A Double Blind, Randomized, Placebo-controlled Trial Evaluating the Efficacy and Safety of BI 1015550 Over at Least 52 Weeks in Patients With Idiopathic Pulmonary Fibrosis (IPF)
Phase: PHASE3
Conditions: Idiopathic Pulmonary Fibrosis
Sponsor: Boehringer Ingelheim

001-MCS-40-106_RD-03 (20.0) / Saved on: 09 Apr 2021
Clinical Trial Protocol
TITLE PAGE
Document Number:
c39145241-04
EudraCT No.
2022-001091-34
BI Trial No.
1305-0014 (FIBRONEERTM – IPF)
BI Investigational
Medicinal Product
BI 1015550
Title
A double blind, randomized, placebo-controlled trial evaluating 
the efficacy and safety of BI 1015550 over at least 52 weeks in 
patients with Idiopathic Pulmonary Fibrosis (IPF)
Lay Title
A study to find out whether BI 1015550 improves lung function 
in people with Idiopathic Pulmonary Fibrosis (IPF)
Clinical Phase
Phase III
Clinical Trial Leader
Tel: 
, Fax:
Investigator
Phone:
, Fax:
Current Version and 
Date
Version 4.0, 20 Sep 2023
Original Protocol 
Date
Version 1.0, 13 Jun 2022
Page 1 of 149
Proprietary confidential information.
2023 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 
Original Protocol date
Latest revision date
13 Jun 2022
20 Sep 2023
BI Trial No.
1305-0014
Title of trial
A double blind, randomized, placebo-controlled trial evaluating the 
efficacy and safety of BI 1015550 over at least 52 weeks in patients 
with Idiopathic Pulmonary Fibrosis (IPF)
Investigator 
Phone: 
, Fax: 
Trial sites
Multi-centre trial conducted in approximately 400 sites and in 
45 countries
Clinical phase
Phase III
Trial rationale
The purpose of this trial is to evaluate the efficacy, safety, and 
tolerability of BI 1015550 9 mg bid and 18 mg bid compared to 
placebo in patients with IPF in addition to patient’s standard of care 
over the course of at least 52 weeks. 
New treatments with better tolerability are needed for patients with 
IPF to further reduce the decline in lung function and improve 
quality of life. Based on its anti-inflammatory and antifibrotic 
properties and the preliminary clinical evidence described, 
BI 1015550 may provide an additional treatment option to patients 
with pulmonary fibrosis irrespective of concomitant treatment with 
standard of care.
Benefit-risk assessment 
and ethical 
considerations
Patients with IPF who receive treatment with BI 1015550 have the 
potential benefit of slowing lung function decline, improving 
symptoms, and improving quality of life over a long-term period. 
The toxicology data support administration of BI 1015550 to women 
and men in the planned Phase III clinical trials in patients with IPF 
and other forms of progressive pulmonary fibrosis irrespective of 
background antifibrotic treatment, except for women who are 
pregnant or breastfeeding. 
Data from the Phase II trial 1305-0013 in patients with IPF indicated 
a beneficial treatment effect of 18 mg BI 1015550 bid, with the 
preservation of Forced Vital Capacity (FVC) over 12 weeks together 
with an acceptable safety and tolerability profile supporting further 
investigation in Phase III clinical trials as a treatment for IPF and 
other forms of progressive pulmonary fibrosis. 

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Trial objectives
The primary objective is to demonstrate a reduction in lung function 
decline as measured by the change from baseline in FVC for 
BI 1015550 when compared to placebo in patients with IPF.
The main secondary objective of the trial is to demonstrate 
BI 1015550’s ability in reducing the occurrence of clinically 
meaningful events such as acute IPF exacerbation, hospitalization 
for respiratory cause or death over the duration of the trial when 
compared to placebo in patients with IPF. An additional secondary 
objective of the trial is to show an effect of BI 1015550 on 
symptoms and lung function.
Trial endpoints
The primary endpoint is the absolute change from baseline in FVC
[mL] at Week 52.
The key secondary endpoint in this trial is time to the first 
occurrence of any of the components of the composite endpoint:time 
to first acute IPF exacerbation, first hospitalization for respiratory 
cause, or death (whichever occurs first) over the duration of the trial.
Trial design
A multi-centre, multi-national, prospective, randomized, placebo-
controlled, double blind clinical trial to investigate the efficacy and 
safety of BI 1015550 at a dose of 9 mg bid and 18 mg bid in patients 
with IPF over at least 52 weeks.
Total number of 
patients randomized
Approximately 963 patients
Number of patients per
treatment group
Approximately 321 patients in each active treatment group and in
the placebo group.
Diagnosis,
main inclusion and 
exclusion criteria
Inclusion criteria:

Patients ≥40 years old at the time of signed consent

IPF diagnosis based on 2022 ATS/ERS/JRS/ALAT Guidelines
[P22-03204]

FVC ≥45% of predicted normal 

DLCO ≥25% of predicted normal corrected for hemoglobin (Hb)

On stable treatment with nintedanib or pirfenidone for at least 
12 weeks or not on treatment with either nintedanib or 
pirfenidone for at least 8 weeks
Exclusion criteria:

Prebronchodilator FEV1/FVC <0.7

Acute IPF exacerbation within 3 months and/or during the 
screening period

Treated with immunomodulatory medications (other than oral 
corticosteroids) or prednisone >15 mg/day or equivalent for 
respiratory or pulmonary reasons

Active, unstable or uncontrolled vasculitis within 8 weeks 

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 
Trial intervention and 
test product
BI 1015550

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Dose and mode of 
administration
9 mg bid, oral
18 mg bid, oral
Comparator product
Placebo
Dose and mode of 
administration
Matching, oral
Duration of treatment
At least 52 weeks and up to approximately 130 weeks
Statistical methods
This trial’s primary objective is to demonstrate the ability of 
BI 1015550 to reduce lung function decline based on FVC between 
baseline and at Week 52 when compared to placebo.
Primary analysis for primary endpoint will be restricted maximum 
likelihood estimation based on a mixed-effect model for repeated 
measures (MMRM) analysis to compare change from baseline in 
FVC at Week 52 between treatment groups. This model will include 
discrete fixed effects for treatment at each visit, baseline intake of 
antifibrotic treatment at each visit, and continuous fixed effects for 
baseline FVC value at each visit. 
An interim analysis assessing futility of the 9 mg dose vs. placebo 
will be conducted after approximately 300 patients have reached the 
Week 12 primary endpoint assessment. If the 9 mg dose is 
considered futile, the patients will be re-assigned to the 18 mg dose.
Once the last randomized patient completes the Week-52 
assessment, the main analysis of the trial will be carried out by the 
sponsor, who will be unblinded to assess the benefit-risk of the two 
doses of BI 1015550 compared with placebo. Patients will remain on 
their randomized blinded treatment until the sponsor has reviewed 
the efficacy and safety data from the main analysis and 
communicated the end of the trial. Once this trial ends, a final
analysis based on all data will be carried out.

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FLOW CHART
Trial Periods
Screening 
Treatment Period A
Treatment Period 
B
Follow 
up
Visit
1
2
3
4
5
6
7
8
9
101
Every 
12 weeks1
EOT2
EOS17
Week 
Up 
to -8 weeks 
to -1 week*
1
2
6
12
18
26
36
44
52
Day
1
15
43
85
127
183
253
309
365
EOT +7d
Time window
(days)
±3d
±7d
±7d
±7d
±7d
±7d
±7d
±7d
±14d
+3d
Informed consent 
X
Demographics
X
Review of 
eligibility criteria
X
X
Medical history
X
Smoking Status
X
L-PF 
(symptoms/impact)3
X
X
X
X
X
X
X
X
EQ-5D3
X
X
X
X
X
X
X
X
X
X
HADS3
X
X
X
X
X
X
X
X
X
PGIS3
X
X
X
X
X
X
X
X
C-SSRS4
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical 
examination
X
X
X
X
X
X
X
X
X
X
X
X
X
Height
X
Weight
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital signs5
X
X
X
X
X
X
X
X
X
X
X
X
X
SpO2
X
X
X
X
X
12-lead ECG
X
X
X
X
Chest HRCT
central Review6
X
Spirometry7
X
X
X
X
X
X
X
X
X
X
X
X
X
Optional home 
spirometry8
X
X
X
X
X
X
X
DLCO
X
X
X
X
X
X
Laboratory test9
X
X
X
X
X
X
X
X
X
X
X
Vasculitis 
biomarkers
storage10
X
X
Pregnancy test11
X
X
X
X
X
X
X
X
X
X
X
X
X
Infection testing12
X
X
X
PK Sampling13
X
X
X
X
ILD biomarkers 
sampling
X
X
X
X
X
X14
DNA Banking 
(optional)15
X
Serum/Plasma
Banking
(optional)15
X
X
X
X
Health Care 
resource Utilization
X
X
X
X
X
X
X
X
X
X
X
All AEs/SAEs/
AESIs16
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant 
therapy
X
X
X
X
X
X
X
X
X
X
X
X
X
Dispense trial drug
X
X
X
X
X
X
X
X
X
IRT 
Call/Notification
X
X
X
X
X
X
X
X
X
X
X

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Trial Periods
Screening 
Treatment Period A
Treatment Period 
B
Follow 
up
Administer trial 
drugs
X
X
X
X
X
X
X
X
X
X
X
Return trial drug
X
X
X
X
X
X
X
X
X
X
Compliance check
X
X
X
X
X
X
X
X
X
X
Completion of 
patient participation
X17
X
Vital status data18
X
X
*
Screening may be extended up to 12 weeks to account for possible missing eligibility results, administrative, or 
organisational reason.
(1)
Following completion of V10 patients will continue to have study visits every 12 weeks until the start of EoT visits 
is announced. The global study will be completed after all patients have performed the EoT visit and the EoS visit 
(if not continuing in the separate extension trial).
(2)
In case of premature discontinuation of trial medication, the EOT visit should only be done if the discontinuation is 
permanent, and a Follow-up (FU) visit is to be performed 7 days (+3 days) after end of treatment. If a patient 
discontinued the trial medication more than a week prior to the EOT visit, this FU visit is not required. A 
scheduled visit may be missed if EOT or FU visit occurs within 4 weeks prior to scheduled visits. After the 
premature EOT, every effort should be made to collect data until the end of the trial.
(3) 
Patient-reported outcomes collected either on paper questionnaires or as ePRO, at home within 3 days before the 
site visit or at the site visit. At the latest, the patients’ questionnaires must be completed prior to the pulmonary 
function tests.
(4) 
At Visit 1, the C-SSRS version to be used is the “screening/baseline” one. At all other visits, the version of 
C-SSRS to be used is the version “since last visit”.
(5)
Vital signs will be taken as one measurement at predose.
(6)
Send chest HRCT not older than 12 months for central review. If the patient does not have a HRCT within 
12 months of Visit 1 or the available HRCT scan fails to meet the required image acquisition specification, a new 
HRCT can be performed and submitted provided the patient meets all other inclusion and no exclusion criteria. To 
perform a HRCT within the trial, all local regulatory requirements to perform an HRCT have to be met. In 
Germany, no HRCT will be performed as trial procedure; only historical HRCT will be submitted.
(7) 
Order of lung function measurements: 1. FVC followed by patient’s rest; 2. DLCO: Two DLCO measurements 
will be performed approximately at the same time of the day, at least within the same half-day (morning vs.
afternoon, reference time at Visit 2).
(8)
Assisted home spirometry will be offered at selected centres where every patient should have a training and 
measurement with the device ideally at Visits 2 or 3. If the requirement to use the iSpiro appears later in the trial, 
then this timepoint can be shifted. Remote measurement can be performed as per investigator’s judgement but 
should not replace the on-site FVC measurement.
(9)
Safety laboratory tests will be performed predose. This includes blood and urine collection. Of note, in case of a 
suspected vasculitis event, additional blood sampling is required. For details please see Section 5.2.3.
(10)
Additional blood sample to be taken for storage and analysis in case of vasculitis adverse event during the trial.  
(11)
Women of childbearing potential only. Serum pregnancy test to be performed at V1; urine dipstick pregnancy test 
to be performed at V2 and following visits (if positive, urine dipstick test to be followed by serum test for 
confirmation). More frequent pregnancy testing may be done if required.
(12)
Infection testing includes HBV, HCV, HIV, and tuberculosis (Section 5.2.3.2)
(13) 
PK samples to analyse BI 1015550 will be collected predose (before drug administration).
(14)
Only drawn if EOT is performed at 52 weeks (study completion phase).
(15) 
Collection of biobanking samples (plasma, serum, DNA) is optional and is not a prerequisite for participation in 
the trial. Only for patients who signed a separate informed consent. DNA sample will be taken at Visit 2 preferably 
or at any subsequent visit until EOT.
(16)
Includes assessment of exacerbations, hospitalisations for respiratory cause, vasculitis, and diarrhoea
(17)
Patients may be eligible to enter an extension trial if they complete this study on blinded treatment and meet the 
eligibility criteria for the extension trial. 
For patients who complete all study visits and roll over to extension trial, end of study is EOT. A follow-up visit 
(EOS) is only required for those who do not roll-over in the separate extension trial (or could not roll-over within a 
week of EOT visit) and if the last drug intake was less than 7 days before the EOT visit.
(18)
Patients who discontinue trial treatment prematurely and have agreed to be contacted, should be called at least at 
the end of the 12-month observation period (52 weeks) and at the end of their scheduled trial participation to obtain 
their vital status information.

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TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS .....................................................................2
FLOW CHART........................................................................................................................5
TABLE OF CONTENTS ........................................................................................................7
ABBREVIATIONS AND DEFINITIONS...........................................................................12
1.
INTRODUCTION...............................................................................................17
1.1
MEDICAL BACKGROUND.............................................................................17
1.2
DRUG PROFILE................................................................................................17
1.3
RATIONALE FOR PERFORMING THE TRIAL.........................................19
1.4
BENEFIT - RISK ASSESSMENT.....................................................................20
1.4.1
Benefits.................................................................................................................20
1.4.2
Risks .....................................................................................................................20
1.4.3
Discussion.............................................................................................................25
2.
TRIAL OBJECTIVES AND ENDPOINTS......................................................25
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS........25
2.1.1
Main objectives....................................................................................................25
2.1.2
Primary endpoint................................................................................................25
2.1.3
Key Secondary endpoint.....................................................................................26
2.1.4
Secondary 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(S)......................................................................................29
3.3
SELECTION OF TRIAL POPULATION .......................................................30
3.3.1
Main diagnosis for trial entry ............................................................................31
3.3.2
Inclusion criteria .................................................................................................31
3.3.3
Exclusion criteria ................................................................................................32
3.3.4
Discontinuation of patients from treatment or assessments ...........................33
3.3.4.1
Discontinuation of trial treatment .........................................................................33
3.3.4.2
Withdrawal of consent to trial participation .........................................................35
3.3.4.3
Discontinuation of the trial by the sponsor...........................................................35
4.
TREATMENTS...................................................................................................35
4.1
INVESTIGATIONAL TREATMENTS ...........................................................35
4.1.1
Identity of the Investigational Medicinal Products..........................................35
4.1.2
Selection of doses in the trial and dose modifications......................................36
4.1.3
Method of assigning patients to treatment groups...........................................38
4.1.4
Drug assignment and administration of doses for each patient......................38

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4.1.5
Blinding and procedures for unblinding...........................................................39
4.1.5.1
Blinding.................................................................................................................39
4.1.5.2
Unblinding and breaking the code ........................................................................40
4.1.6
Packaging, labelling, and re-supply...................................................................40
4.1.7
Storage conditions...............................................................................................40
4.1.8
Drug accountability.............................................................................................41
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS ................................................................................................41
4.2.1
Other treatments and emergency procedures..................................................41
4.2.2
Restrictions ..........................................................................................................43
4.2.2.1
Restrictions regarding concomitant treatment ......................................................43
4.2.2.2
Restrictions on diet and lifestyle...........................................................................44
4.2.2.3
Contraception requirements..................................................................................44
4.3
TREATMENT COMPLIANCE........................................................................45
5.
ASSESSMENTS..................................................................................................45
5.1
ASSESSMENT OF EFFICACY........................................................................45
5.1.1
FVC ......................................................................................................................45
5.1.2
Exacerbation of IPF............................................................................................46
5.1.3
Time to death.......................................................................................................47
5.1.4
Hospitalization due to respiratory cause ..........................................................47
5.1.5
Patient-Reported Outcome Questionnaires......................................................47
5.1.5.1
Living with Pulmonary Fibrosis Symptoms and Impact Questionnaire (L-PF)...48
5.1.5.2
EuroQol 5-Dimensional quality of life Questionnaire (EQ-5D)...........................48
5.1.5.3
Patient’s Global Impression of Severity (PGIS) of Cough, Shortness of Breath 
and Fatigue............................................................................................................49
5.1.6
DLCO...................................................................................................................49
5.2
ASSESSMENT OF SAFETY.............................................................................50
5.2.1
Physical examination ..........................................................................................50
5.2.2
Vital signs.............................................................................................................50
5.2.3
Safety laboratory parameters ............................................................................50
5.2.3.1
Routine safety lab tests .........................................................................................51
5.2.3.2
Infection serology .................................................................................................52
5.2.3.3
Immunological vasculitis markers ........................................................................53
5.2.4
Electrocardiogram ..............................................................................................53
5.2.5
Other Safety parameters ....................................................................................54
5.2.5.1
Suicidal risk (C-SSRS)..........................................................................................54
5.2.5.2
Depression and anxiety.........................................................................................54
5.2.6
Assessment of adverse events.............................................................................54
5.2.6.1
Definitions of AEs ................................................................................................54
5.2.6.1.1
Adverse event........................................................................................................54
5.2.6.1.2
Serious adverse event............................................................................................55
5.2.6.1.3
AEs considered “Always Serious”........................................................................56
5.2.6.1.4
Adverse events of special interest.........................................................................56
5.2.6.1.5
Intensity (severity) of AEs....................................................................................57
5.2.6.1.6
Causal relationship of AEs....................................................................................58
5.2.6.2
Adverse event collection and reporting ................................................................58
5.2.6.2.1
AE Collection........................................................................................................58

