatic disorders 
Crisaborole (Eucrisa) 
Moderate atopic dermatitis (patients >2 
years old) 
Drotaverine (also inhibits L-type 
voltage-operated calcium channel) 
(No-Spa, Doverin) 
Functional bowel disorders; pain caused by 
smooth muscle spasm 
PDE10A
Papaverine (Pavabid, Pavagen) 
Visceral spasm, vasospasm and erectile 
dysfunction 


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10.9
PRIOR CALCULATION
Below are some further details on the informative priors for the placebo group of patients not 
on antifibrotic treatment and those on antifibrotic treatment 
Prior for the placebo group of patients not on antifibrotic treatment
The estimated adjusted means and standard errors from Table 7.2.2.1:1 were used in the 
meta-analytic predictive (MAP) prior approach using the ‘gMap’ function from the RBest 
package. The used beta prior within the gMap function was defined as mean=0 and an 
SD=189. For the between-trial heterogeneity the tau prior was defined as mean=0 and 
SD=189/4. The graphical summary of this MAP analysis can be seen in Figure 10.9:1 below.
Figure 10.9:1 MAP forest plot using the 5 historical studies.
In a next step the ‘automaxfit’ function is used to approximate the MAP prior with parametric 
density. The informative prior now consists of the following 3 components:
Component 1
Component 2
Component 3
Weight
0.5623
0.3714
0.0663
Mean
-74.0307
-71.1166
-70.2132
SD
9.4634
24.8125
57.5269


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To achieve robustness in case of prior-data conflict, a vaguely informative mixture 
component is added (Components 4 with weight=0.5, mean=-73 and SE=185.7). Finally, the 
prior is further down weighted by increasing the SD of all components by a factor of 1.7 to 
come to an effective sample size of around 20. This allows approximate 50% weight for new 
data collected in this study. The density plot of the final prior for the placebo group of 
patients not on SoC antifibrotic treatment can be found in Figure 10.9:2.
Figure 10.9:2 Density plot of the informative prior (black line) and its 4 components 
(coloured dashed lines).
The final informative prior consists of the following 4 components:
Component 1
Component 2
Component 3
Component 4
Weight
0.2811
0.1857
0.0331
0.5
Mean
-74.0307
-71.1166
-70.2132
-73
SD
16.0807
42.1812
97.7958
315.7164
Prior for the placebo group of patients on SoC antifibrotic treatment
The estimated adjusted means and standard errors from Table 7.2.2.1: 1 were used in the 
meta-analytic predictive (MAP) prior approach using the ‘gMap’ function from the RBest 
package. The used beta prior within the gMap function was defined as mean=0 and an 


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SD=186. For the between-trial heterogeneity the tau prior was defined as mean=0 and 
SD=186/4. The graphical summary of this MAP analysis can be seen in Figure 10.9:3 below.
Figure 10.9:3 MAP forest plot using the 8 historical studies.
In a next step the‘automaxfit’ function is used to approximate the MAP prior with parametric 
density using the. The informative prior now consists of the following 3 components:
Component 1
Component 2
Component 3
Weight
   0.5436
   0.3933
   0.0631
Mean
-20.0640
-17.0402
-15.4163
SD
   7.7454
  18.9645
41.7590
To achieve robustness in case of prior-data conflict, a vaguely informative mixture 
component is added (Components 4 with weight=0.5, mean=-19 and SE=183.6661). Finally, 
the prior is further down weighted by increasing the SD of all components by a factor of 2.1 
to come to an effective sample size of around 20. This allows approximately 50% weight for 
new data collected in this study. The density plot of the final prior for the placebo group of 
patients on SoC antifibrotic treatment can be found in Figure 10.9:4.


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Figure 10.9:4 Density plot of the informative prior (black line) and its 4 components 
(coloured dashed lines).
The final informative prior consists of the following 4 components:
Component 1
Component 2
Component 3
Component 4
Weight
   0.2718
  0.1966
   0.0316   
0.5
Mean
-20.0640
-17.0402
-15.4163
-19
SD
16.2653
39.8255
  87.6940
385.6988


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
11.1
GLOBAL AMENDMENT 1
Date of amendment
27 May 2020
EudraCT number
EU number
2019-004167-45
BI Trial number
1305-0013
BI Investigational Medicinal 
Product(s)
BI 1015550
Title of protocol
A randomised, double-blind, placebo-controlled 
parallel group  study in IPF patients over 12 weeks 
evaluating efficacy, safety and tolerability of BI 
1015550 taken orally.
Global Amendment due to urgent safety reasons
Global Amendment
X
Section to be changed
Title
Description of change
Dose and regimen deleted
Rationale for change
To fullfill internal rules of disclosure. No change 
of the trial design.
Section to be changed
Flowchart – footnote#11
Description of change
Clarification about DNA and serum/plasma 
biobanking samples.
Rationale for change
To correct a mistake which is already operationally 
corrected. The central laboratory builds laboratory 
kits for the trial according to this specification. To 
include the correction already described in a note 
to file prepared on 01 Apr 20. No changes to the 
procedures performed in the trial.
Section to be changed
Table 5.2.3.1
Description of change
Addition of a missing letter and deletion of a coma.
Rationale for change
Typo correction.
11.2
GLOBAL AMENDMENT 2
Date of amendment
02 Jun 2020
EudraCT number
EU number
2019-004167-45
BI Trial number
1305-0013
BI Investigational Medicinal 
Product(s)
BI 1015550
Title of protocol
A randomised, double-blind, placebo-controlled 
parallel group  study in IPF patients over 12 weeks 
evaluating efficacy, safety and tolerability of BI 


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1015550 taken orally.
Global Amendment due to urgent safety reasons
Global Amendment
X
Section to be changed
Flowchart – footnote#9
Description of change
Clarification for Germany that only historical 
HRCT can be used for the trial.
Rationale for change
To clarify this point. No change on the trial design.
Section to be changed
Section 1.4.2 – table risks
Description of change
Format change for some part which were in hidden 
text in version 1.0 :
Risks associated with blood sampling, HRCT and 
lung measurements (PFT and DLCO) were 
missing as well as risk and mitigation plan for 
placebo use.
Rationale for change
To make the whole text legible. Risks are 
described in the informed consent of the trial from 
the beginning.
Section to be changed
Section 5.2.4 – Electrocardiogram recording
Description of change
Correction of a mistake : no post dose ECG at V2 
and not triplicate ECG expected.
Rationale for change
To correct a mistake as this assessment was not
expected to be performed.
Section to be changed
Section 5.2.6.1.5 Acute IPF exacerbations.
Description of change
Precision of the term to be reported. Deletion of 
the fact that a dedicated page has to be completed 
into the eCRF.
Rationale for change
To correspond to the final design of the eCRF.
Section to be changed
Section 5.6.1 Digital lung Auscultation Test
Description of change
Less points of auscultations used and clarification 
that the results will not be reported into the clinical 
trial report.
Rationale for change
To correct a mistake.
Section to be changed
Section 5.6.2 24 hours cough measurement.
Description of change
Addition of an inclusion criteria to enter the sub
study. Clarification on the evaluations performed.