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5.2.6.2.2
AE reporting to the sponsor and timelines............................................................59
5.2.6.2.3
Pregnancy..............................................................................................................59
5.2.6.3
Independent safety monitoring and adverse events with additional information 
collection...............................................................................................................60
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS...................................................................................60
5.3.1
Assessment of pharmacokinetics .......................................................................60
5.3.2
Methods of sample collection .............................................................................61
5.4
ASSESSMENT OF BIOMARKERS.................................................................61
5.4.1
Pharmacodynamics biomarkers ........................................................................61
5.4.1.1
Methods and timing of sample collection.............................................................62
5.5
BIOBANKING ....................................................................................................62
5.5.1
Methods and timing of sample collection..........................................................62
5.6
OTHER ASSESSMENTS...................................................................................63
5.6.1
Chest HRCT assessment.....................................................................................63
5.6.2
Health care resource utilization (HCRU) .........................................................63
5.7
APPROPRIATENESS OF MEASUREMENTS..............................................63
6.
INVESTIGATIONAL PLAN.............................................................................64
6.1
VISIT SCHEDULE.............................................................................................64
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS .................65
6.2.1
Screening period..................................................................................................65
6.2.2
Treatment periods...............................................................................................66
6.2.2.1
Conduct of a regular site visit ...............................................................................66
6.2.2.2
Conduct of a fallback visit (remote/home visit)....................................................67
6.2.2.3
End of treatment visit ...........................................................................................68
6.2.3
Follow-up period and trial completion..............................................................68
7.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE 
SIZE......................................................................................................................69
7.1
NULL AND ALTERNATIVE HYPOTHESES ...............................................69
7.2
PLANNED ANALYSES.....................................................................................71
7.2.1
General considerations .......................................................................................71
7.2.2
Handling of intercurrent events.........................................................................72
7.2.3
Primary objective analyses.................................................................................73
7.2.3.1
Sensitivity Analyses..............................................................................................74
7.2.3.2
Subgroup Analyses ...............................................................................................74
7.2.3.3
Supplementary Analyses.......................................................................................75
7.2.4
Secondary objective analyses.............................................................................75
7.2.4.1
Analysis of key secondary endpoint .....................................................................75
7.2.4.2
Analysis of other secondary endpoints .................................................................75
7.2.5
Further objective analyses..................................................................................76
7.2.6
Safety analyses.....................................................................................................76
7.2.7
Other Analyses ....................................................................................................77
7.2.7.1
Pharmacokinetic Methods.....................................................................................77
7.2.8
Interim analyses ..................................................................................................77
7.3
HANDLING OF MISSING DATA ...................................................................78

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7.3.1
Efficacy endpoints...............................................................................................78
7.3.2
Safety endpoints ..................................................................................................79
7.4
RANDOMIZATION...........................................................................................80
7.5
DETERMINATION OF SAMPLE SIZE .........................................................80
8.
INFORMED CONSENT, TRIAL RECORDS, DATA PROTECTION, 
PUBLICATION POLICY, AND ADMINISTRATIVE STRUCTURE ........85
8.1
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED 
CONSENT ...........................................................................................................85
8.2
DATA QUALITY ASSURANCE ......................................................................86
8.3
RECORDS...........................................................................................................86
8.3.1
Source documents ...............................................................................................86
8.3.2
Direct access to source data and documents.....................................................88
8.3.3
Storage period of records ...................................................................................88
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS ..................................88
8.5
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY........88
8.5.1
Collection, storage and future use of biological samples and 
corresponding data .............................................................................................89
8.6
TRIAL MILESTONES.......................................................................................89
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL ...................................89
9.
REFERENCES....................................................................................................91
9.1
PUBLISHED REFERENCES............................................................................91
9.2
UNPUBLISHED REFERENCES......................................................................92
10.
APPENDICES.....................................................................................................93
10.1
SPIROMETRY: BRONCHODILATOR WASHOUT 
RECOMMENDATIONS....................................................................................93
10.2
PATIENT-REPORTED OUTCOMES.............................................................94
10.2.1
Living with Pulmonary Fibrosis Symptoms and Impact Questionnaire 
(LPF) ....................................................................................................................94
10.2.2
EuroQol 5-Dimensional quality of life Questionnaire (EQ-5D)....................104
10.2.3
Hospital Anxiety and Depression Scale (HADS)............................................107
10.2.4
Patient’s Global Impression of Severity (PGIS) for Cough, Shortness of 
Breath, and Fatigue...........................................................................................108
10.3
COLUMBIA SUICIDAL SEVERITY RATING SCALE (C-SSRS) ...........108
10.3.1
Visit 1 – Screening/baseline version ................................................................110
10.3.2
C-SSRS – since last visit ...................................................................................113
10.4
RESTRICTED MEDICATIONS TABLES....................................................115
10.4.1
Strong CYP3A4 inhibitors ...............................................................................116
10.4.2
Equivalent doses of corticosteroids .................................................................117
10.4.3
Restricted PDE inhibitors ................................................................................117
10.5
OPPORTUNISTIC INFECTIONS .................................................................118
10.6
ELIGIBILITY CONFIRMATION OF IPF DIAGNOSIS............................118
10.7
TRIAL PARTICIPANT FEEDBACK............................................................120
11.
DESCRIPTION OF GLOBAL AMENDMENT(S) .......................................122
11.1
GLOBAL AMENDMENT 1 ............................................................................122

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11.2
GLOBAL AMENDMENT 2 ............................................................................125
11.3
GLOBAL AMENDMENT 3 ............................................................................140

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ABBREVIATIONS AND DEFINITIONS
ADME
Absorption, Distribution, Metabolism, Excretion
AE
Adverse Event
AESI
Adverse Event of Special Interest
AF
Antifibrotic
ALAT
Latin American Thoracic Association
ALT
Alanine Aminotransferase
AMP
Auxiliary Medicinal Products
ANCA
Antineutrophil cytoplasmic antibodies
AP
Alkaline phosphatase
aPTT
Activated partial thromboplastin time 
AST
Aspartate aminotransferase
ATS
American Thoracic Society
AUC
Area under the Curve
AZA
Azathioprine
BI 
Boehringer Ingelheim
bid 
bis in die (twice daily dosing)
BMI
Body Mass Index
CA
Competent Authority
Cancer Antigen
cAMP
Cyclic Adenosine Monophosphate
CI
Confidence Interval
CK
Creatine kinase
CKD-EPI
Chronic Kidney Disease - Epidemiology Collaboration
Cmax
Maximum Plasma Concentration
Cmin
Minimum Plasma Concentration
Cpre,ss
Predose Concentration of Analyte in Plasma at Steady State
(e)COA
(electronic) Clinical Outcome Assessment
COVID-19
Coronavirus Disease 2019
CRA
Clinical Research Associate
(e)CRF
(electronic) Case Report Form
CRO
Contract Research Organization
CRP
C-Reactive Protein
C-SSRS
Columbia-Suicide Severity Rating Scale
CT
Computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report

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CYP
Cytochrome P450
DBL
Database Lock
DILI
Drug Induced Liver Injury
DLCO
Diffusing Capacity (of Lung) for Carbon Monoxide
DMC
Data Monitoring Committee
DNA
Deoxyribonucleic Acid
ECG
Electrocardiogram
eDC
Electronic Data Capture
EDMS
Electronic Document Management System
EDTA
Ethylenediaminetetraacetic Acid
eGFR
Estimated glomerular filtration rate
EOS
End of Study (corresponds with End of Trial)
EOT
End of Treatment
ePRO
Electronic Patient-Reported Outcome
EQ-5D
EuroQol 5 Dimensional Quality of Life Questionnaire
ERS
European Respiratory Society
ES
Entered Set
EU 
European Union
EudraCT
European Union Drug Regulating Authorities Clinical Trials Database
EuroQol
European Quality of Life Group
FAS
Full Analysis Set
FDA
Food and Drug Administration
FEV1
Forced Expiratory Volume in 1 second
FU
Follow-up
FVC
Forced vital capacity
GBM
Glomerular Basement Membrane
GCP
Good Clinical Practice
GGT
Gammaglutamyl transferase
GLI
Global Lung Initiative
gMean
Geometric Mean
GMP
Good Manufacturing Practice
HA
Health Authority
HADS
Hospital Anxiety and Depression Scale
Hb
Hemoglobin
HBV/HCV
Hepatitis B or C Virus
HCRU
Health Care Resource Utilization
HIV
Human Immunodeficiency Virus
HPLC-MS/MS
High Performance Liquid Chromatography with Tandem Mass 
Spectrometry

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HR
Hazard Ratio
HRCT
High-resolution Computed Tomography
i.v.
Intravenous
IB
Investigator’s Brochure
IC50
mean half-maximal inhibition
ICF
Informed Consent Form
ICH
International Council on Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use
IDMS
Isotope Dilution-mass Spectrometry
IEC
Independent Ethics Committee
IFN-γ
Interferon gamma
IGRA
Interferon-Gamma Release Assay
IL
Interleukin
ILD
Interstitial Lung Disease
IMP
Investigational Medical Product
INN
International Non-Proprietary Name
INR
International Normalized Ratio
IPD
Important Protocol Deviation
IPF
Idiopathic Pulmonary Fibrosis
IRB
Institutional Review Board
IRT
Interactive Response Technology
ISF
Investigator Site File
ISO
International Organization for Standardization
iSpiro
Handheld spirometer
IUD
Intrauterine Device
IUS
Intrauterine Hormone-releasing System
IXRS
Interactive Voice/Web Response Software
JRS
Japanese Respiratory Society
LABA
Long Acting Beta Agonist
LAMA
Long Acting Muscarinic Antagonist
LOAEL
Lowest Observed Adverse Effect Level
L-PF
Living with Fibrosis Symptoms and Impact Questionnaire
LPLT
Last patient last treatment
LPLV
Last patient last visit
LPS
Lipopolysaccharide
LTFU
Lost To Follow Up
MACE
Major Adverse Cardiovascular Event
MAR
Missing At Random
MCH
Mean Corpuscular Hemoglobin

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MCHC
Mean Corpuscular Hemoglobin Concentration
MCV
Mean Corpuscular Volume
MedDRA
Medical Dictionary for Drug Regulatory Activities
mmHg
Millimeters Mercury
MMRM
Mixed-model repeated measures
MRD
Multiple Rising Dose
mRNA
Messenger Ribonucleic Acid
miRNA
Micro Ribonucleic Acid
MTX
Methotrexate
NICE
National Institute for Health and Care Excellence
NOAEL
No observed adverse effect level
OC
Oral contraceptive
OPU
Operative Unit
p.o.
per os (oral)
PCR
Polymerase Chain Reaction
PDE
Phosphodiesterase enzyme
PDE4B
Phosphodiesterase 4B
PDE4i
Phosphodiesterase inhibitor
PF
Pulmonary Fibrosis
PF-ILD
Progressive Fibrosing Interstitial Lung Disease
PFT
Pulmonary Function Test
PGIS
Patient’s Global Impression of Severity 
PGx
Pharmacogenomics
PK
Pharmacokinetics
PK/PD
Pharmacokinetics/Pharmacodynamics
PPD
Purified Protein Derivative
PRO
Patient-Reported Outcome
PT
Preferred Term
Prothrombin Time
PV
Pharmacovigilance
RA
Regulatory Authority
RBC
Red blood cells
RDW
Red Cell Distribution Width
REML
Restricted maximum likelihood
REP
Residual effect period
RMP
Risk Management Plan
RNA
Ribonucleic Acid
RS
Randomized Set
SABA
Short Acting Beta Agonist

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SAE
Serious Adverse Event
SAMA
Short-acting muscarinic antagonist
SARS-CoV-2
Severe Acute Respiratory Syndrome Coronavirus-2
SC
Steering Committee
SD
Standard Deviation
SMC
Safety Monitoring Committee
SMQ
Standardized MedDRA Queries
SoC
Standard of Care
SOP
Standard Operating Procedure
SpO2
Oxygen Saturation
SRD
Single Rising Dose
SUSAR
Suspected Unexpected Serious Adverse Reactions
t1/2
Half-life time
TB
Tuberculosis
TBLC
Transbronchial lung cryobiopsy
tmax
Timepoint of maximum plasma concentration
TMF
Trial Master File
TNF-α
Tumor Necrosis Factor alpha
TS
Treated Set
TSAP
Trial Statistical Analysis Plan
UGT
Uridine Diphosphoglucuronosyl Transferase
UIP
Usual interstitial pneumonia
ULN
Upper limit of normal
US
United States
V
Visit
vs.
Versus
vWF
von Willebrand Factor
WBC
White blood cells
WHO
World Health Organisation
WOCBP
Woman of childbearing potential

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1.
INTRODUCTION
BI 1015550, a preferential inhibitor of the phosphodiesterase 4B (PDE4B) isoenzyme which 
hydrolyzes and inactivates cyclic adenosine monophosphate (cAMP), is being developed by 
Boehringer Ingelheim (BI) for the treatment of idiopathic pulmonary fibrosis (IPF) and other 
forms of progressive pulmonary fibrosis.
1.1
MEDICAL BACKGROUND
IPF and other progressive fibrosing interstitial lung diseases (PF-ILDs) share common 
pathophysiologic characteristics; alveolar epithelial cell injury and subsequent dysregulated 
repair, characterized by excessive deposition of extracellular matrix and loss of normal 
parenchymal architecture and lung function [P11-07084]. In IPF, fibroblasts exhibit 
unregulated proliferation and differentiate into myofibroblasts. The latter is considered the 
hallmark cell in the development and establishment of lung fibrosis [P12-03241]. Several 
growth factors are implicated in the proliferation, migration and transdifferentiation of the 
fibroblast and myofibroblast pool in pulmonary fibrosis.
As of date, 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 [P15-07362, R18-2794]. Nintedanib is also 
approved in the US, the European Union and many other countries for the treatment of other 
fibrosing ILDs with progressive phenotype. Despite the availability of these drugs, the 
medical need remains high in these devastating diseases.
1.2
DRUG PROFILE
BI 1015550 is an oral preferential inhibitor of the PDE4B with broad anti-inflammatory and 
antifibrotic activities. Based on its mode of action, BI 1015550 is hypothesised to have 
complementary activity to current therapies in IPF and other forms of progressive pulmonary
fibrosis. BI 1015550 shows a mean half-maximal inhibition (IC50) at 10 nM, with a nine-fold 
selectivity over phosphodiesterase 4D (PDE4 D; mean IC50 91 nM) without relevant known 
interaction with other targets (78 receptors and 42 enzymes tested at the very high 
concentration of 10 000 nM). In-vitro anti-inflammatory activity has been confirmed for 
TNF-α (IC50: 12 nM) and IL-2 release (IC50: 5 nM) from purified human peripheral blood 
mononuclear cells.
Key pharmacokinetic characteristics and drug-drug interactions
The PK of BI 1015550 was linear over all dose groups tested in SRD and MRD studies. After 
oral administration, BI 1015550 was rapidly absorbed with peak plasma concentrations 
occurring at a median tmax between
post-dose. The gMean t1/2 was approximately
. 
After single and multiple oral doses, BI 1015550 exposure (Cmax and AUC0-∞) appeared to 
increase dose proportionally. Steady state of BI 1015550 and its metabolites was achieved by 
 Accumulation ratio based on AUC and Cmax amounted up to
. Administration of BI 1015550 together with food lead to a delayed tmax to
 and 
 Cmax by
 but there was no change in AUC and, therefore, did not 
change the overall exposure to BI 1015550 to a clinically relevant extent. 

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In the human ADME (mass balance) study, the total recovery of [14C]BI 1015550-related 
material was on average 95% of the administered dose with 58% excreted in faeces and 36% 
excreted in urine where 12% was excreted unchanged as parent compound.
Drug-Drug Interaction:
BI 1015550 is mainly metabolized by CYP3A with minor contributions from UGTs.
Administration of BI 1015550 together with a strong CYP3A4 inhibitor increased AUC of 
BI 1015550 2.2-fold and Cmax 1.3-fold. In a clinical drug-drug interaction study with 
midazolam (sensitive CYP3A4 substrate), BI 1015550 was not shown to have a clinically 
relevant CYP3A induction.
Results from the Phase II trial 1305-0013 in patients with IPF showed that pre- and post-dose 
concentration levels of BI 1015550 were similar between patients treated with nintedanib and 
those not treated with any antifibrotic, suggesting nintedanib did not impact the exposure of 
BI 1015550. However, a 35-50% lower exposure was observed in IPF patients on 
background treatment with pirfenidone. Clinical relevance of this level of decrease in 
BI 1015550 exposure is unclear based on the limited data and will further be evaluated in a 
separate drug-drug interaction trial.
Residual Effect Period
The Residual Effect Period (REP) of BI 1015550 is 
. This is the period after the last 
dose with measurable drug levels and/or pharmacodynamic effects still likely to be present.
Data from non-clinical toxicology studies
The toxicity profile for BI 1015550 has been assessed in safety pharmacology studies, genetic 
toxicity studies, and repeat dose toxicity studies in the rat, minipig, and monkeys of up to 26, 
39, and 39 weeks, respectively. In addition, a fertility and early embryonic development (rat) 
and embryo-fetal development toxicity studies (rat and rabbit) were conducted. Decreased 
mating, fertility, and pregnancy indices were observed in male and female rats at a dose level
that also caused evidence of severe toxicity in both sexes. In rats but not in rabbits fetal loss 
was increased. Teratogenicity and fetotoxicity was not observed. In long-term toxicity studies 
in rats (26 weeks), minipig (39 weeks) and monkeys (39 weeks) there was no microscopic 
evidence of changes in female reproductive organs or on male spermatogenesis. A sporadic
menstrual cycle prolongation was observed in the 39-week study in female monkeys 
receiving ≥10 mg/kg/day, i.e., at approximately 4-fold human exposure at 18 mg bid.
Vasculopathy and mortality secondary to vasculopathy are the primary findings defining the 
NOAEL and LOAEL in the rat and minipig, respectively. In contrast, vascular changes were 
not observed in 13-week and 39-week monkey studies at 30 mg/kg/day, supporting the 
decreased sensitivity of primates to PDE4i-induced vascular changes. Vasculopathy is a well 
characterized class-effect pathology associated with PDE4 inhibitors [R10-1559] and has not 
been demonstrated in humans administered marketed PDE4i apremilast and roflumilast.  
Data from clinical studies
Treatment with BI 1015550 at 18 mg twice daily in a Phase II proof-of-concept trial 
preserved lung function in patients with IPF over a period of 12 weeks, either as a 
monotherapy or on top of approved antifibrotic standard of care (nintedanib or pirfenidone). 
BI 1015550 showed acceptable safety and tolerability in the overall study population and in 
the subgroups of patients without or with background antifibrotic treatment.