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Rationale for change
To ensure that participants to the sub study cough 
enough to be evaluated and to clarify the 
comparisons which will be performed.
Section to be changed
Section 6.2
Description of change
Deletion of the mention of a post dose ECG at 
Visit 2.
Rationale for change
To correct a mistake as this assessment was not 
planned to be performed.
11.3
GLOBAL AMENDMENT 3
Date of amendment
09 Sep 2020
EudraCT number
EU number
2019-004167-45
BI Trial number
1305-0013
BI Investigational Medicinal 
Product(s)
BI 1015550
Title of protocol
A randomised, double-blind, placebo-controlled 
parallel group  study in IPF patients over 12 weeks 
evaluating efficacy, safety and tolerability of BI 
1015550 taken orally.
Global Amendment due to urgent safety reasons
Global Amendment
X
Section to be changed
Flowchart + footnote #12, Section 3.1, Section 5.6, 
Section 5.6.1, 6.2.4
Description of change
Deletion of optional lung sound substudy
Rationale for change
This substudy will not be held because of timelines 
needed to validate the application to be used to 
record the lung sound and perform the quality 
check of the acquisition.
Section to be changed
1.2.5 Data from non-clinical studies
Description of change
Addition of information pertanining to 
histopathological changes observed during non-
clinical studies. 
Rationale for change
To have a better understanding of the toxicology 
profile of the molecule.
Section to be changed
Table 1.4.2:1 Overview of trial related risks
Description of change
Risk assessment due to COVID-19 pandemic 
situation added
Rationale for change
New information on benefit/risk due to COVID-19 


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pandemic situation.
Section to be changed
3.3 Selection of trial population 
Description of change
Clarification of wording about eligibility 
requirements and randomization. 
Rationale for change
To address a request by German Federal Institute 
for Drugs and Medical Devices (BfArM)
and leading Ethics Committee.
Section to be changed
3.3.3 Exclusion criteria
Description of change
Addition of exclision criteria #27 (exclusion of 
patients with infection with SARS-CoV-2)
Rationale for change
To exclude patients with potential additional risk 
due to SARS-CoV-2 infection.
Section to be changed
3.3.4.1 Discontinuation of trial treatment 
Description of change
Addition of criteria to discontinue patients who 
meet AESI definition of hepatic injury 
Rationale for change
Provision of additional guidance in case AESI 
definitions are fulfilled.
Section to be changed
3.3.4.1 Discontinuation of trial treatment 
Description of change
Addition of criteria to discontinue patients who 
experience infection with SARS-CoV-2 
Rationale for change
To ensure safety of patients who may become 
infected with SARS-CoV-2. 
Section to be changed
4.1.4 Drug assignment and administration of doses 
for each patient
Description of change
Information added outlining shipments direct to 
patient if required due to COVID-19 pandemic
Rationale for change
Direct shipments may be required in order to not 
interrupt treatment if a patient is not able to attend 
a visit due to COVID-19 related constraints. 
Section to be changed
5.2.3 Safety laboratory parameters
Description of change
Correction to clarfy that ESR testing will be 
performed on-site not by central lab. 
Rationale for change
Correction and clarification.  
Section to be changed
6.1 Visit schedule, 6.2.2 Treatment period, 8.1Trial 
approval, patient information, informed consent
Description of change
Specification that and how in exceptional 
circumstances (as e.g. in pandemic situations), 
when it is impossible to conduct study visits at the 
study site, study visits may be performed at 
patient’s home or remotely combined by using 
local laboratories.
Rationale for change
Experiences from the COVID-19 first wave 
situation; to allow flexibility in visit conduct in 
case required due to pandemic or other exceptional
situations to ensure patients safety by ensuring 
continuous treatment.


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Clinical Trial Protocol
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001-MCS-40-106_RD-03 (18.0) / Saved on: 10 Jul 2019
Section to be changed
7.5 Determination of sample size 
Description of change
Correction of rounding error of probabilities, and 
addition of footnote to table 7.5.2 
Rationale for change
To address a request by German Federal Institute 
for Drugs and Medical Devices (BfArM)
and leading Ethics Committee.

SAP_001.pdf: 
TITLE PAGE
TRIAL STATISTICAL ANALYSIS PLAN
c36061687-01
BI Trial No.:
1305-0013 
Title:
A randomised, double-blind, placebo-controlled parallel group 
study in IPF patients over 12 weeks evaluating efficacy, safety 
and tolerability of BI 1015550 taken orally.
(Including Protocol Amendment 1, 2, 3 [c29492723-04])
Investigational
Product(s):
BI 1015550
Responsible trial 
statistician(s):
 
Phone: 
 
Fax: 
Date of statistical 
analysis plan:
08 OCT 2021 SIGNED
Version:
1
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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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1.
TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
1.
TABLE OF CONTENTS......................................................................................2
LIST OF TABLES...................................................................................................................5
2.
LIST OF ABBREVIATIONS ..............................................................................6
3.
INTRODUCTION.................................................................................................8
4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY......................9
5.
ENDPOINTS(S) ..................................................................................................10
5.1
PRIMARY ENDPOINT(S) ................................................................................10
5.2
SECONDARY ENDPOINT(S) ..........................................................................11
5.2.1
Key secondary endpoint(s).................................................................................11
5.2.2
Secondary endpoint(s) ........................................................................................11
6.
GENERAL ANALYSIS DEFINITIONS ..........................................................16
6.1
TREATMENT(S)................................................................................................16
6.2
IMPORTANT PROTOCOL DEVIATIONS....................................................17
6.3
SUBJECT SETS ANALYSED...........................................................................18
6.5
POOLING OF CENTRES .................................................................................18
6.6
HANDLING OF MISSING DATA AND OUTLIERS....................................18
6.6.1
Withdrawals ........................................................................................................18
6.6.2
Efficacy data........................................................................................................19
6.6.2.1
Primary efficacy endpoint.....................................................................................19
6.6.3
Safety data ...........................................................................................................19
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS ...................20
7.
PLANNED ANALYSIS......................................................................................23
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS.........24
7.2
CONCOMITANT DISEASES AND MEDICATION .....................................24
7.3
TREATMENT COMPLIANCE........................................................................25
7.4
PRIMARY ENDPOINT(S) ................................................................................25
7.4.1
Primary analysis of the primary endpoint........................................................25


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7.5
SECONDARY ENDPOINT(S) ..........................................................................26
7.5.1
Key secondary endpoint(s).................................................................................26
7.5.2
Secondary endpoint(s) ........................................................................................26
 
7.7
EXTENT OF EXPOSURE.................................................................................27
7.8
SAFETY ANALYSIS..........................................................................................27
7.8.1
Adverse Events ....................................................................................................28
7.8.2
Laboratory data ..................................................................................................29
7.8.3
Vital signs.............................................................................................................30
7.8.4
ECG......................................................................................................................30
7.8.5
Others...................................................................................................................31
7.8.5.1
Physical examination incl. body weight ...............................................................31
7.8.5.2
C-SSRS category types .........................................................................................32
7.8.5.3
Time to first onset of adverse event diarrhoea......................................................32
7.9
ANALYSIS OF COVID19 IMPACT ................................................................32
7.10
HANDLING OF DMC ANALYSES .................................................................32
8.
TIMEPOINT OF RELEASE OF TREATMENT INFORMATION.............34
9. 
REFERENCES....................................................................................................35


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11.
HISTORY TABLE..............................................................................................43


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LIST OF TABLES
Table 5.1: 1
Summary of intercurrent events and handling strategy....................................10
Table 5.1: 2
Summary and description of intercurrent event handling in the analysis ........11
Table 6.1: 1
Flow chart of analysis phases...........................................................................16
Table 6.3: 1
Subject sets analysed........................................................................................18
Table 6.7: 1
Time window for assignment of efficacy, safety lab, and vital signs 
measurements to visits for statistical analysis of the double-blind treatment 
period................................................................................................................21
 
 
Table 11: 1
History table .....................................................................................................43


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2.
LIST OF ABBREVIATIONS
Term
Definition / description
AE
Adverse Event
AESI
Adverse Event of Special Interest
AF
Antifibrotic
ALT
Alanine Aminotransferase
AST
Aspartate Aminotransferase
b.i.d.
bis in die (twice daily dosing)
BI
Boehringer Ingelheim
BMI
Body Mass Index
C-SSRS
Columbia-Suicide Severity Rating Scale
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
DILI
Drug Induced Liver Injury
ECG
Electrocardiogram
ECGS
ECG set
eCRF
Electronic Case Report Form
EoT
End of Treatment
EoTrial
End of Trial
ES
Entered Set
EudraCT
European Clinical Trials Database
FAS
Full Analysis Set
FEV1
Forced Expiratory Volume in one second
FVC
Forced Vital Capacity
HR
Heart Rate
HRCT
High Resolution Computed Tomography Scan
ICH
International Council on Harmonisation
iPD
Important Protocol Deviation
IPF
Idiopathic Pulmonary Fibrosis


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LPF
Living with Pulmonary Fibrosis
MedDRA
Medical Dictionary for Drug Regulatory Activities
MMRM
Mixed effect Model Repeat Measurement
PoC
Proof of Concept
PPS
Per Protocol Set
PR interval 
ECG interval from the onset of the P wave to the beginning of the QRS 
complex
QRS duration
Combination of the Q, R, and S waves
QT interval
ECG interval from the beginning of the QRS complex to the end of the 
T wave
QTcB
QT interval, heart rate corrected using Bazett’s formula
QTcF
QT interval, heart rate corrected using Fridericia's formula
RA
Regulatory Authority
REP
Residual Effect Period
RMP
Risk Management Program
RS
Randomised Set
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SOP
Standard Operating Procedure
SUSAR
Suspected Unexpected Serious Adverse Reactions
tmax
Timepoint of Maximum Plasma Concentration
TEAE
Treatment Emergent Adverse Events
TS
Treated Set
TSAP
Trial Statistical Analysis Plan
ULN
Upper Level of Normal
UIP
usual interstitial pneumonia


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3.
INTRODUCTION
As per ICH E9 (1), the purpose of this document is to provide a more technical and detailed 
elaboration of the principal features of the analysis described in the protocol, and to include 
detailed procedures for executing the statistical analysis of the primary and secondary 
variables and other data.
This TSAP assumes familiarity with the Clinical Trial Protocol (CTP), including Protocol 
Amendments. In particular, the TSAP is based on the planned analysis specification as 
written in CTP Section 7 “Statistical Methods and Determination of Sample Size”. Therefore, 
TSAP readers may consult the CTP for more background information on the study, e.g., on 
study objectives, study design and population, treatments, definition of measurements and 
variables, planning of sample size, randomization.
The statistical analyses will be performed within the validated working environment CARE,
including SASTM (current Version 9.4, by SAS Institute Inc., Cary, NC, USA), and a 
number of SASTM-based tools (e.g., macros for the analyses of AE data or laboratory data; 
Report Appendix Generator system (RAGe) for compilation/formatting of the CTR 
appendices).
 


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4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY
All analyses as planned in the CTP will be performed and are described in more detail in this 
TSAP.
The following adaptations, which do not affect the planned analysis, have been done:
In Section 7.2.1 of the CTP the following was defined: Specifications of important protocol 
deviations leading to exclusion will be provided in the trial Integrated Quality and Risk 
Management Plan (IQRMP) and all decisions concerning IPDs will be made before un-
blinding. Due to SOP changes, the IPD categories are no longer available in the IQRM plan 
but included in an IPD specification file (2). The IPD categories originally defined in the 
IQRM plan were transferred to this IPD specification file. Minor changes regarding the IPD 
categories were performed.
The priors for placebo and BI treatment presented in Section 7.2.2.1 of the CTP have been
slightly changed in the TSAP (see Section 7.4.1) by using the same set of historical trial data, 
same R programming codes, but with an updated version of the RBesT package (v.1.6.1). 
This is an stable package version that guarantees replicability of the prior derivations.
Further binary efficacy endpoints have been added based on the relative change in FVC (mL 
and %predicted) from baseline to week 12, using cut-offs 3%, 5%, and 10%. The binary FVC 
endpoint based on 3% cut-off will be analysed by a logistic regression model.
Further ECG endpoints have been added for safety analysis, and the respective ECG set has 
been defined in the TSAP.
The Entered Set will be renamed to Enrolled Set (ES) in the CTR Tables.
It has been clarified that patients will be analyzed based on the trial medication they have 
actually received, except for the Enrolled set and Randomised set.
Time to onset of adverse event diarrhoea has been added for Safety analysis.