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In this trial 97 patients were exposed to BI 1015550 and 50 patients to placebo. The most 
frequently reported AEs were gastrointestinal disorders (32.0% in the BI 1015550 group, 
24.0% in the placebo group). Diarrhea was the most common AE, with a higher frequency in 
the BI 1015550 group (23.7%) than in the placebo group (12.0%) and diarrhea was also the 
most common event leading to treatment discontinuation (3 patients, all in the BI 1015550 
group and all on background treatment with nintedanib). However, the majority of diarrhea 
events were mild in intensity. 
AEs leading to discontinuation of trial treatment were only observed in the BI 1015550 
treatment group. Apart from the mentioned 3 patients with diarrhoea and 2 patients with 
COVID-19, all events occurred in single patients without any pattern or cluster.
Serious adverse events were reported in 10.0% of patients in the placebo group and 6.2% of 
patients in the BI 1015550 treatment group. There were two events with fatal outcome in the 
BI 1015550 treatment group, one patient with COVID-19 pneumonia and one patient with 
suspected IPF exacerbation and suspected vasculitis (the diagnosis of vasculitis could not be 
confirmed by the sponsor nor the independent external data monitoring committee). Risk 
factors were present in both fatal events.
There were no clinically relevant changes in vital signs (including body weight) and/or ECG 
parameters (including QTc) observed. No changes in the C-SSRS and no AEs of suicidal 
ideation or behaviour were reported during trial treatment.
The primary endpoint for efficacy in this trial was met, with a relevant treatment effect in 
favour of BI 1015550 on the change from baseline in FVC at 12 weeks in patients with IPF.
Treatment with BI 1015550 preserved FVC irrespective of background antifibrotic treatment, 
in contrast to the placebo groups in which a marked decline in FVC was observed. (non-AF 
stratum: -95.62 ± 30.75 mL under placebo vs. 6.10 ± 22.90 mL with BI 1015550; AF 
stratum: -77.70 ± 23.60 mL under placebo vs. 2.72 ± 18.13 mL). 
Overall, in Phase Ic and II trials in patients with IPF, BI 1015550 at a dose of 18 mg bid for 
up to 12 weeks showed acceptable safety and tolerability, both in patients without or with
background antifibrotic treatment (nintedanib or pirfenidone).
For a more detailed description of the BI 1015550 profile, please refer to the Investigator’s 
Brochure (IB) current version [c02094779].
1.3
RATIONALE FOR PERFORMING THE TRIAL
The purpose of this trial is to evaluate the efficacy, safety, and tolerability of BI 1015550 
9 mg bid and 18 mg bid compared to placebo in patients with IPF in addition to patient’s 
standard of care. This trial’s primary objective is to demonstrate the ability of BI 1015550 to 
reduce lung function decline based on Forced Vital Capacity (FVC) between baseline and 
Week 52 when compared to placebo.
Efficacy and safety of BI 105550 will be assessed in patients with IPF both on approved 
antifibrotic therapy (i.e. nintedanib or pirfenidone) (AF group) or not on an antifibrotic
background therapy (non-AF group).
Despite the availability of nintedanib and pirfenidone as antifibrotic therapies, there remains 
a high unmet medical need for more efficacious and better tolerated treatments for patients 

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living with IPF. Currently available treatments reduce the decline in FVC compared to 
placebo, but do not completely stop the deterioration of lung function over time; patients still 
experience worsening of symptoms and quality of life or experience exacerbations of their 
disease. Mortality remains high in this patient population. Suboptimal tolerability with 
current treatment options is an unmet need that can impact patient’s ability to remain on 
standard of care.
Based on its anti-inflammatory and antifibrotic properties and the preliminary clinical 
evidence described, BI 1015550 may provide an additional treatment option to patients with 
pulmonary fibrosis irrespective of concomitant treatment with currently approved 
antifibrotics as standard of care.
1.4
BENEFIT - RISK ASSESSMENT
1.4.1
Benefits
IPF and other progressive fibrosing ILDs are serious debilitating conditions characterised by 
worsening symptoms and quality of life, progressive loss of lung function, ultimately 
resulting in respiratory failure, and early death. At the same time, the currently approved 
antifibrotic treatments have limitations: they do not impact symptoms and cannot stop or 
reverse fibrosis, i.e. the disease trajectory.
Data from the Phase II trial 1305-0013 in patients with IPF indicated a beneficial treatment 
effect of 18 mg BI 1015550 bid, with the preservation of FVC over 12 weeks together with 
an acceptable safety and tolerability profile supporting further investigation in Phase III 
clinical trials as a treatment for IPF and other forms of progressive pulmonary fibrosis. 
Patients with IPF who receive treatment with BI 1015550 have the potential benefit of 
slowing lung function decline, improving symptoms, and improving quality of life over a 
long-term period.
1.4.2
Risks
There are no identified risks (side effects) for BI 1015550, based on the toxicology program 
or any clinical trials conducted for this product to date. Vasculitis and foetal loss are 
considered as important potential risks based only on nonclinical findings.
Apart from risks related to trial procedures, the risks shown in Table 1.4.2: 1 below are 
hypothetical in nature; these are derived from general safety considerations of 
immunomodulatory drugs and from nonclinical and clinical data of compounds with a 
comparable mode of action. For clinical data including adverse events reported during 
clinical trials with BI 1015550 please refer to Section 1.2.

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Table 1.4.2: 1 
Overview of 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: compound/class specific (refer to Section 1.2)
Pharmacokinetic 
interaction with strong 
CYP3A4 inhibitors
CYP450 3A4 is regarded as the major 
enzyme responsible for BI 1015550 
metabolism in human hepatocytes and 
predicted to contribute to ~70% of its 
hepatic metabolism.
In a drug-drug interaction trial, the 
strong CYP3A4 inhibitor itraconazole 
increased the exposure to BI 1015550 
by 1.3-fold (Cmax) and 2.2-fold 
(AUC).
Potent CYP3A inhibitors are 
restricted medication.
If short-term treatment with potent 
CYP3A4 inhibitor is needed, trial 
medication needs to be paused 
Vasculitis
Vasculopathy is an established 
nonclinical toxicity of PDE4 inhibitors.
Vasculitis has been shown in both the 
rats and minipigs following oral 
administration of BI 1015550 but not 
in 13- or 39-week studies in monkeys.
Vasculitis is listed as an important 
potential risk in the RMP for the 
marketed PDE4- inhibitor apremilast. 
In marketed PDE4 inhibitors, vasculitis 
has not been identified as an adverse 
drug reaction in humans
Active vasculitis (unstable or 
uncontrolled) is an exclusion 
criterion.
Vasculitis assessment as part of AE 
questioning
Close clinical monitoring for AEs of 
vasculitis
Assessment of (suspected) vasculitis 
events by independent adjudication 
and data monitoring committee. 
Treatment interruption in case of any 
vasculitis adverse event. Restart only 
if not BI 1015550 related and 
considered acceptable by the 
investigator
Weight decrease in 
underweight patients 
(BMI <18.5 kg/m2)
For the marketed PDE4-inhibitors 
apremilast and roflumilast weight loss 
in underweight patients is an identified 
important risk.

Body weight evaluated regularly 
during the trial.
Patients who have a BMI 
<18.5 kg/m2, and subsequently 
experience unexplained and clinically 
significant weight loss (>10%) will 
be discontinued from trial treatment.

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Possible or known 
risks of clinical 
relevance for this 
trial
Summary of data, rationale for the 
risk
Mitigation strategy
Psychiatric disorders:

Depression and 
anxiety

Suicidality
For the marketed PDE4 inhibitors 
depression is listed as a side effect. 
They are associated with increased risk 
of depression with some patients 
reporting suicidal ideation and/or 
attempts, with some reported cases of 
completed suicide.
High incidence of depression in the 
ILD population per se.
In IPF patients treated with 18 mg 
BI 1015550 bid for up to 12 weeks, no 
on-treatment events of suicidal 
ideation or behavior and no events of 
depression or anxiety were reported
Acute or chronic severe depression 
defined as Hospital Anxiety and 
Depression Scale (HADS) subscore 
>14 at screening will be excluded
Any suicidal behavior in the past 
2 years and any suicidal ideation of 
type 4 or 5 on the Columbia-Suicide 
Severity Rating Scale (C-SSRS) in 
the past 3 months or at Visit 1 are 
exclusion criteria.
Prospective monitoring for 
depression and anxiety will be 
performed using the HADS and the 
C-SSRS
Patient’s withdrawal criteria in case 
of new-onset severe depression 
defined as HADS subscore >14 
and/or suicidal behavior or any 
suicidal ideation of type 4 or 5 in the 
C-SSRS.
Severe Infections 
including, serious,
opportunistic and 
Mycobacterium 
tuberculosis infections 
Inhibition of the immune response due 
to the anti-inflammatory mode of 
action of BI 1015550 potentially 
increases the risk of infections, 
including COVID-19
Serious infections were balanced 
between placebo and BI 1015550 in 
Phase II trial
Nasopharyngitis was more frequently 
reported under treatment with BI 
1015550 in Phase Ic/II but not in Phase 
I trials and the numbers were very 
small
Screening procedures for infections 
are defined for this trial. Patients with 
any relevant chronic or acute 
infections including human 
immunodeficiency virus (HIV), viral 
hepatitis or active tuberculosis are 
excluded from the trial. 
Treatment of infections should be 
initiated promptly according to 
standards of care.
Treatment interruption in case of 
severe acute infection until the 
patient has recovered based on the 
investigator’s medical judgement
MACE and 
tachyarhythmia
Important potential risk for marketed 
PDE4 inhibitor apremilast
In nonclinical studies with BI 1015550 
no adverse cardiovascular findings 
detected
In clinical trials with BI 1015550 no 
relevant findings were observed
These risks will be addressed by 
careful safety monitoring and safety 
measures such as
o
close clinical monitoring for 
AEs
o
regular monitoring of vital signs 
and ECG assessments
Adjudication committee for MACE 
events in Phase III

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Possible or known 
risks of clinical 
relevance for this 
trial
Summary of data, rationale for the 
risk
Mitigation strategy
Malignancies
Inhibition of the immune response with 
an immunomodulatory drug may 
potentially impair immune defences 
and thus theoretically decrease 
immune defense against malignancies.
Patients with a recent history of 
malignancy within 5 years will be 
excluded from participation in this 
trial except patients with 
appropriately treated basal cell 
carcinoma or in situ squamous cell 
carcinoma of the skin or in situ 
carcinoma of uterine cervix
In case of occurrence of malignant 
neoplasm other than appropriately 
treated basal cell carcinoma or in situ 
squamous cell carcinoma of the skin 
or in situ carcinoma of uterine cervix, 
the investigator should discontinue 
trial treatment 
Diagnostics and treatment have to be 
initiated according to local standard 
of care.
Gastrointestinal
disorders (e.g.
diarrhoea, nausea,
vomiting, abdominal 
pain)
Vomiting and diarrhea are important 
dose-limiting side effects of marketed 
oral PDE-4 inhibitors. 
Diarrhoea was the most frequently 
reported adverse event in Phase II with 
the majority of events being of mild 
intensity.
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 
recommended.
Management strategies as described 
in approved labels of antifibrotics 
have to be followed.
Symptomatic treatment, e.g. 
loperamide, if required
Treatment interruption if needed 
Reproductive toxicity:

Fetal loss

Decreased 
fertility
No teratogenicity was seen in 2 species 
in preclinical studies and exposure 
with BI 1015550 via the semen is 
expected to be very low.
In rats, male and female fertility was 
potentially reduced. Long term toxicity 
studies with BI 1015550 in rat and 
monkey showed no microscopic 
evidence of changes in female 
reproductive organs or male 
spermatogenesis. For another PDE4 
inhibitor with comparable nonclinical 
findings, clinical data showed no effect 
on male fertility and sperm in humans. 
In monkeys, a sporadic prolongation in 
menstrual cycles was observed at 
approximately ≥4-fold human 
exposure at 18 mg BI 1015550 bid.
Fetal loss was increased in female rats 
treated with BI 1015550.  
Women of childbearing potential 
(WOCBP) need to use a highly 
effective method of contraception. 
WOCBP taking oral contraceptives 
(OCs) also have to ensure the use of 
one barrier method during sexual 
intercourse with their partner, e.g., 
condom to account for the risk of 
potentially reduced efficacy of the 
OCs in the event of severe vomiting 
and diarrhea
In case of vomiting or diarrhea,
instructions in the label of the OC 
should be followed
In case of prolonged (>48h) or 
repeated vomiting/diarrhea, the use of 
an alternative highly effective 
contraceptive measure should be 
considered
Regular pregnancy testing for 
WOCBP
Treatment discontinuation in case of 
pregnancy

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Possible or known 
risks of clinical 
relevance for this 
trial
Summary of data, rationale for the 
risk
Mitigation strategy
General safety topics
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. 
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 (paraesthesia), 
impaired sensation of touch and 
persistent pain.
These risks will be addressed by 
careful safety monitoring and risk 
mitigation measures such as:
o
close clinical monitoring for 
AEs
o
selection of experienced sites 
and site staff 
Chest HRCT
The more radiation is received over the 
course of a life, the greater risk of 
having cancerous tumours 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.
New HRCT measurement only 
required in case no historical record 
(not older than 12 months at the time 
of screening) is available or in case of 
insufficient quality.
These risks will be addressed by 
careful safety monitoring and risk 
mitigation measures such as:
o
close clinical monitoring for 
AEs
o
selection of experienced sites 
and site staff 
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:
o
close clinical monitoring for 
AEs
o
selection of experienced sites 
and site staff
Training from vendor to conduct 
correct manoeuvre.
Other risks
Administration of 
Placebo or 
BI 1015550
If the patient is randomized to receive 
a placebo or BI 1015550, the patient’s 
condition could get worse during the 
course of the trial.
In an event of disease worsening, 
treatment with standard of care is 
always an option per physician 
discretion for all randomized patients

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1.4.3
Discussion
Treatment with BI 1015550 has the potential to provide significant benefit to patients with 
IPF and other progressive fibrosing ILDs by ultimately slowing lung function decline, 
improving symptoms and quality of life over a long-term period. 
The obtained toxicology data support administration of BI 1015550 to women and men in the 
planned Phase III clinical trials in patients with IPF and other forms of progressive 
pulmonary fibrosis irrespective of background antifibrotic treatment, except for women who 
are pregnant or breastfeeding. Women of childbearing potential must use a highly effective 
method of contraception (for details please refer to Sections 3.3.2 and 4.2.2.3). 
Data from the Phase II trial 1305-0013 in patients with IPF indicated a beneficial treatment 
effect of 18 mg BI 1015550 bid, with the preservation of FVC over 12 weeks together with 
an acceptable safety and tolerability profile supporting further investigation in Phase III 
clinical trials as a treatment for IPF and other forms of progressive pulmonary fibrosis. Based 
on the clinical and nonclinical data available to date, no risks (side effects) were identified.
There are no listed events.
Considering the unmet medical need and anticipated benefit of BI 1015550, and the lack of 
compound or mechanism related safety signals, the benefit risk evaluation of BI 1015550 for 
the treatment of IPF and other progressive fibrosing ILDs is favourable.
2.
TRIAL OBJECTIVES AND ENDPOINTS
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS
2.1.1
Main objectives
The trial will evaluate efficacy and safety of BI 1015550 9 mg and 18 mg bid compared to 
placebo in patients with IPF in addition to the patient’s standard of care treatment. 
The primary objective is to demonstrate a reduction in lung function decline as measured by 
the change from baseline in FVC for BI 1015550 when compared to placebo in patients with 
IPF.
The main secondary objective of the trial is to demonstrate BI 1015550’s ability in reducing 
the occurrence of clinically meaningful events such as acute IPF exacerbation, hospitalization 
for respiratory cause or death over the duration of the trial when compared to placebo in 
patients with IPF. An additional secondary objective of the trial is to show an effect of 
BI 1015550 on symptoms and lung function.
2.1.2
Primary endpoint
The primary endpoint of the trial is the absolute change from baseline in Forced Vital 
Capacity (FVC) [mL] at Week 52.

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2.1.3
Key Secondary endpoint
The key secondary endpoint in this trial is time to the first occurrence of any of the 
components of the composite endpoint: time to first acute IPF exacerbation, first 
hospitalization for respiratory cause, or death (whichever occurs first) over the duration of the 
trial.
2.1.4
Secondary endpoints
The secondary endpoints of the trial are:

Time to first acute IPF exacerbation or death over the duration of the trial

Time to hospitalization for respiratory cause or death over the duration of the trial

Time to absolute decline in FVC % predicted of >10% from baseline or death over the
duration of the trial

Time to absolute decline in (DLCO) % predicted of >15% from baseline or death 
over the duration of the trial

Time to death over the duration of the trial

Absolute change from baseline in Living with Pulmonary Fibrosis (L-PF) Symptoms 
Dyspnea domain score at Week 52

Absolute change from baseline in Living with Pulmonary Fibrosis (L-PF) Symptoms 
Cough domain score at Week 52

Absolute change from baseline in Living with Pulmonary Fibrosis (L-PF) Symptoms 
Fatigue domain score at Week 52

Absolute change from baseline in FVC % predicted at Week 52

Absolute change from baseline in DLCO % predicted at Week 52

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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN 
This Phase III trial (1305-0014) is a multi-centre, multi-national, prospective, randomized, 
placebo-controlled, double blind clinical trial to investigate the efficacy and safety of 
BI 1015550 at a dose of 9 mg bid and 18 mg bid in patients with IPF over at least 52 weeks.
A total of approximately 963 patients will be randomized into the trial of which 321 patients 
will be in each active treatment group and in the placebo group.