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5.
ENDPOINTS(S)
5.1
PRIMARY ENDPOINT(S)
Section 2.1.2 of the CTP: The primary endpoint is the change from baseline in FVC at 12 
weeks (in mL).
Section 7.2.2. of the CTP: 
The main analysis for the primary endpoint will be conducted separately for patients not on 
antifibrotic treatment and for patients on antifibrotic treatment at baseline […]
The primary estimand of interest is the treatment effect assuming all patients took 
randomized treatment for the duration of the trial using a hypothetical approach, i.e. trial 
drug is taken as directed. The primary analysis of the primary endpoint will include all data 
collected while on treatment. Any data collected at the follow up will not be included in the 
primary analysis. The resulting missing data will be assumed to be missing at random 
(MAR). Patients will be analysed according to the stratum to which they belong (regardless 
of any mis-assignment to treatment based on identification of the wrong stratum), as such an 
error occurs before randomisation and is therefore consistent with regulatory guidance.
The expected intercurrent events of interest and handling strategies in this trial are as follows:
Table 5.1: 1
Summary of intercurrent events and handling strategy
While on treatment:
Use data while on-treatment 
until week 12, and before 
occurrence of the intercurrent 
event.
Treatment policy:
Use all data collected until 
week 12, regardless of 
whether or not the intercurrent 
event occurs.
Intercurrent events
Treatment discontinuation
x
x
Start use of restricted medication, 
different from AF treatment 
(nintedanib / pirfenidone) 
x
Switch of non-AF baseline 
treatment to AF treatment
x


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Table 5.1: 2
Summary and description of intercurrent event handling in the analysis
Intercurrent event
Strategy (primary analysis)
Strategy (sensitivity analysis)
Treatment discontinuation a
use data until date of treatment 
discontinuation
include available follow-up data 
until week 12.
Start use of restricted 
medication b, different from 
AF treatment (nintedanib / 
pirfenidone)
include data after starting use of 
restricted medication.
include data after starting use of 
restricted medication.
Switch of non-AF baseline 
treatment c to AF treatment
include data after switching from 
non-AF baseline treatment to AF 
treatment. Keep patient in the non-
AF baseline stratum.
include data after switching from 
non-AF baseline treatment to AF 
treatment. Keep patient in the  non-
AF baseline stratum.
a Data of REP (7 days) after last medication intake should be included.
b Only restricted medications leading to important protocol deviations will be considered as intercurrent events.
c Wrong assignment of a patient to a AF baseline stratum is not considered an intercurrent event. In this case the 
patient will simply be re-assigned to the right stratum.
5.2
SECONDARY ENDPOINT(S)
5.2.1
Key secondary endpoint(s)
Not applicable.
5.2.2
Secondary endpoint(s)
Section 2.1.3 of the CTP: The percentage N (%) of patients with Treatment Emergent 
Adverse Events (TEAE).


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENT(S)
For basic study information on treatment to be administered, assignment of treatment groups, 
and selection of doses, refer to CTP Sections 3 and 4.  This phase II trial will be performed as 
a double-blind, placebo-controlled comparison of BI 1015550 18 mg b.i.d over 12 weeks in 
IPF patients treated with antifibrotic treatment or not treated with antifibrotic treatment at
baseline.
Eligible patients will be randomised in the trial in a 2:1 ratio (BI 1015550 18 mg b.i.d/
placebo b.i.d) and will be treated for 12 weeks. The randomization will be stratified by 
background of antifibrotic treatment. After the patients have terminated their treatment 
period, they will enter a 1-week follow-up period. Follow up visit will be the End of Trial.
It is planned to randomize a maximum of 150 patients, with at least 60 patients in each 
stratum with/without antifibrotic treatment at baseline.
Section 1.2.4 of CTP: The Residual Effect Period (REP) of BI 1015550 is 7 days. This is the 
period after the last dose with measurable drug levels and/or pharmacodynamic effects still 
likely to be present.
Section 7.2.5 of the CTP: The analysis and reporting of adverse events will concentrate on 
treatment-emergent adverse events, i.e. all adverse events occurring between start of 
treatment and end of the REP. Adverse events that start before first drug intake and 
deteriorate under treatment will also be considered as ‘treatment-emergent’.
For the analysis of adverse events (AEs), the following study phases are defined:
Table 6.1: 1
Flow chart of analysis phases
Study analysis phase
Label
Start (inclusive)
End (exclusive)
Screening
Screening
Date of informed consent
Date/time of first administration
of study drug
On-treatment
Pbo, 
18 mg BI,
respectively
Date/time of first 
administration of study drug
12:00 a.m. on the day after last 
administration of study drug + 
REP (7 days) 
or 12:00 a.m. on the day after
patient's trial termination date, 
whichever occurs earlier
Follow-up1
F/U Pbo, 
F/U 18 mg BI,
respectively
12:00 a.m. on the day after 
last administration of study 
drug + REP (7 days)
12:00 a.m. on the day after
patient's trial termination date
1 Follow-up phases might not exist, e.g. if the patient's trial termination date is within 7 days after last administration of 
BI 1015550.


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For treatment interruptions, the occurrence of AEs between the start of interruption and re-
start of treatment will be assigned to the randomized treatment. These cases will be flagged in 
the safety listings as occurring during the off-treatment period.
Reporting of AEs will be stratified by background of antifibrotic treatment and combined for
the two strata.
AEs will be displayed by study treatment (BI 18 mg b.i.d and Placebo), and will be provided
in the report:
Section 15.3 and Appendix 16.1.13.1.8 (for ClinicalTrials.gov and EudraCT) of the CTR 
displays. In addition, the total over all on-treatment phase included in this analysis (“Total”)
will be provided.
In Section 15.4 and Appendix 16.2 (Listings) of the CTR displays, screening and follow-up 
periods will be included and no totals will be provided.
Tables of vital signs, laboratory values and other safety-relevant data will present results of 
on treatment phase.
For the efficacy analyses (Section 7.4 and Section 7.6) the on treatment phase will be 
considered taking into account the intercurrent events (see Section 5.1). Efficacy endpoints 
measured later than end of treatment + REP (7 days) will be discussed at MQRM/BRPM. 
The analyses is planned to be performed once all patients have completed the study or early 
discontinued.
For detailed information on the handling of the treatments refer to Technical TSAP ADS 
(analysis data set) plan and Analysis Data Reviewers guide.
6.2
IMPORTANT PROTOCOL DEVIATIONS
Consistency check listings (for identification of violations of time windows) and a list of 
protocol deviations (e.g. deviations in drug administration, in blood sampling times, etc.) will 
be provided to be discussed at the MQRM, at the Trial Oversight Meeting prior to DBL or at 
the BRPM. At these meetings, it will be decided whether a discrepant data value can be used 
in analyses or whether it must be corrected in the clinical database. Each protocol deviation 
must be assessed to determine whether it is an important protocol deviation (iPD). For 
definition of iPDs, and for the process of identification of these, refer to "Identify and 
Manage Important Protocol Deviations (iPD) (3).
If any iPDs are identified, they are to be summarised into categories and will be captured in 
the MQRM/BRPM minutes or the TOM minutes and additionally via an accompanying Excel 
spreadsheet. The iPDs may lead to exclusion of subjects from analysis sets (e.g. the Per 
Protocol Set). The documentation of the iPD categories and how to handle iPDs in the 
analysis is included in the DV domain specifications and stored within the TMF in EDMS. If 
the data show other iPDs, this domain will be supplemented accordingly.
Non-important COVID-19 related PDs will only be listed.
A summary of iPD decisions will be provided in the decision log.


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6.3
SUBJECT SETS ANALYSED
The subject sets for statistical analysis will be used as defined in the CTP, Section 7.2.1. 
Patients will be analyzed based on the trial medication they have actually received, except for 
the ES and RS.
Additionally, the ECG set is defined.
ECG Set (ECGS): This patient set includes all patients in the TS who do not have artificial 
cardiac pacemakers and have at least one on-treatment value for at least one ECG endpoint.
Table 6.3: 1
Subject sets analysed
Patient set
Class of endpoint
ES
RS
TS
ECGS
FAS
PPS
PKS
Disposition
X
Exposure
X
IPDs
X
Demographic/baseline 
X
Primary endpoint
X
X
Secondary endpoint
X
Other safety/tolerability 
X
ECG endpoints
X
ES: Enrolled set, RS: Randomised set, TS: Treated set, ECGS: ECG set, FAS: Full analysis set, PPS: Per-protocol set,    
PKS: PK set.
6.5
POOLING OF CENTRES
This section is not applicable because centre/country is not included in the statistical model.
6.6
HANDLING OF MISSING DATA AND OUTLIERS
6.6.1
Withdrawals
The reasons for withdrawal from treatment will be reported as indicated on the eCRF.


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6.6.2
Efficacy data
6.6.2.1
Primary efficacy endpoint
Missing data for primary analysis (continuous endpoint) will not be imputed. The MMRM 
approach used for primary analysis (see Section 7.4.1) allows for missing data, assuming they 
are missing at random. 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 dropout would have behaved similarly to those who remained in 
the study. Hence, the primary analysis will be performed using the while on treatment 
strategy  (see Section 5.1).
Sensitivity analyses will be conducted to investigate the potential effect of missing data on 
the results of the primary analysis. The analysis will be performed using the treatment policy 
strategy for handling intercurrent events (see Section 5.1). 
Details about implementation into the statistical analysis are described in Section 7.4.3.
6.6.3
Safety data
Missing values of safety related data will not be imputed. The only planned imputation is 
related to AE dates, and start/stop dates of concomitant medication. 
Missing or incomplete AE dates are imputed according to BI standards (4).
Concomitant therapies: In case of (partially) missing start and end dates of concomitant 
medication, the dates will be imputed to enable subsequent calculation (but not for display) 
by the "worst case" approach, so that the extent of exposure to the concomitant therapy is 
maximal, i.e. the first day (month) of the month (year) for incomplete start dates and the last 
day (month) of the month (year) for incomplete end dates.


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ECG
If single cardiac cycles of an ECG are missing, the arithmetic mean for this single ECG will 
be computed with the reduced (1, 2 or 3) number of cardiac cycles.
If baseline is missing, a QTcF/QT interval > 500 msec at any time on treatment will be a 
notable finding.
The handling of missing values regarding the overall ECG interpretation is described in 
additional Section 10.4.2.
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
Baseline is defined as data collected at visit 2 prior to administration of first dose of study 
medication (BI 1015550 or Placebo), or screening data if visit 2 data are missing. For 
laboratory safety measurements, the last assessments / measurements taken prior to start of 
treatment will be considered as baseline.
Measurements taken after start of administration of trial treatment will be considered on-
treatment values based on the definition in Section 6.1, and will be assigned to visits for 
statistical analysis, if applicable, as defined below.
Analysis of AE data, potentially clinically significant abnormal laboratory values, 
concomitant medication or non-drug therapies, as well as use of rescue therapy will not be 
based on visits. Therefore, no assignment to time windows will be necessary for such data.
The derivation of the last value, minimum value and maximum value of laboratory and vital 
signs data will consider all on-treatment values (whether or not selected in any time window; 
see Table 6.1: 1 for definition of the on-treatment period) within the period of interest; these 
will be derived for analysis of laboratory and vital signs data. 
All other safety and efficacy measurements will be assigned to visits based on extended time 
windows around the planned visit dates, defined relative to the day of first trial treatment 
(which is scheduled for Visit 2). These extended time windows are defined in Table 6.7: 1, 
Table 6.7: 2, Table 6.7: 3.
Repeated and unscheduled efficacy and safety measurements (except for laboratory data) will 
be handled similarly to scheduled measurements and will also be assigned to a time window 
depending upon the date of measurement. For handling of laboratory measurements see also 
Section 7.8.2.
Only one observation per time window will be selected for statistical analysis at a particular 
visit. For non-PFT measurements, the value which is closest to the protocol planned visit day 
will be selected. If there are two observations which have the same difference in days to the 


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planned day, the later value will be selected. If there are two observations on the same day, 
the worst value will be selected. For PFT measurements, the scheduled PFT measurement 
that is closest to the protocol planned visit day will be selected for analysis. If a scheduled 
measurement is not available, a measurement from unscheduled visits will be selected for 
analysis (e.g. the value which is closest to the protocol planned visit day). Other rules 
mentioned for the non-PFT measurements also applies here. In addition, for ECG 
measurements, the value for analysis will be selected in the same way as for the PFT 
measurements.
Table 6.7: 1
Time window for assignment of efficacy, safety lab, and vital signs 
measurements to visits for statistical analysis of the double-blind treatment period
Visit number/ 
name
Visit 
label
Planned 
day
Time window (Days)
Window 
(per CTP)
Start
(per CTP)
End
(per CTP)
Start 
(extended)
End 
(extended)
V1/V2
Baseline
Day 1
n/a
n/a1
1
  n/a1
1
V3
Week 2
Day 15
+/- 3 
12
18
2
19
V4
Week 4
Day 29
+/- 7
22
36
20
42
V5
Week 8
Day 57
+/- 7
50
64
43
70
V6
End of Treatment
(EoT)
Week 12
Day 85
- 7/+4
78
89
71
EoTend 2
V7
End of Trial
EoT + 
1 week
EoT + 
7 days
+ 3 
EoT + 
7 days
EoT + 
10 days
EoTend + 
1 day
End of 
Trial
visit date
Days are counted relative to the day of first treatment, which is defined as Day 1.
1 Note that measurements made at Day 1 and assigned to the on-treatment period (because mistakenly made after start of 
administration of trial treatment) via assessment on date and time (i.e. safety laboratory) will not be assigned to Day 1. Such 
data will be listed only.
2 The end of time window equals:
maximum[day 89, last treatment day +1], for patients who completed the trial medication. 
maximum[day 89, End of Treatment visit day +1], for patients early discontinued from the trial medication. 