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After signing the informed consent, the initial visit (Visit 1) will be conducted to determine 
eligibility. Eligible patients will enter the randomization visit (Visit 2) to allow collection of 
all clinical and safety information and review of all inclusion and exclusion criteria. Patients
will be randomized in a 1:1:1 ratio into either BI 1015550 9 mg bid, BI 1015550 18 mg bid or 
placebo and then enter the treatment phase for at least 52 weeks. 
Patient randomization will be stratified by the presence of background treatment with 
antifibrotics (AF group vs. non-AF group).

Non-AF group: patients not treated with an approved antifibrotic medication 
(nintedanib or pirfenidone) in the last 8 weeks prior to enrolment, (e.g. patients 
previously treated with antifibrotics, but discontinued that treatment or patients 
never treated with antifibrotics before). 

AF group: patients on a stable treatment with an approved antifibrotic drug (e.g. 
nintedanib or pirfenidone) for at least 12 weeks at study entry, and are planned to 
stay on this background treatment after randomization.
The trial will be conducted in 2 parts. Treatment Period A of the trial will consist of Visits 2 
through 10, until one year after randomization. Treatment Period B will begin following 
completion of the Week 52 visit (Visit 10); patients will continue treatment with blinded trial 
medication in Treatment Period B and have trial visits every 12 weeks. Assuming a 
respective recruitment period (about 18 months), first randomized patients may be on trial 
treatment for up to 130 weeks. 
The main analysis of this study will be performed once the last randomized patient reaches 
the Week-52 visit (Visit 10 at the end of Part A). At that time, a first database lock (DBL1; 
Figure 3.1: 1) will occur and all data will be unblinded to the sponsor. Efficacy and safety 
analyses will be performed on the data from Part A of the trial to assess the benefit-risk of 
BI 1015550 over 52 weeks. In addition, data collected in Part B of the trial (after 52 weeks) 
and available at the time of data cut-off for the main analysis will be reported together with 
data from Part A (i.e. over the whole trial).
Trial 1305-0014 Part B, will continue until all patients have completed the EOT visit and the 
EOS visit as applicable. A final database lock (DBL2; Figure 3.1: 1) will then occur and a 
final analysis based on the data over the whole trial will be carried out.
Depending on the results of the evaluation based on DBL1 and determination of the 
BI 1015550 dose with the more favorable benefit-risk profile, patients receiving trial 
medication until the end of Part B will be eligible for open-label treatment with BI 1015550
in a separate extension trial.
After review of the efficacy and safety data available at DBL1, the sponsor will communicate 
the end of the trial and all patients still on blinded study treatment will perform an End of 
Treatment (EOT) visit and an End of Study (EOS) visit if applicable. The trial ends when all 
patients complete these visits. Details on follow-up and rollover to the extension trial are 
given in Section 6.2.3.

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Figure 3.1: 1
Trial design overview at patient level (upper panel) and trial level (lower 
panel)
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)
This trial is a placebo-controlled, randomized, double-blind trial to provide the highest 
scientific rigor and is thus considered the most appropriate design. FVC measurement over 
time is a widely accepted clinical endpoint in the indication of the trial for the evaluation of 
treatment effects on lung function. FVC assessments are supported by clinically meaningful 
outcomes and patient-reported outcomes as secondary endpoints.
A placebo-controlled study design is considered justified in the trial, as it will be conducted 
in addition to the patient’s standard of care at the time of enrollment:

Patients who are on a stable treatment with antifibrotic treatment at the time of 
screening and randomization are planned to continue this background treatment 
during the trial. 

Patients without an AF background treatment at enrollment and randomization will be 
allowed to initiate a treatment with an approved antifibrotic agent in case of IPF 
progression and/or exacerbation after the first 12 weeks of treatment in the trial. 
Stratification will be based on presence of AF background treatment and will facilitate the 
interpretation of the efficacy and safety data in patients that use BI 1015550 alone or in 

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addition to an antifibrotic agent. The expected proportion of the respective subgroups of 
patients with or without background antifibrotic treatment corresponds to the current 
treatment/prescription practices across the participating countries (70% vs. 30%), so that 
patients can be accepted to the trial without modification of the ongoing SoC treatment.
The minimum treatment period of 52 weeks is selected according to the respective guidance 
from the American and European Clinicians organisations on the investigation of treatment 
effects on FVC in IPF (2015 ATS/ERS/JRS/ALAT Guideline [P15-07362]), where based on 
the natural decline during disease progression, a minimal follow up of the effects of new 
drugs for 52 weeks is recommended. However, clinical endpoint data are needed to provide 
evidence of a clinically meaningful effect beyond a decreased decline of FVC. Based on the 
incidence rates of these clinically meaningful events included in the key secondary endpoint
(IPF exacerbation, respiratory hospitalization, and death), the blinded treatment should be 
extended to a long-term treatment beyond 52 weeks. This is reflected with the continuation of 
study participation for up to 130 weeks with the additional Treatment Period B for patients 
that are recruited early in the trial. The additional data collected while patients remain on 
blinded treatment beyond 52 weeks will provide supportive long-term efficacy and safety 
data on the effect of BI 1015550 in a controlled manner. Due to the varying length of follow-
up in Part B of the trial, the efficacy analyses incorporating data from Part A and Part B will 
focus on time-to-event endpoints.
This trial will include an option for participants and participant caregivers to complete 
anonymized questionnaires to provide feedback on their clinical trial experience. Providing 
this feedback is not required for trial participation, and information collected from these 
questionnaires will not be analyzed as part of the clinical data for the trial (see Section 10.7).
3.3
SELECTION OF TRIAL POPULATION
Patients with IPF will be screened at approximately 400 sites to ensure randomization of 
about 963 patients, 321 in the active treatment arms and 321 in the placebo group.
During the recruitment period, the number of patients randomized with an approved 
background AF-treatment and without AF background treatment will be closely monitored. If 
necessary, recruitment of one group may be stopped in order to achieve sufficient 
representation of both groups.
Screening of patients for this trial is competitive, i.e. screening for the trial will stop at all 
sites once a sufficient number of patients has been screened. Investigators will be notified 
about screening completion and will then not be allowed to screen additional patients for this 
trial. Patients already in screening at this time will be allowed to continue to randomization 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.
If retrospectively it is found that a patient has been randomized in error (did not meet all 
inclusion criteria or met one or more exclusion criteria), the sponsor or delegate should be 

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contacted immediately. Based on an individual benefit-risk assessment, a decision will be 
made whether continued trial participation is possible or not.
3.3.1
Main diagnosis for trial entry
Patients diagnosed with IPF who comply with trial requirements may qualify to participate in 
the trial. The diagnosis is based on (Appendix 10.6):

The 2022 ATS/ERS/JRS/ALAT Guideline [P22-03204] as confirmed by the 
investigator based on chest HRCT scan taken within 12 months of Visit 1 and, if 
available, surgical lung biopsy or transbronchial lung cryobiopsy, and

“UIP” or “Probable UIP” HRCT pattern consistent with the clinical diagnosis of IPF, 
as confirmed by central review prior to Visit 2. 
o
Patients with an “Indeterminate” HRCT finding are eligible if a clinical 
diagnosis of IPF can be confirmed locally based on (historical) surgical lung 
biopsy or cryobiopsy demonstrating a “UIP” or “Probable UIP” 
histopathology pattern. (Table 10.6: 1)
o
Patients with an “Alternative diagnosis” HRCT finding are eligible if a clinical 
diagnosis of IPF can be confirmed locally based on (historical) surgical lung 
biopsy or cryobiopsy demonstrating a “UIP” histopathology pattern. (Table 
10.6: 1)
Please refer to Section 8.3.1 (Source Documents) for the documentation requirements 
pertaining to the inclusion and exclusion criteria.
3.3.2
Inclusion criteria
1. Patients ≥40 years old at the time of signed informed consent.
2. Signed and dated written informed consent in accordance with ICH-GCP and local 
legislation prior to admission to the trial.
3. Diagnosis of IPF (Section 3.3.1)
4. Patients may be either:
o
on a stable therapy* with nintedanib or pirfenidone for at least 12 weeks prior to 
Visit 1 and during screening and are planning to stay on this background treatment 
after randomization. Combination of nintedanib plus pirfenidone is not allowed.
*stable therapy is defined as the individually and general tolerated regimen of 
either nintedanib or pirfenidone (no dose changes) for at least 12 weeks.
o
not on a treatment with nintedanib or pirfenidone for at least 8 weeks prior to 
Visit 1 and during the screening period (e.g. either AF-treatment naïve or 
previously discontinued) and do not plan to start or re-start antifibrotic treatment.
5. Forced Vital Capacity (FVC) ≥45% of predicted normal at Visit 1.
6. DLCO ≥25% of predicted normal corrected for hemoglobin (Hb) at Visit 1.
7. Women of childbearing potential (WOCBP)1 must be ready and able to use highly 
effective methods of birth control. WOCBP taking oral contraceptives (OCs) also have to 
use one barrier method; please refer to Section 4.2.2.3.
____________________________________________
1 A woman is considered of childbearing potential (WOCBP), i.e.fertile, following menarche and until becoming 
postmenopausal unless permanently sterile. Permanent sterilisation methods include hysterectomy, bilateral 
salpingectomy and bilateral oophorectomy. Tubal ligation is NOT a method of permanent sterilisation. A 
postmenopausal state is defined as no menses for 12 months without an alternative medical cause.

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3.3.3
Exclusion criteria
1. Prebronchodilator FEV1/FVC <0.7 at Visit 1
2. In the opinion of the Investigator, other clinically significant pulmonary abnormalities.
3. Acute IPF exacerbation within 3 months prior to Visit 1 and/or during the screening 
period (investigator-determined).
4. Relevant chronic or acute infections including human immunodeficiency virus (HIV) and 
viral hepatitis.
5. Confirmed infection with SARS-CoV-2 not fully recovered according to investigator 
judgement within the 4 weeks prior to randomization (Visit 2).
6. Major surgery (major according to the investigator’s assessment) performed within 
6 weeks prior to Visit 2 or planned during the trial period, e.g. hip replacement.
Registration on lung transplantation list would not be considered as planned major 
surgery.
7. 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, in situ 
squamous cell carcinoma of the skin or in situ carcinoma of uterine cervix.
8. AST or ALT >2.5 x ULN or total Bilirubin >1.5 x ULN at Visit 1.
9. eGFR ≤30 ml/min/1.73 m2 at Visit 1. (Chronic Kidney Disease Epidemiology 
Collaboration [CKD-EPI] formula or Japanese version of CKD-EPI for Japanese patients)
10. Patients with underlying liver cirrhosis (Child Pugh A, B or C hepatic impairment).
11. 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, stroke or transient ischemic attack within 6 months of Visit 1
c.
Unstable cardiac angina within 6 months of Visit 1
12. Patients who are treated with immunomodulatory medications (other than oral 
corticosteroids) or prednisone >15 mg/day or equivalent for respiratory or pulmonary 
reasons.
13. Active vasculitis, unstable or uncontrolled within 8 weeks prior to Visit 1 or during the 
screening period.
14. Any suicidal behaviour in the past 2 years (i.e. actual attempt, interrupted attempt, 
aborted attempt, or preparatory acts or behavior).
15. Any suicidal ideation of type 4 or 5 on the C-SSRS in the past 3 months or at Visit 1 
and/or Visit 2 (i.e. active suicidal thought with method and intent but without specific 
plan; or active suicidal thought with method, intent and plan).
16. Acute or chronic severe depression defined as HADS subscore >14 at Visit 1 and/or 
Visit 2.
17. Patients who must or wish to continue the intake of restricted medications (see 
Section 4.2.2.1) or any drug considered likely to interfere with the safe conduct of the 
trial. Please note: potent CYP3A4 inhibitors should not be taken 5 half-life times prior to 
Visit 1.
18. Patients treated with PDE1, PDE3, PDE4, PDE10 inhibitors, and non-selective PDE 
inhibitors within 30 days before Visit 1
19. Patients not expected to comply with the protocol requirements or not expected to 
complete the trial as scheduled (e.g. chronic alcohol or drug abuse or any other condition 
that, in the investigator’s opinion, makes the patient an unreliable trial participant).

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20. Inability to refrain from smoking on trial visit days.
21. History of allergy or hypersensitivity or contraindications to the class of drugs under 
study including known hypersensitivity to the drug or its excipients.
22. Patients with a significant disease or condition other than the ILD under study, which in 
the opinion of the investigator, 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.
23. Patients with active tuberculosis (TB). 
24. Previous randomization in this trial or in trial 1305-0023.
25. 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).
26. Women who are pregnant, nursing, or who plan to become pregnant while in the trial.
27. History of stem cell therapy for the treatment of pulmonary fibrosis.
3.3.4
Discontinuation of patients from treatment or assessments
Patients may discontinue trial treatment or withdraw consent to trial participation as a whole
(“withdrawal of consent”) with very different implications; please see Sections 3.3.4.1 and 
3.3.4.2 below.
However, if the patient agrees, every effort should be made to keep randomized patients in 
the trial, even if continuing trial treatment is not possible. They should attend further trial 
visits to ensure their safety and to collect important trial data, e.g. FVC measurement at 
Week 52.
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 
respective reason must be documented in the patient files and CRF. If applicable, consider the 
requirements for Adverse Event collection and reporting (please see Section 5.2.6.2).
3.3.4.1
Discontinuation of trial treatment
The End of Treatment (EOT) visit activities will be performed when a patient discontinues 
trial medication permanently.
A premature Follow-up (FU) visit is to be performed 7 days (+3 days) after end of treatment.
If the patient discontinued the trial medication more than a week prior to the EOT visit, this 
FU visit is not required. 
Ideally, patients who permanently discontinue trial medication should attend all remaining 
visits after treatment discontinuation. For those patients who are unable to complete the 
scheduled visits, at least phone contacts should occur at the scheduled visit time points. 
Should that not be acceptable, a phone contact at 52 weeks after randomization and at the end 
of the planned observation period should occur to collect the most relevant information: vital 
status (please see Section 5.2.6.2.1), adverse events, or last contact date in case of lost to 

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follow-up (LTFU). Every effort should be done to obtain the vital status information in case 
of LTFU. The number of LTFU patients should be limited. The need to obtain vital status 
information will be part of the patient information/informed consent procedure.
An individual patient will discontinue trial treatment permanently if:

The patient wants to discontinue trial treatment. The patient will be asked to explain the 
reasons but has the right to refuse to answer.

The patient has repeatedly shown to be non-compliant with important trial procedures 
and, in the opinion of both the investigator and sponsor representative, the safety of the 
patient cannot be guaranteed as he/she is not willing or able to adhere to the trial 
requirements in the future.

The patient exhibits suicidality, in the clinical judgment of the investigator or according 
to the following criteria:
o
any suicidal behavior (i.e. actual attempt, interrupted attempt, aborted attempt, or 
preparatory acts or behaviour)
o
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)

In case of occurrence of malignant neoplasm other than appropriately treated basal cell 
carcinoma or in situ squamous cell carcinoma of the skin or in situ carcinoma of uterine 
cervix

The patient will undergo lung transplantation, with an assigned date of surgery.

The patient becomes pregnant. For further details, please refer to Section 5.2.6.2.3

Patients with a BMI <18.5 kg/m2 that experience an additional, unexplained and clinically 
significant (>10%) weight loss during trial treatment
An individual patient should discontinue trial treatment temporarily if:

The patient has a new onset of severe depression as defined by a HADS subscore >14. 
o
Re-introduction of IMP could be considered after the patient has recovered, 
individual benefit-risk evaluation by the investigator and exclusion of 
BI 1015550-induced depression

The patient fulfills the AESI definition of hepatic injury. 
o
Re-introduction of IMP could be considered after the patient has recovered, 
individual benefit-risk evaluation by the investigator and exclusion of 
BI 1015550-induced liver injury

The patient has an event suspicious of vasculitis
o
If thorough evaluation does not confirm a causal relationship between trial 
medication and the event, treatment may be restarted based on the investigator’s 
medical judgement.

The patient needs to take concomitant medication that interferes with the safety of the 
investigational medicinal product or other trial treatment, e.g. CYP3A4 inhibitors as listed 
in Appendix 10.4.1,
o
Re-introduction of IMP could be considered at least 5 half-life times after the 
restricted medication has been stopped

The patient has to stop trial treatment for medical reasons such as surgery, adverse events, 
other diseases.