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7.
PLANNED ANALYSIS
The format of the listings and tables will follow the BI standards "Standards for reporting of 
clinical trials and project summaries" (6),
 
The individual values of all patients will be listed, sorted by antifibrotic stratum (AF/non-
AF), study treatment (placebo/BI 1015550), patient number and visit (if visit is applicable in 
the respective listing). AE listings will be sorted by antifibrotic stratum and study treatment 
(see Section 7.8.1 below for details). The listings will be contained in Appendix 16.2 of the 
CTR.
For end-of-text tables, the set of summary statistics of continuous variables (
is:
N 
number of non-missing observations
Mean 
arithmetic mean
SD 
standard deviation
Min 
minimum
Median 
median
Max 
maximum
 
 
 
 
 
Tabulations of frequencies for categorical data will include all possible categories and will 
display the number of observations in a category as well as the percentage (%). Percentages 
will be rounded to one decimal place. The category missing will be displayed if and only if 
there actually are missing values. Percentages will be based on all patients in the respective 
patient set whether they have non-missing values or not.
Units of variables should be given in the titles or column/row descriptors in square brackets 
(e.g. [mg]).


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In addition to the standard disposition tables subject enrolment and study conduct will be 
analysed relative to COVID-19 disruption.
The primary analysis will not consider country level evaluations due to small number of 
patients per participating centers and countries.
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Only descriptive statistics are planned for this section of the report, based on the TS. The data 
will be summarised by antifibrotic stratum and study treatment, and in total.
7.2
CONCOMITANT DISEASES AND MEDICATION
Only descriptive statistics are planned for this section of the CTR, based on the TS.
Concomitant diseases and concomitant non-drug therapies will be coded according to the 
most recent version of MedDRA. Concomitant medication will be coded according to the 
most recent version of the World Health Organisation – Drug Dictionary. The coding version 
number will be displayed as a footnote in the respective output.
Concomitant diseases which are present at start of the study will be descriptively summarized 
by treatment.
A medication/non-drug therapy will be considered concomitant to treatment, if it

is ongoing at the start of randomized trial treatment or

starts within the on-treatment period (see Section 6.1 for a definition of study analysis 
phases).
A medication/non-drug therapy will be considered as prior medication/non-drug therapy, if 
the end date of the medication/therapy is at any time prior to the start of randomized trial 
treatment.
Concomitant medication use will be summarized with frequency and percentage of patients 
by ATC3 class and preferred name. Summaries will be presented for concomitant medication 
starting any time prior to start of trial treatment and starting any time during the on-treatment 
period (cf. Section 6.1).
Concomitant use of non-drug therapies will be summarized with frequency and percentage. 
Summaries will be presented for concomitant non-drug therapies starting any time prior to 
start of trial treatment and starting any time during the on-treatment period (cf. Section 6.1).
Restrictions regarding concomitant treatment at the study periods are defined in Section 
4.2.2.1  of the CTP.
The relevance of the concomitant therapies to the evaluation of PK will be decided no later 
than at the BRPM.


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7.3
TREATMENT COMPLIANCE
Only descriptive statistics are planned according to percentage of patients meeting the 
compliance target, %compliance, and categories of %compliance. Descriptives will be 
provided per visits and overall (see Section 5.4.2).
7.4
PRIMARY ENDPOINT(S)
7.4.1
Primary analysis of the primary endpoint
The primary endpoint will be analysed in combination with ‘while on treatment’ strategy of 
handling intercurrent events (see Section 5.1).
Refer to Section 7.2.2 of the CTP for a description of the statistical analysis for the change 
from baseline in FVC at 12 weeks (in mL).
The adjusted mean FVC [ml] change from baseline at 12 weeks and its standard deviation 
will be obtained from MMRM for the placebo and treatment groups. The estimate of the 
placebo group will be combined with prior historical data for placebo group to derive its
respective posterior distribution. Similarly, the estimates of the BI 1015550 treatment group
will be combined with a vaguely-informative prior to derive the respective posterior 
distribution for BI 1015550 treatment group. These posterior distributions will be used to 
evaluate the posterior FVC [ml] difference change from baseline between BI treatment and 
placebo. 
SAS code for the MMRM model will be based on the following structure:
PROC MIXED DATA=alldat cl method=reml; 
  CLASS visit trt subject; 
  MODEL chg =  visit*trt base*visit / ddfm=kr s CL; 
  REPEATED visit / subject= subject type=un r rcorr; 
  LSMEANS visit*trt /pdiff=all om cl alpha=0.05 slice=visit; 
RUN;
In the event of model non-convergence, the methods described in Section 10.5 will be 
attempted (in order) to overcome it.
The prior derivations for placebo and BI treatment were obtained separately for antifibrotic 
and non-antifibrotic strata (cf. Section 7.2.2.1 of the CTP) by using RBesT package version 
1.6.1, and R Software version 4.0.1, as follows:

for the placebo group of patients (mixture normal distributed prior with 3 informative 
and 1 vaguely informative components)
o
non-antifibrotic stratum:
,	 ~0.26N(−73.8, 15.5) + 0.19(−71.7, 38.8) + 0.05(−72.5, 83.8)
+ 0.5(−73.0, 315.7)


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o
antifibrotic stratum:
,	 ~ 0.26N(−19.7, 15.7) + 0.22(−17.0, 40.2) + 0.02(−13.5, 103.4)
+ 0.5(−19.0, 385.7)

for the BI 1015550 treatment group (vaguely-informative prior, this prior does not 
consist of a mixture of priors)
o
non-antifibrotic stratum:
, ~ N(−73.0, 315.7)
o
antifibrotic stratum:
, ~ N(−19.0, 385.7)
The posterior distributions for the FVC [ml] difference in change from baseline between BI 
treatment and placebo will be implemented following derivations in additional Section 10.6. 
The posterior median and 95% credible intervals will be reported. The posterior probabilities
that the difference is higher than a range of boundary values, e.g. 0, 10, 20, 30, 35, 40, 50, 60, 
70 ml will be evaluated.
7.5
SECONDARY ENDPOINT(S)
7.5.1
Key secondary endpoint(s)
This section is not applicable as no key secondary endpoint has been specified in the 
protocol.
7.5.2
Secondary endpoint(s)
The analysis of the secondary endpoint percentage N (%) of patients with Treatment 
Emergent Adverse Events (TEAE) is described in Section 7.2.5 of the CTP.


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7.7
EXTENT OF EXPOSURE
Descriptive statistics are planned for this section of the report based on the TS. The date and 
time of each drug administration will be listed for each subject.
7.8
SAFETY ANALYSIS
All safety analyses will be performed on the TS following BI standards. No hypothesis 
testing is planned. All safety analysis will be performed on treatment phase.


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7.8.1
Adverse Events
AEs will be coded with the most recent version of MedDRA.
Statistical analysis and reporting of adverse events will be conducted separately for the 
patients on antifibrotic treatment and the patients not on antifibrotic treatment and combined 
for the two strata. 
The analyses of AEs will be descriptive in nature. All analyses of AEs will be based on the 
number of patients with AEs and not on the number of AEs.
For further details on summarization of AE data, please refer to "Analysis and presentation of 
adverse event data from Clinical Trials" (9) and "Handling of missing and incomplete AE 
dates" (4). 
The analysis of AEs will be based on the concept of treatment emergent AEs. That means 
that all AEs occurring between first drug intake till 7 days after last drug intake will be 
assigned to the randomised 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.
If only the start date of an AE is collected (without start time), any AE occurrence on the 
same day as the first BI 1015550 administration will be assigned to the on-treatment phase.
An overall summary of AEs will be presented by antifibrotic stratum and study treatment, 
and in total. This overall summary will comprise summary statistics for the class of AESIs.
CTP: The following are considered as AESIs:

Hepatic injury:
A hepatic injury is defined by the following alterations of hepatic laboratory parameters:
○
an elevation of AST (Aspartate Aminotransferase) and/or ALT (Alanine 
Aminotransferase) ≥3 fold ULN combined with an elevation of total bilirubin ≥2 fold 
ULN measured in the same blood draw sample, or
○
aminotransferase (ALT, and/or AST) elevations ≥10 fold ULN.

Vasculitis
In this trial protocol vasculitis is defined as any event term included in the MedDRA SMQ 
Vasculitis (broad).
The investigator had to classify on the eCRF whether an observed AE was an AESI or not.
Only those AEs that are indicated by the investigator as AESI in the eCRF will be analysed in 
this category.
According to ICH E3 (10), 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).


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The frequency of patients with AEs will be summarised in total, and by antifibrotic stratum, 
study treatment, primary system organ class (SOC) and preferred term (PT). Separate tables 
will be provided for patients with serious AEs, patients with Acute IPF exacerbations, 
patients with AESIs, patients with fatal AEs, patients with discontinuations due to AEs.
Separate tables will also be provided by safety topics (overall AEs, fatal AEs, and serious 
AEs), see list of safety topics in additional Section 10.9.
In addition, the patients with AEs will be summarised by treatment, worst intensity, causal 
relationship, primary system organ class (SOC) and preferred term (PT).
The SOCs and PTs will be sorted by descending frequency (within SOC). The MedDRA
version number will be displayed as a footnote in the respective output.
The frequency of patients with AEs such as Suicidal Risk (assessed by C-SSRS) or self-
injurious behavior will also be summarised. 
For disclosure of AE data on ClinicalTrials.gov, the frequency of patients with non-serious 
AEs occurring with an incidence of greater than 5 % (in preferred terms) will be summarised 
by treatment, primary system organ class and preferred term. The frequency of patients with 
SAEs will also be summarised.
For disclosure of AE data in the EudraCT register, the frequency of AEs, the frequency of 
non-serious AEs with an incidence of greater than 5 % (in preferred terms) and the frequency 
of SAEs will be summarized.
7.8.2
Laboratory data
The analyses of laboratory data will be descriptive in nature and will be based on BI 
standards "Handling, Display and Analysis of Laboratory Data" (11). Note that data from the 
central Laboratory will be used for all displays described below, unless otherwise specified.
The analysis of continuous laboratory parameters will be based on normalised values, which 
means transforming to a standard unit and to a standard reference range. The last assessment 
before the first randomized treatment at visit 2 is chosen as the baseline value.
Descriptive statistics of laboratory values over time and for the difference from baseline (see 
Section 6.7) will be based upon normalised values and provided by visit, including 
summaries of the last value on treatment, the minimum and maximum value on treatment.
Laboratory values will be compared to their reference ranges; a shift table will be provided 
for the number of patients within and outside the reference range at baseline and at the last 
measurement on treatment. This analysis will be based on standardized laboratory values.
Potentially clinically significant abnormalities will be identified based on BI standard rules 
which are based on converted values and converted reference ranges using SI lab units. These 
rules will be listed in the SDL appendix of the CTR. Frequency tables will summarize the 
number of patients with potentially clinically significant abnormalities. Patients having an 


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abnormal lab value at baseline will be presented separately. A separate listing will present 
potentially clinically significant abnormal lab values.
All individual laboratory data will be listed. Values outside the reference range will be 
flagged. In addition, potentially clinically significant values will be flagged in the listing.
To support analyses of liver related adverse drug effects, the frequency of patients with AST 
and/or ALT ≥ 3xULN combined with a total bilirubin ≥ 2xULN, and the frequency of 
patients with AST and/or ALT ≥ 10xULN, will be displayed. This analysis will be based on 
standardized laboratory values. A graphical analysis of the ALT and total bilirubin during the 
on-treatment period will also be performed; the so called eDISH plot. In the graph, for each 
subject, the peak total bilirubin is presented as a fold increase over the ULN against the peak 
ALT as a fold increase over the ULN, on a log10 scale. The measurements displayed or total 
bilirubin and ALT may, or may not, occur on the same date. Two reference lines, 2xULN for 
total bilirubin and 3xULN for ALT, are drawn onto the graph in order to divide the plane into 
four quadrants. Normal cases are in the lower left quadrant, potential DILI cases are in the 
upper right quadrant (Hy’s Law quadrant), while the lower right quadrant is known as the 
Temple’s corollary range (ALT ≥ 3xULN and total bilirubin < 2xULN).
Clinically relevant findings in laboratory data will be reported as baseline conditions (at 
screening) or as AEs (during the trial) if judged clinically relevant by the investigator, and 
will be analysed as such.
Results from the pregnancy test will only be listed.
7.8.3
Vital signs
The analyses of vital signs (blood pressure, pulse rate, and body weight) will be descriptive in 
nature. Descriptive statistics of vital signs over time and for the difference from baseline (see 
Section 6.7) will be provided.
Clinically relevant findings in vital signs data will be reported as baseline conditions (at 
screening) or as AEs (during the trial) if judged clinically relevant by the investigator, and 
will be analysed as such.
7.8.4
ECG
12-lead ECG
Abnormal findings will be reported as baseline conditions (at screening) or as AEs (during 
the trial) if judged clinically relevant by the investigator. 
The evaluation of ECG data will be based on the ECGS. The ECG analysis will be conducted 
separately for the patients on antifibrotic treatment and the patients not on antifibrotic 
treatment and combined for the two strata.