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For patients who temporarily pause the trial treatment due to specific adverse events (refer to 
Section 4.2.1) such as diarrhoea, severe infections, vasculitis, and concomitant medication 
related issues, every effort should be made to restart trial treatment if medically justified. The 
decision and associated reasoning for the restart of trial treatment should be documented in 
source data. 
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 or take any 
other appropriate action to guarantee the safety of the trial patients.
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.
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 refer to Section 3.3.4.1.
3. Deviations from GCP, the trial protocol, or the contract impairing the appropriate conduct 
of the trial.
Further treatment and follow up of patients affected will occur as described in 
Section 3.3.4.1.
The investigator / the trial site will be reimbursed for reasonable expenses incurred in case of 
trial termination (except in case of the third reason).
4.
TREATMENTS
4.1
INVESTIGATIONAL TREATMENTS
The investigational product has been manufactured by BI Pharma GmbH & Co. KG.
4.1.1
Identity of the Investigational Medicinal Products
The characteristics of the test products are given below:

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Table 4.1.1: 1
BI 1015550 9 mg
Substance:
BI 1015550
Pharmaceutical formulation:
Film-coated tablets
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG
Unit strength:
9 mg
Posology:
bid
Mode of administration:
Oral
Table 4.1.1: 2
BI 1015550 18 mg
Substance:
BI 1015550
Pharmaceutical formulation:
Film-coated tablets
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG
Unit strength:
18 mg
Posology:
bid
Mode of administration:
Oral
Table 4.1.1: 3
Placebo matching BI 1015550 9 mg
Substance:
Placebo matching in size, weight, colour and shape 
to BI 1015550
Pharmaceutical formulation:
Film-coated tablets
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG
Unit strength:
NA
Posology:
bid
Mode of administration:
Oral
Table 4.1.1: 4
Placebo matching BI 1015550 18 mg
Substance:
Placebo matching in size, weight, colour and shape 
to BI 1015550
Pharmaceutical formulation:
Film-coated tablets
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG
Unit strength:
NA
Posology:
bid
Mode of administration:
Oral
4.1.2
Selection of doses in the trial and dose modifications
Preclinical in vitro data and indirect target engagement data from Phase I trials support 
antifibrotic and anti-inflammatory activity of BI 1015550 at plasma concentrations related to 
the dose of 9 mg bid and 18 mg bid.
The predicted BI 1015550 trough plasma concentration at the steady state of both 9 mg 
 and 18 mg bid
doses are above the IC50 values for the inhibition of 

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target human PDE4B (10.3 nM). Furthermore, Phase I trials in healthy volunteers showed an 
indirect target engagement, using an ex vivo whole blood assay with an inhibition of LPS-
stimulated TNF-α and IFN-γ release (anti-inflammatory activity), starting at multiple doses of 
6 mg bid.
In the Phase I trials, single doses up to 48 mg and multiple doses up to 18 mg bid with up to 
12 weeks of treatment have been evaluated in healthy volunteers and patients with IPF. The 
maximum tolerated dose was not reached as BI 1015550 was well tolerated. The selected 
18 mg dose was tested in a Phase Ic trial (1305-0012) in IPF patients not on background 
antifibrotic treatment, administered for 4 to 12 weeks. In the Phase II trial (1305-0013), 
BI 1015550 at 18 mg bid dose was evaluated vs. placebo over a course of 12 weeks in 
147 IPF patients, of whom 74 were on a background treatment with antifibrotic (AF group) 
and 73 without antifibrotic background treatment (non-AF group). This trial showed 
substantial evidence of treatment benefit of BI 1015550 on FVC change from baseline at 
12 weeks in both the AF and non-AF groups [c37065416]. Treatment of BI 1015550 at a 
dose of 18 mg bid demonstrated an acceptable safety and tolerability in IPF patients over 
12 weeks.  
In addition, based on population PK/PD analysis of Phase II study 1305-0013 in IPF patients, 
the FVC response did not change as a function of exposure within the exposure range 
observed for the BI 1015550 18 mg bid dose given over 12 weeks. This suggested that the
maximum effect of BI 1015550 on FVC has been reached with the 18 mg bid dose 
[c37934954] consistent with the observed clinical stabilization of FVC over the treatment 
period. 
Based on the simulated exposure, 9 mg bid dose provides a sufficient differentiation in the 
distribution of exposure compared to 18 mg bid dose, supporting that 9 mg and 18 mg bid
doses provide wide ranges of plasma exposure to explore dose-response and exposure-
response relationship.
IPF and other forms of progressive pulmonary fibrosis are serious debilitating conditions 
characterized by worsening symptoms and quality of life, progressive loss of lung function, 
ultimately resulting in respiratory failure, and early death. At the same time, the currently 
approved antifibrotic treatments have limitations: they do not impact symptoms and cannot 
stop or reverse fibrosis. Under these circumstances, the highest BI 1015550 dose that is 
considered safe and well-tolerated (18 mg bid) was selected for the Phase III trials to 
maximise the potential for efficacy of the treatment, i.e. to preserve lung function and quality 
of life of patients. In order to provide further dose-response and exposure-response data, a 
dose of 9 mg bid has been chosen based on available preclinical data on target engagement 
and simulated exposure assessments, so that both efficacy and safety with this lower dose can 
be investigated with an expected therapeutic effect. Based on the data from the Phase II trial,
demonstrating a stabilization in FVC and an acceptable safety and tolerability profile, these
doses seem to provide a reasonable benefit to risk ratio for the patient treatment in this 
Phase III trial.

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4.1.3
Method of assigning patients to treatment groups
After the assessment of all inclusion and exclusion criteria, each eligible patient will be 
randomized in 1:1:1 ratio to either BI 1015550 9 mg bid, BI 1015550 18 mg bid, or placebo 
at Visit 2. Randomization (stratified by patient’s background AF-treatment at baseline) will 
be conducted via Interactive Response Technology (IRT). The appropriate medication 
number(s) will be assigned and documented in the CRF. Note that the medication number is 
different from the patient number (the latter is generated already during screening via the IRT 
system).
4.1.4
Drug assignment and administration of doses for each patient
During Visit 2, after randomization the patient will begin treatment for at least 52 weeks. The 
treatment will be assigned by an IRT contact during Visits 2, 4, 5, 6, 7, 8, 9. Patients that are 
treated in Treatment Period B will be assigned treatment at Visit 10 and the respective visits 
of Treatment Period B (every 12 weeks). The patient will receive either active treatment at a 
dose of 9 mg, 18 mg, or placebo. The first dose of BI 1015550 or placebo will be 
administered to the patient at the end of Visit 2 (Day 1) under direct supervision of the 
investigator or designee. On the day of any further clinic visit, supervision of administration
is not required but the treatment will preferably be administered to the patient during the visit.
Table 4.1.4: 1
Number of IMP kits dispensed at each visit
Trial visits
2
3
4
5
6
7
8
9
10   Treatment Period B    
Number of 
IMP kits 
dispensed
2
0
2
2
3
3
3
3
4*  4 per visit
* IMP kits will only be dispensed in case Visit 10 is not replaced with the EOT visit.
The trial medication will consist of 2 tablets to be taken orally twice daily. The patient should 
swallow the trial medication in its entirety (without chewing) with a glass of water 
(~250 mL), observing a 12-hour dose interval. The patient should ensure to take the trial 
medication at the same time every day (±30 mins), ideally between 6:00 and 11:00 in the 
morning and between 18:00 and 23:00 in the evening. There are no specific requirements 
regarding the timing of doses in relation to meals.
If taken around the same time (approximately within an hour), patients on nintedanib or 
pirfenidone background should take trial medication first, followed by the antifibrotic 
background medication. A missed 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. If an episode of vomiting 
happens after medication intake, redose with trial medication is not advised.
After a temporary interruption, trial treatment may be restarted (Section 3.3.4.1).
The investigational product should only be dispensed to participating patients according to 
the protocol by authorised personnel as documented in the ISF.

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4.1.5
Blinding and procedures for unblinding
4.1.5.1
Blinding
Patients, investigators, central reviewers, and everyone involved in trial conduct or analysis
or with any other interest in this double-blind trial will remain blinded regarding the 
randomized treatment assignments until the database is declared ready for analysis according 
to the sponsor’s SOPs. 
At the main analysis database lock (DBL1; see Section 3.1), the sponsor will be unblinded to 
assess the benefit-risk of both doses of BI 1015550 vs placebo and select the dose with the 
more favorable benefit-risk profile for the open-label extension trial. Patients, investigators, 
and other site personnel will remain blinded to the randomized treatment assignment until the 
end of the trial. 
The trial medication is identified by a medication code number and packaging is identical. 
The color, size, and shape of the respective 9 mg and 18 mg BI 1015550 and the matching 
placebo tablets will be indistinguishable. The access to the randomization code will be kept 
restricted until its release for analysis at DBL1. Further details regarding the timepoint of 
unblinding the database for analysis is documented in the TSAP.
The randomization codes will be provided to bioanalytics before DBL1 to exclude placebo or 
comparator samples from the PK analysis. Bioanalytics will not disclose the randomization
code or the results of their measurements until DBL1.
A dedicated database snapshot (not a partial DBL) will be generated prior to DBL1, after all 
patients have completed the last PK visit (i.e. Week-26 visit), to allow for development and 
refinement of the population PK model (for “fast-track” PK analysis). Details of the analysis 
will be defined in the PK/PD analysis plan. In addition, the data will be used for front-loading 
of descriptive analysis for PK. Only personnel involved in the population PK and descriptive
analyses will be granted access to the unblinded PK data before DBL1, whereas the trial team 
and all other functions not involved in the population PK and PK descriptive analyses will 
remain blinded (details will be provided in a separate logistics and access plan). The analysis 
plan for the population PK analysis will be finalized and signed prior to this dedicated
database snapshot.
No formal interim report will be generated for the population PK analysis. The final PK and 
PK/PD analyses will be reported separately from the clinical trial report (CTR) after DBL1.
The external DMC will review unblinded data upon request and for the futility interim 
analysis as described in Section 7.2.8, and only under conditions that ensure that patients, 
investigators, everyone involved in trial conduct or analysis, and anyone with any other 
participation in this double-blind trial will remain blinded.
If the 9 mg dose is considered futile based on the respective interim analysis (see 
Section 7.2.8), the patients will be re-assigned to the 18 mg dose in a blinded manner and the 
18 mg dose will be given at the next scheduled visit.

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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.
To avoid unblinding of the study team through drug safety reports which are to be unblinded
as per regulatory requirements, a procedure will be maintained to keep codebreaking in these
cases invisible to study team.
Due to the requirements to report Suspected Unexpected Serious Adverse Reactions 
(SUSARs), it may be necessary for a representative from BI’s Pharmacovigilance group to 
access the randomization code for individual patients during trial conduct. The access to the 
code will only be given to authorised pharmacovigilance representatives for processing in the 
PV database system and not be shared further. 
4.1.6
Packaging, labelling, and re-supply
The trial medication will be tablets containing 9 mg of BI 1015550, 18 mg of BI 1015550, or 
the respective matching placebo in a double-dummy design. Each trial medication kit is 
packaged in a child-resistant tamper-evident wallet containing 112 tablets of 9 mg or 18 mg 
BI 1015550 or the respective matching placebo. Wallets will cover 4 weeks of treatment.
Each wallet will be labelled with a multi-language booklet or country specific label according 
to the requirements of the participating countries.
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 expiration dates of supplies available at the sites.
For details of packaging and the description of the label, refer to the ISF.
4.1.7
Storage conditions
Drug supplies will be kept in their original packaging and in a secure limited access storage 
area according to the recommended storage conditions on the medication label. A
temperature log must be maintained for documentation.
If the storage conditions are found to be outside the specified range, the Clinical Research 
Associate (CRA, as provided in the list of contacts) must be contacted immediately.
All unused trial medication must be returned to the Sponsor or appointed Contract Research
Organization (CRO). Receipt, usage, and return must be documented on the respective
forms/IRT system. Account must be given for any discrepancies.

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4.1.8
Drug accountability
The investigator or designee will receive the investigational drugs delivered by the sponsor or 
delegate when the following requirements are fulfilled:

Approval of the clinical trial protocol by the IRB/ethics committee, HA/RA if applicable.

Availability of a signed and dated clinical trial contract between the sponsor or delegate
and the investigational site,

Approval/notification of the regulatory authority, e.g. competent authority,

Availability of the curriculum vitae of the Principal Investigator,

Availability of a signed and dated clinical trial protocol,

Availability of the proof of a medical license for the Principal Investigator,

Availability of FDA Form 1572 (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, expiration (‘use-by’) dates, 
and the unique code numbers assigned to the investigational medicinal product and trial
patients. The investigator or designee will maintain records that document adequately that the 
patients were provided the doses specified by the Clinical Trial Protocol (CTP) and reconcile 
all investigational medicinal products received from the sponsor. At the time of return to the 
sponsor and/or appointed CRO, the Investigator or designee must verify that all unused or 
partially used drug supplies have been returned by the clinical trial patient and that no 
remaining supplies are in the investigator’s possession.
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS
4.2.1
Other treatments and emergency procedures
There are no special emergency procedures to be followed.
Temporary treatment interruption is allowed to manage adverse events. All efforts should be 
made to re-start IMP after resolution of the adverse event according to the Investigator’s 
assessment.
Please find management guidance for specific adverse events below:
Diarrhea
Depending on the intensity of the events, the following management strategies are 
recommended: 

Counselling of patients, including potential diet modifications 

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
Monitor and maintain adequate hydration 

Treatment with loperamide or other antidiarrheal medications

For patients on antifibrotic medication, management strategies (e.g., dose reduction 
and/or temporary interruption) as described in the respective prescribing information 
should be followed
Temporary interruption of trial treatment can be considered, and trial treatment may be 
restarted when the patient has recovered according to investigator’s assessment.
Severe infections (CTCAE >2), serious infections, opportunistic or mycobacterium 
tuberculosis infections
Treatment of the infection should be initiated promptly according to local standard of care. 
No further trial medication should be administered until the active infection has resolved and 
trial treatment may be restarted when the patient has recovered according to investigator’s 
assessment.
Malignancies
In case of occurrence of malignant neoplasm other than appropriately treated basal cell 
carcinoma or in situ squamous cell carcinoma of the skin or in situ carcinoma of uterine 
cervix, the investigator should permanently discontinue trial treatment. Diagnostics and 
treatment must be initiated according to local standard of care.
Vasculitis
In case of events suspicious for vasculitis, trial treatment will be discontinued. A thorough 
work-up has to be initiated including at least but not limited to

appropriate imaging, including angiography

biopsy if possible

appropriate laboratory screening, including measurements of vasculitis markers at the 
central lab, see Section 5.2.3.3. In addition, an analysis of the previously collected and 
stored samples (baseline and/or Visit 10 samples) will need to be requested and 
considered.

thorough documentation of all reported symptoms
Referral to a vasculitis expert is recommended. If required, vasculitis treatment should be 
initiated according to standard of care. If thorough evaluation does not confirm a causal 
relationship between trial medication and the event, trial treatment may be restarted based on 
the investigator’s medical judgement.
New onset of severe depression or suicidality
In case of new onset of severe depression defined as HADS >14 or the patient exhibits any 
suicidal behaviour or serious suicidality ideation defined as type 4 or 5 in the C-SSRS 
interview, trial treatment has to be discontinued. Referral to a psychiatrist for further 
diagnoses and initiation of treatment is recommended.
In case of severe depression: If thorough evaluation does not confirm a causal relationship 
between trial medication and the event, and the patient has recovered, trial treatment may be 
restarted based on the investigator’s medical judgement (in case of new-onset of suicidality 
treatment has to be permanently discontinued).

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4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
Treatment with antifibrotic medication (nintedanib, pirfenidone)
AF group:
Patients who are on a stable dose of marketed antifibrotic treatment (nintedanib or 
pirfenidone) should plan to remain on this treatment for the duration of the trial. Interruption
and/or dose reductions of the background antifibrotic medication are left at the discretion of 
the investigator, e.g. to manage side effects in line with the respective prescribing 
information. Combined treatment with nintedanib plus pirfenidone is not allowed.
Non-AF group:
For patients not receiving nintedanib or pirfenidone in the 8 weeks prior to study entry, 
nintedanib and pirfenidone are restricted medications during the full duration of the blinded 
treatment period. Nintedanib or pirfenidone should not be initiated in the first 12 weeks of 
trial treatment. After that timeframe, initiation of nintedanib or pirfenidone is only allowed as 
rescue medication in case of disease worsening defined as disease under study progression 
and/or IPF exacerbation (by investigator judgement). 
Immunomodulatory treatment
Immunomodulatory medications (other than oral corticosteroids) or prednisone >15 mg/day 
or equivalent should not be started for respiratory indications during the screening or 
treatment period. However, prednisone >15 mg/day or equivalent can be prescribed during 
the treatment period in case of (suspected) acute IPF exacerbation.
Other restricted concomitant medication
While enrolled in this trial, patients must not participate in another investigational drug or 
device trial or receive other investigational treatment(s). 
Stem cell therapy for the treatment of pulmonary fibrosis is not allowed.
Treatment with non-selective PDE inhibitors as well as PDE4 inhibitors is not allowed.
Potent CYP3A4 inhibitors should not be administered during the screening and trial treatment 
periods. If short-term treatment with potent CYP3A4 inhibitor is needed (e.g., Paxlovid for 
the treatment of COVID-19; clarithromycin for antibiotic treatment), IMP should be 
temporarily discontinued (see Section 3.3.4.1 about conditions to re-introduce IMP). Non-
exhaustive lists of potent CYP3A inhibitors and PDE inhibitors are provided in the 
Appendix 10.4.1.

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Table 4.2.2.1: 1
Restrictions regarding concomitant treatment
Medication
Prior to Study1
Screening Period
Treatment Period A 
and B
Follow up 
period
Potent CYP3A inhibitors
Not permitted
Not permitted
Not permitted2
Permitted
Stem cell therapy for the 
treatment of pulmonary 
fibrosis
Not permitted
Not permitted
Not permitted
Not permitted
PDE4 and non-selective 
PDE inhibitors 
Not permitted
Not permitted
Not permitted
Not permitted
Immunomodulatory 
medications (other than oral 
steroids) or
Prednisone >15mg/day or 
equivalent3
used for respiratory/ 
pulmonary reasons
Permitted4
Not permitted
Not permitted5
Permitted
1.
Duration of restriction before screening see exclusion criteria Section 3.3.3
2.
If any short-term treatment with potent CYP3A4 inhibitor is needed, IMP should be temporarily discontinued
3.
Inhaled, intra-nasal, and topical corticosteroids are allowed
4.
Referring to historical episodes of intake, permitted unless the treatment is ongoing at time of Visit 1
5.
Prednisone >15 mg/day or equivalent can be prescribed during the treatment period in case of (suspected) acute 
IPF exacerbation.
4.2.2.2
Restrictions on diet and lifestyle
Patients should refrain from drinking grapefruit juice during the duration of the trial.
Patients should refrain from smoking or vigorous activity 1 hour before performing 
spirometry assessments.
4.2.2.3
Contraception requirements
Women of childbearing potential (WOCBP)2 must use highly effective methods of birth 
control per ICH M3 (R2) that result in a low failure rate of less than 1% per year when used 
consistently and correctly throughout the trial, and for a period of at least 7 days after last 
trial drug intake. A list of contraception methods meeting these criteria is provided below and 
in the patient information.
____________________________________________
2 A woman is considered of childbearing potential (WOCBP), i.e.fertile, following menarche and until becoming 
postmenopausal unless permanently sterile. Permanent sterilisation methods include hysterectomy, bilateral 
salpingectomy and bilateral oophorectomy. Tubal ligation is NOT a method of permanent sterilisation. A 
postmenopausal state is defined as no menses for 12 months without an alternative medical cause.

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Acceptable highly effective methods of contraception include:

Non-oral hormonal methods of contraception associated with inhibition of ovulation:
o
Intravaginal or transdermal combinations of estrogen and progestogen
o
Injectable or implantable progestogen

Oral hormonal contraceptives together with one barrier method (e.g. condom) to account 
for the risk of potentially reduced efficacy of the OCs in the event of severe vomiting and 
diarrhea. In case of vomiting or diarrhea, instructions in the label of the OC should be 
followed in addition. In case of prolonged (>48h) or repeated vomiting/diarrhea, the use 
of an alternative highly effective contraceptive measure should be considered

Intrauterine device (IUD) or intrauterine hormone-releasing system (IUS)

Bilateral tubal occlusion

Vasectomised sexual partner with appropriate post-vasectomy documentation of the 
absence of sperm in the ejaculate, provided that partner is the sole sexual partner of the 
study participant

Complete abstinence from male-female sex when this is in line with the preferred and 
usual lifestyle of the study participant. 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 or delegate.
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.
5.
ASSESSMENTS
5.1
ASSESSMENT OF EFFICACY
5.1.1
FVC
Spirometry measurements will be performed according to ATS/ERS 2019 guideline 
[R20-2419]. FVC will be assessed using standardised spirometry equipment which will be 
provided centrally with supplies of precalibrated disposable flow sensors. These sensors meet 
International Organization for Standardization (ISO) 26782 standards, but with a maximum 

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permissible accuracy error of ±2.5%, in accordance with the American Thoracic Society 
(ATS)/European Respiratory Society (ERS) Technical Statement [R20-2419]. 
As such there is no need to conduct daily calibration prior to use. Only these spirometers are 
to be used for this trial. Spirometry performance will be centrally reviewed.
Spirometry will be conducted with the patient 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 FVC obtained on any of three blows meeting the 2019 ATS/ERS 
criteria (with a maximum of eight attempts). Predicted normal values will be calculated 
according to GLI (Global Lung Initiative).
Efforts should be made to schedule the spirometric measurements at approximately the same 
time of the day, at least within the same half-day (morning vs. afternoon), with reference to 
baseline measurement (Visit 2). On days of study visits, patients should be encouraged to 
refrain from vigorous activity and smoking within 1 hour of pulmonary function testing. If 
treated with bronchodilators, washout according to Appendix 10.1 should be advised before 
spirometry and documented in the source documents.  
Spirometry results will be electronically transmitted. To ensure the quality of the primary 
endpoint measurement, a central spirometry review is put in place to provide feedback to the 
investigational site and the CRA on the quality of the data received from the site. In case 
unacceptable results for FVC/FEV1 at V1 or FVC at V10 are obtained after the review, the 
patient must be reassessed.
Further instructions regarding FVC measurements will be provided in the ISF.
Optional assisted home spirometry measurements
At selected sites with respective setup, assisted home spirometry can be conducted 
intermittently during the trial and as a fallback/contingency option. 
For the assisted home spirometry, patients may be using a handheld spirometer (iSpiro) 
together with a mobile phone with the installed iSpiro App provided by site. Training of the 
patients on the use of the iSpiro device and App can be done at any visit, ideally at Visit 2 or 
Visit 3 together with a first recording. During the treatment phase, the iSpiro device and the 
respective phone with the App will be provided to the patient upon decision of the 
investigator in order to perform an assisted (via video call) home spirometry either at 
unscheduled visits or as a fallback solution if the patient is unable to get to the site for the 
scheduled visit. 
These home spirometry measurements will not replace the onsite FVC measurement at Visit
2 (Day 1), Visit 5 (Week 12), Visit 7 (Week 26), Visit 10 (Week 52) and the visit for EOT; 
every effort should be made to obtain an onsite spirometry within the planned visit window.
5.1.2
Exacerbation of IPF
The most recent definition of acute IPF exacerbation will be used [P16-06899]. 

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Such events 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 1 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 as adverse event in the category “acute exacerbation of disease 
under investigation”.  
Events that are clinically considered to meet the definition of acute IPF exacerbation but fail 
to meet all diagnostic criteria above due to missing CT data must be reported as “suspected 
acute exacerbations of disease under investigation” (as long as this assessment persists). Both 
confirmed and suspected cases will be considered for the endpoint evaluation.
5.1.3
Time to death
Time to death will be based either on the date of death on the AE report for patients with AEs 
leading to death or will be based on the information from the vital status assessment.
5.1.4
Hospitalization due to respiratory cause
Hospitalization due to respiratory cause will be collected on a specific non-elective 
hospitalization CRF page. The CRF page will capture the date of hospitalization, whether the 
non-elective hospitalization was due to respiratory cause, and the primary admission 
diagnosis.
5.1.5
Patient-Reported Outcome Questionnaires
The patient will complete patient-reported outcome (PRO) questionnaires preferably 
according to the prespecified order defined hereafter:
Questionnaires completed by patient:
1. Living with Pulmonary Fibrosis Symptoms and Impact Questionnaire (L-PF)
2. EuroQol 5-Dimensional quality of life Questionnaire (EQ-5D)
3. Hospital Anxiety and Depression Scale (HADS, Section 5.2.5.2)
4. Patient’s Global Impression of Severity (PGIS) for Cough, Shortness of Breath, and 
Fatigue
Patients may complete these questionnaires at site or at home if they so choose to. The 
questionnaires may be completed either on paper versions, with site provided tablet, a mobile 
phone provided centrally or via an App downloaded to patient’s personal device.
Patients are asked to be in a quiet area/room prior to any other trial related examination and 
should complete these questionnaires without any help from or interpretation by other people. 
If the patient is too sick to complete the questionnaires him/herself but is able to reply 
verbally, a member of the study team should read the instructions, questions, and response 
options aloud to the patient and collect the patient’s verbal response in as neutral and 

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unbiased a manner as possible. If this is not possible either, the questionnaires are not to be 
completed. 
If done at home, patient should compile the questionnaire preferably the same half-day as the 
intended scheduled site visit (morning or afternoon) and within the last 3 days before the site 
visit. 
For the compilation of paper questionnaires, the site personnel will check the patient
questionnaires for completeness prior to the patient leaving the site, but the response to each 
item will not be tampered with, and a patient should not be influenced in any manner on how 
to respond to the question. Scores will be entered into the eCRF by the site-personnel. 
For patient-reported outcomes compiled on electronic devices, completeness and consistency 
checks will be programmed into the App and no further check by site personnel is needed. 
Data from these patient outcome reports will be electronically submitted.
5.1.5.1
Living with Pulmonary Fibrosis Symptoms and Impact Questionnaire (L-PF)
The Living with Pulmonary Fibrosis (L-PF) questionnaire is a 44-item questionnaire with two 
modules: 1) Symptoms (23 scored items plus 5 oxygen questions) and 2) Impacts (21 items). 
L-PF was developed with the input of patients with pulmonary fibrosis (PF) and thus is 
intended to capture perceptions specific to PF patients. 
The Symptoms module yields three domain scores: 1) dyspnea, 2) cough, and 3) fatigue as 
well as a total Symptoms score. There are 5 additional questions pertaining to oxygen use at 
the end of the Symptoms module. The Impacts module yields a single Impacts score. 
Symptoms and Impacts scores are summed to yield a total L-PF score. Scoring is performed 
as a summary score, the mean of the dimension ratings multiplied by 100. For details, please 
refer to the TSAP.
The L-PF Symptoms and Impact Questionnaire (Appendix 10.2.1) will be self-administered
by the patient at visits indicated in the flow chart.
5.1.5.2
EuroQol 5-Dimensional quality of life Questionnaire (EQ-5D)
The EQ-5D was developed by the European Quality of Life Group (EuroQol Group) and is a 
standardized instrument for use as a measure of health outcomes [R96-2382]. The version 
used in this trial is the new five-level version (EQ-5D-5L).
The questionnaire essentially consists of 2 pages. The first page is the descriptive system with 
5 questions to the patient´s health state today. Each question captures one dimension of health 
(e.g. mobility, self-care) and has five levels to answer. The second page records the patient´s 
self-rated health status of today on a vertical graduated (0 to 100) visual analogue scale.
The EQ-5D (Appendix 10.2.2) will be self- administered by the patient at visits indicated in 
the flow chart.

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5.1.5.3
Patient’s Global Impression of Severity (PGIS) of Cough, Shortness of Breath
and Fatigue
The PGIS questionnaire will ask the patient to think about their cough and reflect how it was 
in the past 7 days: “recall whether you have had a cough and if so, how frequently it has 
occurred, how severe it has been, and whether cough has affected how you feel and how you 
function in your daily life. Considering all these, please rate the severity of your cough over 
the last 7 days by placing a tic in the one box corresponding to your response: not present, 
very mild, mild, moderate, severe, and very severe.”
The patient will be asked to think about shortness of breath and reflect on the last 7 days: 
“call to mind how severe it has been and whether shortness of breath has affected how you 
feel and how you function in your daily life. Considering all these, please rate the severity of 
your shortness of breath over the last 7 days by placing a tic in the one box corresponding to 
your response: not present, very mild, mild, moderate, severe, and very severe.”
If applicable, the patient will be asked to complete the PGIS fatigue to assess the patient’s
severity of fatigue. The measure consists of 1 item/question asking patients to rate their 
severity of fatigue on a 5-point Likert scale ranging from “no symptoms” to “very severe” 
including a recall “over the past 24 hours”.
The PGIS (Appendix 10.2.4) will be self- administered by the patient at visits indicated in the 
flow chart.
5.1.6
DLCO
The site will use its own carbon monoxide diffusion capacity (DLCO) equipment and 
conduct all measurements with the same DLCO equipment in case that several devices are 
available at the site. Single-breath DLCO measurement will be carried out according to the 
ATS/ERS guideline on DLCO measurements [R06-2002]. Raw data (gas mixture, equation 
used for prediction of normal, further adjustments made if so) must be traced.
Two acceptable DLCO measurements and the corresponding alveolar volume will be taken at 
time points indicated in the flow chart. Both acceptable DLCO measurements will be 
recorded. Maneuvers will be demonstrated before beginning of the test, and the patient will 
be carefully instructed. 
Predicted DLCO value will be corrected for hemoglobin (Hb). The site has to enter the 
unadjusted predicted DLCO result without Hb correction in the eCRF. This value will be 
adjusted for the most recent Hb value. 
At Visit 1, the most recent Hb value (ideally on the same day) will be entered into the eCRF 
to correct the DLCO value. During subsequent visits, Hb values will be transferred from the 
central lab and corrections will be done automatically (not visible into the eCRF).
For predicted normal values, different sites may use different prediction formulas, based on 
the method used to measure DLCO. In any case, the calculation method used must be in 
compliance with the ATS/ERS guideline on DLCO measurements [R06-2002] and the 
prediction formula appropriate for that method. 

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Predicted DLCO corrected for Hb, with Hb expressed in g·dL-1 [R06-2002], will be 
calculated in the eCRF as:

Males:
DLCO predicted for Hb = DLCO predicted [1.7Hb / (10.22 + Hb)]

Females: DLCO predicted for Hb = DLCO predicted [1.7Hb / (9.38 + Hb)]
Percent predicted DLCO corrected for Hb (unit: %) at Visit 1 will be calculated in the 
eCRF with the following formula:
Percent predicted DLCO corrected for Hb = (Mean value of two DLCO measurements, 
expressed in mmol/min/kPa) / Predicted DLCO corrected for Hb) * 100
For each patient, spirometry testing and DLCO should always start at approximately the same 
time of day. DLCO must be performed after spirometry on the same day.
5.2
ASSESSMENT OF SAFETY
5.2.1
Physical examination
A 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. Measurements of height and body weight will be performed at the time 
points specified in the flow chart. The results must be included in the source documents 
available at the site. 
All abnormal findings at baseline will be recorded on the Baseline Condition eCRF page. 
New abnormal findings or worsening of baseline conditions detected at the subsequent 
physical examinations, if judged clinically relevant, will be recorded as adverse events on the 
appropriate eCRF page.
5.2.2
Vital signs
Vital signs will be evaluated at the time points specified in the flow chart, prior to blood 
sampling.
This includes systolic and diastolic blood pressure and pulse rate (electronically or by 
palpation count for 1 minute) in a seated position after 5 minutes of rest. Additionally, SpO2 
will be measured via pulse oximetry.
The results must be included in the source documents available at the site.
5.2.3
Safety laboratory parameters
Safety laboratory parameters to be assessed are listed in Table 5.2.3.1: 1. For the sampling 
time points please see the flow chart.
All analyses will be performed by a central laboratory, the respective reference ranges will be 
provided in the ISF. 

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Patients do not have to be fasted for the blood sampling for the safety laboratory. 
Instructions regarding sample collection, sample handling/processing and sample shipping 
are provided in the Laboratory Manual in the ISF. 
The central laboratory will send reports to the investigator. It is the responsibility of the 
investigator to evaluate the laboratory reports. Clinically relevant abnormal findings as 
judged by the investigator will be reported as adverse events (please refer to Section 5.2.6).
In case the criteria for hepatic injury are fulfilled, a number of additional measures will be 
performed (please see Section 5.2.6.1.4 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 or delegate.
5.2.3.1
Routine safety lab tests
Table 5.2.3.1: 1 Safety laboratory tests
Functional lab group
Test name 
Hematology
Hematocrit
Hemoglobin
Red blood cells (RBC)
White blood cells (WBC)
Platelet count
MCV
MCH
MCHC
RDW
Automatic WBC differential 
(relative and absolute)
Neutrophiles total
Lymphocytes total
Eosinophiles 
Basophiles 
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 (PT)
INR
Enzymes
Aspartate aminotransferase (AST) 
Alanine aminotransferase (ALT) 
Alkaline phosphatase (AP)
Gammaglutamyl transferase (GGT)  
Creatine kinase (CK)
Lipase
Amylase
Substrates
Glucose
Creatinine

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Functional lab group
Test name 
Urea Nitrogen
Uric Acid
Total bilirubin 
Direct bilirubin
Total protein
Albumin
Globulin
Albumin / Globulin ratio
C-Reactive Protein (CRP) 
Total cholesterol 
Electrolytes
Calcium
Sodium
Potassium
Chloride
Phosphate
Serum Pregnancy test (only for female patients of 
childbearing potential) at screening (V1) and at any 
visit where urine pregnancy test is positive
Human Serum Chorionic Gonadotropin
Urinalysis (qualitative determination)
Urine nitrite
Urine protein
Urine glucose
Urine ketone
Urine bilirubin
Urine hemoglobin ( detects erythrocytes) 
Urine leukocyte esterase (detects leucocytes)
Urine pH
Specific gravity
Urine sediment (microscopic examination if 
erythrocytes, leukocytes nitrite or protein are 
abnormal in urine)
Only positive findings will be reported (e.g. presence 
of sediment bacteria, casts in sediment, squamous 
epithelial cells, erythrocytes, leukocytes)
Urine Pregnancy test (only for female patients of 
childbearing potential) at V2 and following visits
Human Chorionic Gonadotropin in the urine
eGFR will be analyzed and calculated by the central laboratory at the same timepoints as 
other safety laboratory parameters (refer to flow chart). eGFR will be calculated by using the 
CKD-EPI formula and using the Jaffe assay for serum creatinine measurement, IDMS 
standardized.
5.2.3.2
Infection serology
The following lab tests for infection serology will be performed as indicated in the flow 
chart:

Hepatitis B surface antigen (qualitative) and Hepatitis B core antibody (qualitative)

HBV-DNA PCR (quantitative), which should be conducted if Hepatitis B core 
antibody is positive and Hepatitis B surface antigen is negative

Hepatitis C antibodies (qualitative), where a positive Hep C antibodies test result 
should be confirmed by PCR

HIV-1 and HIV-2 antibody (qualitative)

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
IGRA-T (e.g. QuantiFERON®-TB Gold IT Test, provided by central lab):
If the first QuantiFERON®-TB-Gold Plus (or if applicable, T-Spot®) test result is 
undetermined, a retest should be performed. 
If the retest QuantiFERON®-TB-Gold Plus test result is undetermined, a PPD skin test 
should be performed.
For specific countries (e.g. Japan): T-Spot® TB test may be performed at local labs 
instead of QuantiFERON®TB test
In case of positive TB test, further diagnostic work up to confirm/exclude the 
diagnosis of latent or active is needed (documentation on respective eCRF page).
5.2.3.3
Immunological vasculitis markers
At Visit 2, Visit 10 and in case of a suspected vasculitis an additional blood sample will be 
taken. It will be stored and analyzed for the following immunological vasculitis markers:

MPO-ANCA 

PR3-ANCA

IL-6 

antiglomerular basement membrane (GBM) antibodies 

anti-C1q antibodies (immune complex-associated small-vessel vasculitis)

rheumatoid factor

antinuclear antibodies

complement C3, C4, CH 50, anti-C1q antibodies.
Due to stability matter during storage, ANCA markers (MPO-ANCA and PR3-ANCA) from 
Visit 2 and Visit 10 are analyzed upon receipt, but investigators will not receive these results 
as it could influence their judgement regarding a suspected vasculitis. The rest of the analysis 
of immunological vasculitis markers is performed if an unscheduled “Vasculitis event” is 
collected. In this situation, the site will receive the result for all vasculitis markers previously 
performed (from V2 and V10 if already done) and from the unscheduled “Vasculitis event” 
kit. These results are shared by the trial team to the site via the CRA.
5.2.4
Electrocardiogram
The 12-lead ECGs must be administered by a qualified technologist and results will be 
recorded as scheduled in the flow chart. The investigator or a designee will evaluate whether 
the ECG is normal or abnormal and assess clinical relevance. ECGs may be repeated for 
quality reasons and a repeated recording used for analysis. 
Additional ECGs may be recorded for safety reasons. Dated and signed printouts of ECG 
with findings should be documented in patient’s medical record.
Clinically relevant abnormal findings will be reported either as baseline condition (if 
identified at the screening visit) or otherwise as AEs and will be followed up and / or treated 
as medically appropriate.