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Listing of individual data
For all quantitative endpoints, listings of individual data will be shown in Appendix 16.2. For 
QTcB and RR, only listings will be provided. Occurrences of values above thresholds (refer 
to the ECG endpoint description in Section 5.3) will be flagged.
Categorical Endpoints
For the categorical endpoints, frequency tables will be provided. Frequencies of the increases 
in QTcF and QT intervals above thresholds (refer to Section 5.3) such as 450 msec, 480 
msec, and 500 msec between baseline and on-treatment values will be displayed in two-way 
shift tables by antifibrotic strata and per treatment.  
Categorical endpoints will also include morphological findings that might be attributable to 
treatment. In particular, new onsets of findings not present at baseline will be explored. A 
morphological finding observed on treatment that was not reported at baseline will be 
categorized as a ‘new onset’ of this finding.
For all subjects with any notable finding in ECG intervals, a separate listing will be created as 
end-of-text display (based on the same display template as in Appendix 16.2), and the 
corresponding values will be presented graphically.
Patients in the TS who have notable findings but are excluded from the ECG Set will be 
listed in separate listings which will be presented in Section 15 of the CTR.
Quantitative endpoints
Descriptive statistics (N, mean, SD, min, median, max) will be provided for the absolute 
values and changes from baseline over time of QTcF, HR, QT, PR and QRS by antifibrotic 
strata, per treatment and time point. The mean and SD for the absolute values and changes 
from baseline will also be displayed graphically.
7.8.5
Others
7.8.5.1
Physical examination incl. body weight
Physical examination findings will be reported as relevant medical history/baseline condition 
(i.e., a condition already existent before intake of study drug) or as AE (if they occurred on 
treatment) and will be summarised as such. 
Special emphasis is given to body weight once at each study visit. Statistical analysis will be 
in line with the analysis applied for vital signs: Descriptive statistics including change from 
baseline and percent change from baseline will be calculated by study treatment and by 
planned time point. Time profiles of mean and SD will be provided and displayed graphically 
by study treatment. Tables and figures will be provided based on the TS. Listings of patients 
with weight loss categories <5%, 5-10%, > 10%, and any weight increase, will be provided. 


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For findings in further parameters of the physical examination, no separate listing or analysis 
will be prepared.
7.8.5.2
C-SSRS category types
All C-SSRS reports of suicidal ideation type 1, 2, 3, 4 and 5, and group type 1-3 and 4-5, will 
be summarized at each study visit. Shift tables of type 1-3 to 4-5 per visit will be provided.
7.8.5.3
Time to first onset of adverse event diarrhoea
Descriptive statistics for the time to first onset [days] of AE diarrhoea will be obtained using 
the Kaplan-Meier approach. Frequency for categories of time to onset will also be provided
with cut-off days: 31, 61, and 91. 
Number and duration of AE episodes of diarrhoea will also be presented.
7.9
ANALYSIS OF COVID19 IMPACT
There is currently an outbreak of respiratory disease, COVID-19 worldwide which has 
impacted the conduct of this trial. This public health emergency has raised more difficulties 
for patients to meet protocol-specified procedures, including administering or using the 
investigational product or adhering to protocol-mandated visits and laboratory/diagnostic 
testing. Site personnel or trial subjects are also under the risk to get infection with COVID-
19. 
Consequently, there are unavoidable protocol deviations due to COVID-19 illness and/or 
COVID-19 public and individual health control measures. To assess the impact on patients’ 
safety and drug efficacy in this trial, the following analyses are planned:
Disposition, PD and iPD:
Frequency of the patient with missing visits or early discontinuation due to COVID-19 will 
be listed. PDs and iPDs related to COVID-19 will be also listed if any. 
In addition, if there is any case, COVID-19 infection will be reported.
This study started after the COVID-19 disruption (start date chosen to be 1st March 2020). 
Therefore, evaluations of efficacy or adverse event assessments by prior versus post 
disruption are not applicable in this trial.
7.10
HANDLING OF DMC ANALYSES
An external DMC, independent of the trial and project teams, was set-up to review all 
available safety data as well as selected efficacy data in an unblinded manner at regular 
intervals following first-patient-in. A separate DMC SAP which describes the analyses 
required for assessment by the DMC was produced. Further details were provided in a DMC 
charter.


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8.
TIMEPOINT OF RELEASE OF TREATMENT 
INFORMATION
Once the last patient has completed their End-of-Treatment (EOT) visit and all corresponding 
data has been entered and cleaned to the level documented in the “Data Delivery Request” 
(DDR) form, the data will be declared ready to be unblinded via the “Data Ready to be 
Unblinded and/or Final Trial Closure Notification” (RUN) form. Then the treatment 
information will be released for analysis.
The data collection for the off-treatment residual effect period until the End-of-Study (EoS)/ 
Follow-Up visit will continue into the unblinded trial database. Once trial data collection has 
been completed and all data has been entered and cleaned as documented on the RUN form, a 
final data lock will be performed.
After the release of treatment information, it is expected that only trial data related to the off-
treatment residual effect period will be entered and changed. Therefore, after the timepoint of 
release of treatment information, all changes affecting trial data up to the End-of-Treatment 
(EoT) visit will be documented and summarized in the CTR.
The treatment information will be released to produce key efficacy and safety results at the 
time of preliminary DBL. The access to the data will not be restricted to the project and trial 
team members after preliminary DBL, and therefore no logistic and access plan is needed.


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9.
REFERENCES
1.
CPMP/ICH/363/96: "Statistical Principles for Clinical Trials", ICH Guideline Topic 
E9, Note For Guidance on Statistical Principles for Clinical Trials, current version.
2.
BI-KMED-BDS-TMP-0059: “iPD specification document (sdtm-dv-domain-
specification)”, template, current version, KMED.
3.
001-MCS-40-413: Identify and Manage Important Protocol Deviations (iPD)”, current 
version, Group “Clinical Operations”, IDEA for CON.
4.
BI-KMED-BDS-HTG-0035: “Handling of Missing and Incomplete AE Dates”, current 
version; KMED.
5.
 
6.
BI-KMED-BDS-HTG-0045: “Standards for Reporting of Clinical Trials and Project
Summaries”, current version; KMED.
7.
 
 
9.
KM Asset BI-KMED-BDS-HTG-0066: "Analysis and Presentation of Adverse Event 
Data from Clinical Trials", current version; KMED.
10.
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.
11.
BI-KMED-BDS-HTG-0042: “Handling, Display and Analysis of Laboratory Data”, 
current version; KMED.


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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
08-OCT-2021
None
This is the final TSAP