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5.2.5
Other Safety parameters
5.2.5.1
Suicidal risk (C-SSRS)
Prospective monitoring will be conducted throughout this trial using the Columbia-Suicide
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 behaviour 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/baseline’ version) with the aim to 
exclude patient’s suicidal ideation type 4 to 5 within the preceding 3 months or at Visit 1 or 
any suicidal behaviour in the past 2 years. The lifetime history of suicidal ideation and 
behaviour will also be recorded.
After Visit 1, the assessment ‘since last visit’ will be performed at each clinic visit (‘since last 
visit’ version).
Appendix 10.3 details how the C-SSRS will be assessed.
C-SSRS results will be reported in terms of AEs as described in Section 5.2.6.2.
5.2.5.2
Depression and anxiety
Prospective monitoring using the Hospital Anxiety and Depression Scale (HADS). 
This questionnaire is patient friendly and easy to use and takes less than 5 minutes for 
completion. The questionnaire comprises seven questions for anxiety and seven questions for 
depression that are scored separately. Cut-off scores are available for quantification: The 
HADS questionnaire has been validated in many languages, countries and settings including 
general practice and community settings and is one of the tools recommended by National 
Institute for Health and Care Excellence (NICE) for diagnosis of depression and anxiety and 
is included in the American Thoracic Society’s list of patient-reported outcome measures for 
use in ILD [R22-1857, R22-1856]. The HADS (Appendix 10.2.3) will be self-administered.
5.2.6
Assessment of adverse events
5.2.6.1
Definitions of AEs 
5.2.6.1.1
Adverse event
An AE is defined as any untoward medical occurrence in a patient or clinical investigation 
patient administered a medicinal product and which does not necessarily have to have a 
causal relationship with this treatment.

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An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether considered related or not.
The following should also be recorded as an AE in the 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.
Adverse event report for diarrhea events
In case of events of diarrhoea the following definitions should be followed:
Diarrhoea is defined ≥3 loose/liquid stools per day (WHO definition)
Diarrhoea episode = 2 diarrhoea episodes are separated by at least 7 days without any 
diarrhoea
Adverse event report for depression and anxiety
AE reporting based on the Hospital Anxiety and Depression Scale (HADS): new onset of 
moderate depression, defined as HADS subscore of >10, has to be reported as AE; new onset 
of moderate anxiety, defined as HADS subscore of >10, has to be reported as AE. HADS 
subscore of ≤10 should only be reported as an AE if clinically relevant. See Section 5.2.6.1.4
for reporting of AESI based on HADS.
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 
medial or surgical intervention to prevent one of the other outcomes listed in the 
above definitions. Examples of such events are intensive treatment in an emergency 
room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do 
not result in hospitalisation or development of dependency or abuse. 
For Japan only: 
An event that possibly leads to disability will be handled as ‘deemed serious for any other 
reason’ and, therefore, reported as an SAE.

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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 5.2.6.1.2.
Every occurrence of cancer of new histology must be classified as a serious event regardless 
of the time since the discontinuation of the trial medication and must be reported as described 
in Section 5.2.6.1.2, subsections “AE Collection” and “AE reporting to sponsor and 
timelines”.
SAE reporting in case of 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.
5.2.6.1.4
Adverse events of special interest
The term adverse events of special interest (AESI) relates to any specific AE that has been 
identified at the project level as being of particular concern for prospective safety monitoring 
and safety assessment within this trial, e.g. the potential for AEs based on knowledge from 
other compounds in the same class. AESIs need to be reported to the sponsor’s 
Pharmacovigilance Department within the same timeframe that applies to SAEs, please see 
Section 5.2.6.2.2.
The following are considered as AESIs:

Potential severe DILI

Vasculitis

Severe infections (CTCAE >2), serious, opportunistic, or mycobacterium tuberculosis 
infections (refer to Appendix 10.5)

New onset of severe depression, defined as HADS subscore >14

New onset of severe anxiety, defined as HADS subscore >14
Management of specific AEs is described in Section 4.2.1, specific additional procedures to 
be performed in case of a suspected AESI are described in this section:

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Potential Severe DILI
A potential severe Drug Induced Liver Injury (DILI) that requires follow-up 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 sample, or in samples drawn within 30 days of each 
other, or

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 in the ISF.
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 
analyzed, 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.
For patients with abnormal aminotransaminase levels between >1 and <3 x ULN at baseline:

An elevation of AST and / or ALT ≥3-fold the baseline value combined with an 
elevation of bilirubin ≥2-fold ULN or ≥2-fold the baseline value (if bilirubin is 
elevated at baseline), measured in the same blood sample, or in samples drawn within 
30 days of each other; or;

Aminotransferase elevations ≥5-fold the baseline value.
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.
The investigator should monitor for any signs and symptoms of vasculitis at all times and 
specifically as part of the AE questioning.
In case of (suspected) events of vasculitis, further work-up and management as outlined in 
Section 4.2.1 has to be followed, including biopsy, appropriate imaging/angiography, 
laboratory measures (e.g. additional lab sample for immunological and further inflammation 
markers). Details will be collected on a dedicated eCRF page and events will referred for 
adjudication to an independent adjudication committee.
5.2.6.1.5
Intensity (severity) of AEs
The intensity (severity) of the AE should be judged based on CTCAE grading (see ISF for 
grading of specific events) 
Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only;
intervention not indicated.
Grade 2: Moderate; minimal, local or non-invasive intervention indicated; limiting age
appropriate instrumental activities of daily living 

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Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization 
or prolongation of hospitalization indicated; disabling; limiting self-care activities 
of daily living. 
Grade 4: Life-threatening consequences; urgent intervention indicated. 
Grade 5: Death related to AE.
5.2.6.1.6
Causal relationship of AEs
Medical judgement should be used to determine the relationship between the adverse event 
and the BI investigational compound, considering all relevant factors, including pattern of 
reaction, temporal relationship, de-challenge or re-challenge, confounding factors such as 
concomitant medication, concomitant diseases and relevant history. 
Arguments that may suggest that there is a reasonable possibility of a causal relationship 
could be:

The event is consistent with the known pharmacology of the trial drug.

The event is known to be caused by or attributed to the drug class.

A plausible time to onset of the event relative to the time of drug exposure.

Evidence that the event is reproducible when the drug is re-introduced.

No medically sound alternative aetiologies that could explain the event (e.g. pre-
existing or concomitant diseases, or co-medications).

The event is typically drug-related and infrequent in the general population not 
exposed to drugs (e.g. Stevens-Johnson syndrome).

An indication of dose-response (i.e. greater effect size if the dose is increased, smaller 
effect size if dose is reduced).
Arguments that may suggest that there is no reasonable possibility of a causal relationship 
could be:

No plausible time to onset of the event relative to the time of drug exposure is evident 
(e.g. pretreatment cases, diagnosis of cancer or chronic disease within days / weeks of 
drug administration; an allergic reaction weeks after discontinuation of the trial drug 
concerned).

Continuation of the event despite the withdrawal of the medication, considering 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.

There is an alternative explanation, e.g. situations where other drugs or underlying 
diseases appear to provide a more likely explanation for the observed event than the 
drug concerned.

Disappearance of the event even though the trial drug treatment continues or remains 
unchanged.
5.2.6.2
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.

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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 (EOS) 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 drug related SAEs and trial drug related 
AESIs of which the investigator may become aware of by any means of 
communication, e.g. phone call. Those AEs should be reported on the BI SAE form 
(see Section 5.2.6.2.2), but not on the CRF.
Vital Status Data Collection
Patients who discontinue trial treatment prematurely, who agree to be contacted further but 
do not agree to physical visits, should be followed up as described in Section 3.3.4.1, 
withdrawal from trial treatment. From then on until the individual patient’s end of the trial the 
investigator must any occurrence of cancer, report all deaths/fatal AEs regardless of 
relationship, and trial drug related SAEs and trial drug related AESIs the investigator 
becomes aware of. 
5.2.6.2.2
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 AE or SAE eCRF pages to the sponsor’s unique entry point
within 24 hours of becoming aware of the event, the country specific process will be 
specified in the ISF. The same timeline applies if follow-up information becomes available. 
In specific occasions, the investigator could inform the sponsor upfront via telephone in 
addition.
With receipt of any further information to these events, a follow-up reports have 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.
Should the eDC system not be available for more than 24 hours, reporting must occur via the 
BI paper SAE forms.
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.

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Reporting and consenting must be in line with local regulations. The ISF will contain the trial 
specific information and consent for the pregnant partner.
The outcome of the pregnancy associated with the drug exposure during pregnancy must be 
followed up and reported to the sponsor’s unique entry point on the Pregnancy Monitoring 
Form for Clinical Studies (Part B).
The ISF will contain the Pregnancy Monitoring Form for Clinical Studies (Part A and B).
As pregnancy itself is not to be reported as an AE, in the absence of an accompanying SAE 
and/or AESI, only the Pregnancy Monitoring Form for Clinical Studies and not the SAE form 
is to be completed. If there is an SAE and/or AESI associated with the pregnancy an SAE 
form must be completed in addition.
5.2.6.3
Independent safety monitoring and adverse events with additional information 
collection
An independent data monitoring committee (DMC) will conduct regular reviews of the trial 
safety data, as detailed in  the DMC charter.
An independent adjudication committee will review all fatal cases (to review the primary 
cause of death). The independent adjudication committee will also review all adverse events 
categorized as major adverse cardiovascular events (MACE).
A separate independent adjudication committee will review all events categorized as 
vasculitis (SMQ vasculitis broad).
Before providing any copy of patients’ source documents to the sponsor, 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 to ensure patient 
confidentiality.
Additional details (on top of standard AE and SAE reporting) will be collected in the eCRF 
for the adverse event ‘Diarrhea/gastrointestinal events’, the adverse events in the Standard 
MedDRA Query (SMQ) ‘vasculitis’ and in case of positive TB tests (see Section 5.2.3.2).
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS
5.3.1
Assessment of pharmacokinetics
Cpre,ss (predose concentration of analyte in plasma at steady state) will be the main PK 
parameter determined in this study. Further PK parameters might be calculated as 
appropriate.
Date and clock time of PK sampling, the two preceding and the current drug administrations
will be recorded in the CRFs. The actual sampling times will be used for determination of the 
PK parameters.
PK sampling will be performed predose at the time points indicated in the flow chart.

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5.3.2
Methods of sample collection
For quantification of drug plasma concentrations of BI 1015550, venous blood will be 
collected using a prelabeled EDTA (Ethylenediaminetetraacetic acid) containing blood 
drawing tube at the times indicated in the flow chart. Blood will be withdrawn by means of 
either an indwelling venous catheter or by venipuncture with a metal needle. A detailed 
description of sample collection and handling is provided in the Lab Manual in the ISF. 
Plasma samples will be discarded at latest 6 months after the final clinical trial report has 
been signed.
5.4
ASSESSMENT OF BIOMARKERS
Biomarkers associated with ILD pathology will be explored in serum, plasma, and whole 
blood and will be correlated with clinical endpoints.
5.4.1
Pharmacodynamics biomarkers
Effects of BI 1015550 treatment on several protein biomarkers such as, but not limited to,
KL-6, MMP-7, SP-D, COMP, vWF, CA-125, and CA19-9 will be investigated. Further 
protein markers will be evaluated and correlated to clinical endpoints. In addition, effects of 
BI 1015550 treatment on the formation of
 
and others will be 
evaluated and correlated to clinical endpoints.
Total mRNA expression levels in whole blood and miRNA levels in plasma will be evaluated 
to investigate the drug’s mode of action or the pathology and course of the disease.
All biomarkers assessed in this trial are considered exploratory and qualified assays will be 
used according to the sponsor’s procedures. Characteristics of the analytical methods for the 
analysis of plasma and serum biomarkers will be given in detail in the analytical report.
Genome-wide expression profiling will be performed by RNA sequencing including 
bioinformatics analysis. Further characteristics of the analytical method for the analysis will 
be given in detail in the analytical report.

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Changes in serum and plasma biomarkers, and in gene expression (RNA) levels will be 
analyzed over time, pre- and post-treatment with BI 1015550.
All assessed biomarkers will either be analyzed at the sponsor or at a CRO. The results of 
biomarker analyses will be reported separately in biomarker reports.
5.4.1.1
Methods and timing of sample collection
Whole blood will be collected for the preparation of serum, plasma, and RNA expression 
analysis. 
Overall about 75 mL blood will be taken for explorative biomarker assessment during the 
course of the trial.
Remaining samples may be used for method development and evaluation and will be stored 
for a maximum of 3 years after approval of the clinical trial report.
Details about sample collection and sample handling will be provided in the ISF. A detailed 
overview of biomarker sample collection visits is outlined in the flow chart.
A detailed description of biomarker sample collection and sample handling is provided in the 
ISF.
5.5
BIOBANKING
Participation in biobanking is voluntary and not a prerequisite for participation in the trial. 
Biobanking will only occur after a separate biobanking informed consent has been given in 
accordance with local ethical and regulatory requirements. Any country not approving the 
biobanking will not participate in this process.
5.5.1
Methods and timing of sample collection
Detailed instructions on sampling, preparation, processing, shipment, and storage are 
provided in the laboratory manual. For sampling timepoints see flow chart.
Serum/plasma from the original whole blood sample will be stored at an external biobanking 
facility contracted by the sponsor. 
The following samples will be banked:
Unspecified pharmacogenomics (PGx) samples (DNA banking):
An additional blood sample (approximately 8.5 mL) for DNA banking will be collected in 
PAXgene Blood DNA tube at Visit 2. The DNA banking sample, derived from the original 
blood sample, will be stored at Boehringer Ingelheim. The stored DNA may be 
retrospectively analyzed.

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Unspecified serum/plasma samples (serum/plasma banking):
Whole blood will be collected for the preparation of serum and plasma for banking purposes. 
In total, a maximum of 74 mL of blood will be drawn for the purpose of serum/plasma 
banking. 
5.6
OTHER ASSESSMENTS
5.6.1
Chest HRCT assessment
Screening chest HRCT will be used in all patients to determine study eligibility.  
An historical HRCT can be used to determine eligibility, providing the scan was performed 
within the 12 months prior to screening. If a 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 vendor for central review and confirmation of UIP or 
probable UIP HRCT pattern (for detailed specifications see Appendix 10.6) prior to 
randomization. Confirmation of eligibility must be available prior to randomization Visit 2. 
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.
To perform a HRCT within the trial, all local regulatory requirements to perform an HRCT 
have to be met. In Germany, no HRCT will be performed as trial procedure; only historical 
HRCT will be submitted.
In addition to central reading of the HRCT scans, there is the intention to apply a computer 
scoring technology. If feasible, this technology will only be applied for scientific reasons and 
learnings and results will not be part of the clinical trial report. Determination of eligibility 
will, however, always be based on the central visual reading.
5.6.2
Health care resource utilization (HCRU) 
For the purpose of a separate health economic analysis (such as cost-utility analysis), health 
care resource utilization (HCRU) data will be collected throughout the trial. Resource use 
data collected for calculating direct costs will include unscheduled hospitalizations, 
healthcare provider visits, and emergency room/intensive care unit use. Non-medical resource 
use data will include changes in work productivity. 
The economic evaluation of the HCRU data will not be part of the clinical trial report.
5.7
APPROPRIATENESS OF MEASUREMENTS
All measurements conducted for primary and secondary endpoints are using standard 
methods. The pharmacokinetic parameters and measurements outlined in Section 5.3 are 

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generally used as measurements to assess drug response. Measures conducted for exploratory 
endpoints might be new methodologies used in clinical trials but not yet validated for IPF.
6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
The trial consists of 2 parts: Treatment Period A and B. Treatment Period A will consist of 
Visits 2 through 10, which will occur within one year of randomization. Following 
completion of the Week 52 visit (Visit 10), patients will continue to have trial visits every 
12 weeks (Treatment Period B) until the end of the trial. 
The trial will last the until last patient completes the EOT Visit and the Follow-up Visit as 
applicable (see Figure 3.1: 1).
After giving informed consent, the patient will be screened for inclusion (see Section 3.3.2) 
and exclusion criteria (see Section 3.3.3) for the trial at Visit 1 and Visit 2 (refer to flow chart
Treatment Period A). Visit 2 can be performed once the results from central laboratory of 
Visit 1 and central chest HRCT review are obtained. If for any reason the screening phase for 
an individual patient lasts for more than 8 weeks, then the laboratory examination for Visit 1 
has to be repeated before randomization. The screening phase must be no longer than 12 
weeks. 
The patient will be randomized at Visit 2 if all inclusion criteria (including positive HRCT 
review and acceptable spirometry measurements) and none of the exclusion criteria (lab 
exclusion criteria referring to Visit 1 results) are fulfilled.
The acceptable time windows for visits are provided in the flow chart. Study measurements 
and assessments scheduled to occur ‘before’ trial medication administration on Day 1 are to 
be performed prior to the trial drug administration (including predose values for PK and 
biomarkers).
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 the event of force majeure or other disruptive circumstances (e.g. pandemic, war) the 
execution of the investigational plan as per this clinical trial protocol may not be feasible. 
With the consent of the patient, the sponsor and investigator may agree on alternative, back-
up or rescue methodology which may include but will not be limited to virtual trial 
participant visits and assessments, home healthcare nurse visits, direct-to-patient/direct-from-
patient shipments of trial treatment or bio-sample pick up from the patient’s home. The 
implementation of these measures will depend on patient’s consent, operational feasibility, 
local law and regulations.
Based on a thorough assessment of the benefits and risks, some specific visits may be 
performed remotely, e.g. via telephone and/or internet-based means of communication, 
performance of assisted home spirometry and ePRO collection where applicable, or at the 
patient’s home where a respective study nurse or home healthcare nurse service is feasible. 

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The visits may also be performed as a combination of home and remote visits, see
descriptions of procedures in Section 6.2.2.2.
All 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
In regards to the timing of the investigations/assessments, the following aspects should be 
adhered to:

the patients’ questionnaires (L-PF [symptoms/impact], EQ-5D-5L, HADS, PGIS) are 
to be completed preferably in the order of the flow chart before any other visit 
assessments or treatments, and if possible, before any interaction with the investigator 
or other members of the study team. Alternatively, the patient can complete them at 
home within 3 days before the site visit. At the latest, the patients’ questionnaires
must be completed prior to the pulmonary function tests.

the C-SSRS interview should be done second, before any other procedure or 
assessment at the site

for the pulmonary function tests: FVC (spirometry) must be performed before DLCO

if several measurements including venipuncture are scheduled for the same time, 
venipuncture should be the last of the measurements due to its inconvenience to the 
patient and possible influence on physiological parameters.

IRT call and IMP dosing/dispensing should always be done as the last procedure after 
all visit assessments, except at Visit 1 where the IRT call may be done earlier during 
the patient’s visit.
6.2.1
Screening period
Screening Period
After informed consent is obtained, inclusion and exclusion criteria should be checked 
according to flow chart.

During the screening visit, demographics information will be collected. This includes: 
age on the day of informed consent (in years)

Sex (male, female; to describe the patient’s sex at birth), 

Gender identity (male, female, other; in order to describe how the subject self-
identifies regardless of their genotypic or phenotypic sex)

For women: childbearing potential (yes/no) in order to characterize the patient 
population and as a basis for contraception requirements 

Ethnicity and race in order to sufficiently characterize the patient population, to 
support possible subgroup analyses if needed unless not acceptable according to local 
regulations.
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, height, body weight, and 
physical examination, SpO2, refer to Sections 5.2.1 to 5.2.4.

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For information on spirometry (FEV1 and FVC) and DLCO refer to Sections 5.1.1 and 5.1.6.
For information on the patient-reported outcomes/questionnaires and specific safety related 
questionnaires refer to Sections 5.1.5 and 5.2.5.
For information on chest HRCT, refer to Section 5.6.1.
Re-screening:
If patients fail on specific exclusion criteria during the first screening visit, they may be re-
screened under the following conditions:

If the patient was treated and cured from the acute infection.

If the patient was treated for depression and HADS values are <14, not earlier 
than 3 months after the first screening.

Other reversible conditions after respective treatment or resolution
If a patient results in a screen failure the patient must be registered as a screen failure in IRT 
system. However, re-screening of a previously screen failed patient will be permitted once. 
Details of IRT procedures can be found in the IRT manual located in the Investigator Site 
File (ISF).
Re-screened patients will need to sign a new informed consent before any re-screening 
procedures and will be given a new unique patient number. 
If a patient is re-screened and there are valid screening determinations from patient’s
previous participation in the trial, like for example safety labs, performed within 8 weeks
prior to randomization (Visit 2), these do not need to be repeated.
If the Investigator believes that an ineligible laboratory test result is the result of an error or 
extenuating circumstance, then the test can be repeated once without the patient having to be 
re-screened.
6.2.2
Treatment periods
6.2.2.1
Conduct of a regular site visit
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, height, body weight and 
physical examination, SpO2, refer to Sections 5.2.1 to 5.2.4.
For information on spirometry (FEV1 and FVC) and DLCO refer to Sections 5.1.1 and 5.1.6.
For information on the patient-reported outcomes/questionnaires and specific safety related 
questionnaires refer to Sections 5.1.5 and 5.2.5.

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Each patient will receive the first dose of BI 1015550 or placebo at the end of Visit 2 (Day 1)
under direct supervision of the investigator or designee. Patients will take trial medication
twice daily (bid) orally from that timepoint onwards. On the day of any further clinic visit, 
supervision of administration is not required but trial medication will preferably be 
administered to the patient during the visit (as the last procedure, see Section 6.2).
The patient will have to bring back all IMP kits, used and unused at each on-site visit, 
including Visit 3. At Visit 3, the patient will have to bring back the IMP kits dispensed at 
Visit 2 to cover the trial medication intake until Visit 4.
FVC should be measured at approximately the same time of day, at least within the same 
half-day (morning or afternoon, with reference to the time at Visit 2).
6.2.2.2
Conduct of a fallback visit (remote/home visit)
If a patient is not able to travel to the site for a trial visit (Force majeur or physical 
disablement), remote visits (by phone or video call) should be performed instead. Especially 
for Visits 2, 5, 7, 10, and EOT, patients should be encouraged to perform a site visit as close 
as possible to the intended timepoint per flow chart including visit windows to perform an 
onsite spirometry.
Trial medication may be shipped from the site directly to the patient (if acceptable according 
to local laws and regulations).
The following assessments can be done remotely: 

Collect and assess adverse events, concomitant therapies, assess trial medication 
compliance.

Specific data for investigator reported data: C-SSRS interview, evaluation of 
vasculitis symptoms and HCRU questions.

Patient-reported outcomes: the patient questionnaires can be compiled electronically 
by the patient on the provided device or via the App on his own device. If paper 
questionnaires had been handed out at the last visit, the questionnaires should be 
answered on the day (or within 3 days) of the remote visit and sent back to the site 
thereafter.

Assisted home spirometry: for sites with the respective setup, see Section 5.1.1 and 
the respective home spirometry manual.

Urine dipstick pregnancy test performed by the patient at home
If home visits are possible (e.g. by a Home Healthcare Nurse or qualified site staff visiting 
the patient), the following assessments can be done at the patient’s home:

collection of blood and urine samples to be sent to the central lab or local lab

vital signs

trial medication compliance assessment

dispensing of the next treatment kits, if possible
If blood and urine sampling for central lab at the patient’s home is not possible, safety lab 
analyses including the routine safety lab tasks as per Table 5.2.3.1: 1 should be performed at 

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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.
6.2.2.3
End of treatment visit 
As described in Section 3.1, after the confirmation of the benefit-risk evaluation for a 
potential start of the extension trial based on the main analysis, all patients still on blinded 
study treatment will perform an EOT visit. 
For premature treatment discontinuations, follow instructions in Section 3.3.4.1.
6.2.3
Follow-up period and trial completion
A follow up period of a minimum of 7 days (+3 days) after the end of treatment will be 
required. All patients will complete a visit at the end of the follow-up period for AE 
assessment, laboratory tests, recording of ECG and vital signs, and physical examination.
Patients may be eligible to enter an extension trial if they complete this study on blinded 
treatment and meet the eligibility criteria for the extension trial. For these patients, the last 
visit in this trial and the end of this trial is the EOT visit. For patients who do not roll over to
the separate extension trial (or could not roll over within a week of the EOT visit), the follow-
up visit is required as the regular EOS visit.
Patients prematurely discontinuing trial treatment permanently will perform the EOT visit at 
the time of permanent discontinuation and the follow-up visit 7 days (+3 days) later. As this 
is taking place before the end of study, the patients should perform all regular trial visits as 
indicated in Section 3.3.4.1. For these off-treatment visits, PK samples can be skipped.
The follow-up visit can be skipped if the treatment had been discontinued at least 7 days 
before the actual EOT visit or if the following regular visit after the end of treatment is 
planned at 7-21 days after the last dose was administered.
For patients who withdraw consent at time of trial medication discontinuation, end of study 
is an EOT visit followed by a follow-up visit.
All abnormal values (including laboratory parameters) at the last study visit (EOS) 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 be followed up until they have resolved, have been 
assessed as “chronic” or “stable”, or no further information can be obtained.
If needed in the opinion of the investigator, after the EOS visit additional FU visits may be 
scheduled for continued safety monitoring. 
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”).

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As a default, a patient is considered to have completed the trial in case any of the following 
applies:

Completion of planned follow-up period

Lost to follow-up

Refusal to be followed-up 

Death 
7.
STATISTICAL METHODS AND DETERMINATION OF 
SAMPLE SIZE
This is a multi-centre, multi-national, prospective, randomized, placebo-controlled, double
blind clinical trial to investigate the efficacy and safety of BI 1015550 at a dose of 9 mg bid 
and 18 mg bid, in patients with IPF. The eligible patients will be randomized to BI 1015550 
9 mg bid, BI 1015550 18 mg bid and placebo in 1:1:1 ratio, stratified by intake of AF 
treatment at baseline.
The primary endpoint is the absolute change from baseline in FVC (mL) at Week 52. The 
primary endpoint will be analyzed using a mixed-effect model for repeated measures 
(MMRM) as detailed in Section 7.2.3. 
The key secondary endpoint is time to the first occurrence of any of the components of the 
composite endpoint: time to first acute IPF exacerbation, first hospitalization for respiratory 
cause, or death. The key secondary endpoint will be analyzed using a Cox proportional 
hazards model as detailed in Section 7.2.4 with data from the whole trial, i.e. including data 
beyond 52 weeks.
7.1
NULL AND ALTERNATIVE HYPOTHESES
Multiplicity adjusted analyses will be performed on the primary and key secondary 
endpoints. The graphical testing procedure [R16-4473] as depicted in Figure 7.1: 1 will be 
used to test the primary and key secondary endpoints for both dose levels. As the graphical 
testing procedure abides the closed test principle, it holds strong control of family-wise type I 
error rate at two-sided alpha level of 0.05. 
Statistical hypotheses to be tested for the primary endpoint are:

: there is no difference in the mean change from baseline in FVC in mL at 
Week 52 between BI 1015550 18 mg bid and placebo vs.
Ha1: there is a difference in the mean change from baseline in FVC in mL at Week 52 
between BI 1015550 18 mg bid and placebo.

: there is no difference in the mean change from baseline in FVC in mL at 
Week 52 between BI 1015550 9 mg bid and placebo vs.
Ha2: there is a difference in the mean change from baseline in FVC in mL at Week 52 
between BI 1015550 9 mg bid and placebo.
Statistical hypotheses to be tested for the key secondary endpoint are:

: there is no difference in the time to first acute IPF exacerbation, first 
hospitalization for respiratory cause or death between BI 1015550 18 mg bid and 

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placebo vs.
	: there is a difference in the time to first acute IPF exacerbation, first 
hospitalization for respiratory cause or death between BI 1015550 18 mg bid and 
placebo.


: there is no difference in the time to first acute IPF exacerbation, first 
hospitalization for respiratory cause or death between BI 1015550 9 mg bid and 
placebo vs.
	
: there is a difference in the time to first acute IPF exacerbation, first 
hospitalization for respiratory cause or death between BI 1015550 9 mg bid and 
placebo.
The hypothesis testing of the key secondary endpoint is based on data collected up to the 
main analysis (all data up to DBL1; see Figure 3.1: 1). A supplementary analysis of the key 
secondary endpoint using all data collected over the whole trial will be performed after 
DBL2.
Figure 7.1: 1
Graphical testing procedure for hypothesis testing strategy
The testing procedure will start from testing of  and  for the primary endpoint. 4% 
level of the alpha level will be initially allocated to the comparison between 18 mg bid and 
placebo. 1% level of the alpha level will be initially allocated to the comparison between the 
9 mg bid arm and placebo. At this step, no alpha is reserved for tests of the key secondary 
endpoint. 

If neither  nor  is rejected, all  is deemed as “spent” and no further testing 
will be performed. 

If at least one of  or  is rejected, the retained  from the successful hypothesis 
will be propagated according to the weights on the arrows leaving that hypothesis as 
depicted by the Figure 7.1: 1.
Note that  is set to a negligible amount of 0.0001 at the start, to reflect the priority on 
hypotheses for 18 mg bid vs. placebo, namely  and ! over the 9 mg bid vs. placebo"

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The testing process continues if there is at least one hypothesis in the procedure that can be 
rejected at its allocated α level at that point. Each time a hypothesis is rejected, the graph is 
updated to reflect the reallocation of α. This iterative process of updating the graph and 
reallocating α is repeated until all hypotheses have been tested or when no remaining 
hypotheses can be rejected at their corresponding α levels at that point. 
The primary objective of the trial will be achieved if either  or   is rejected and this 
trial is considered positive.
If the 9 mg bid arm is considered futile at the futility interim, the remaining tests for 18 mg 
bid arm will be tested sequentially for primary and key secondary endpoint with  level of 
0.04 and 0.02 as depicted in Figure 7.1: 1.
No adjustment for multiplicity is planned beyond primary and key secondary objective 
analyses.
7.2
PLANNED ANALYSES
7.2.1
General considerations
All planned efficacy and safety analyses, including for the primary and key secondary 
endpoints will be carried out at DBL1 (Figure 3.1: 1) and the statistical hypotheses described 
in Section 7.1 will be tested. After DBL2, analyses of the efficacy endpoints defined as “over 
the duration of the trial” and all safety analyses will be repeated to include all data collected 
until the end of the trial.
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 analyses of patient disposition.
Randomized Set (RS): This patient set includes all entered and randomized patients. The RS 
will be used for the analyses of patient disposition.
Full Analysis Set (FAS): This patient set includes all randomized patients who received at 
least one dose of study drug. The FAS will be used for baseline demographics and 
characteristics, protocol deviations, and all efficacy analyses, in which patients will be 
analyzed as their randomized treatment group.
Treated Set (TS): This patient set includes all randomized patients who received at least one 
dose of study drug. The TS will be used for all safety analyses, in which patients will be 
analyzed according to the actual treatment they received.
Data from patients who are screened but not randomized will be listed but not included in any 
summary statistics or inferential statistics. Definitions and handling of important protocol 
deviations (IPDs) will be included in the DV domain specifications and will be stored within 
the trial master file (TMF) in the electronic document management system (EDMS). All 
potential important protocol deviations will be discussed during trial oversight meetings and 

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report planning meetings. All final decisions concerning IPDs will be made before un-
blinding.
Further Analysis Sets will be defined in the TSAP, if needed.
7.2.2
Handling of intercurrent events
The expected intercurrent events of interest in this trial are:

Change in background antifibrotic therapy after baseline

Start of a restricted medication

Treatment discontinuation

Death

Lung transplant
The strategies for handling intercurrent events in this trial are as follows:
Primary strategy for primary and key secondary objectives:
All intercurrent events except for death and lung transplant will be handled according to the 
treatment policy approach as defined in ICH E9 (R1). Use of the “treatment policy” approach 
disregards the intercurrent event and uses the value of the variable regardless of the 
occurrence of the intercurrent event (e.g., start of a restricted medication).
The intercurrent event of death will be primarily handled using a mixture of composite and
hypothetical strategy as defined in ICH E9 (R1). Use of the “hypothetical approach” 
considers the effect of what would have happened if the intercurrent event did not occur. Use 
of the “composite approach” considers that a poor outcome will be expected. The intercurrent 
event of lung transplant will be primarily handled using a hypothetical strategy as defined in 
ICH E9 (R1).
Table 7.2.2: 1
Handling of intercurrent events as per ICH E9 (R1) within the 
different strategies
Intercurrent event
Primary strategy for 
primary objective
Primary strategy for 
key secondary 
objective
Change of background antifibrotic 
therapy
Treatment policy
Treatment policy
Start of a restricted medication 
Treatment policy
Treatment policy
Treatment discontinuation or 
interruption (any cause)
Treatment policy
Treatment policy

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Intercurrent event
Primary strategy for 
primary objective
Primary strategy for 
key secondary 
objective
Death
Hypothetical/ 
Composite
Composite (event)
Lung transplant
Hypothetical
Hypothetical 
(censored)
Each analysis will reference the strategy for handling intercurrent events that it will be 
estimating. The estimand for each main analysis in this protocol is the combination of the 
relevant detailed clinical objective from Section 2.1 and this strategy.
The secondary strategy will handle change of background antifibrotic therapy and treatment 
discontinuation by a hypothetical approach. Remaining intercurrent events will be handled in 
the same way as the primary strategy.
Any intercurrent events that are not listed will be decided by blinded review based on the 
general principle outlined and secondary strategies will be documented in the TSAP.
7.2.3
Primary objective analyses
Planned analyses for primary endpoint
The primary analysis is a restricted maximum likelihood (REML) based approach using a 
mixed model with repeated measurements (MMRM) comparing the change from baseline in 
FVC at Week 52 between treatment groups. The analysis will include the fixed, categorical
effects of treatment at each visit, baseline intake of AF treatment at each visit, and the fixed 
continuous effects of baseline FVC value at each visit. Visit will be treated as the repeated 
measure with an unstructured covariance structure used to model the within-patient
measurements. The statistical model will be as follows:
 =  +  +  + 
~(0, Σ)
-
 = change from baseline in FVC value [mL] for patient ! in intake of AF 
treatment at baseline stratum " at visit # receiving treatment $,
-
 = FVC baseline measurement (mL) of patient !, ! = 1,2, …
-
 = coefficient of baseline effect at visit #
-
 = the effect of treatment $ at visit #, # = 1, … , ( and $ = 1, . . , * ,
-
 = the effect of intake of AF treatment at baseline stratum " at visit j, " = 1,2. 
Intake of AF treatment at baseline is used as reported in the CRF (“No” as the class of 
reference, regardless of any mis-assignment to treatment based on identification of the 
wrong stratum in IXRS)

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-
 = the random error associated with the #th visit of the !th patient. Errors are 
independent between patients.

= an unstructured covariance matrix
The Kenward-Roger approximation will be used to estimate denominator degrees of freedom
and adjust standard errors. Significance tests will be based on least-squares means using a
two-sided α according to the multiple testing strategy specified in Section 7.1. The primary 
treatment comparison will be the contrast between treatments at Week 52. 
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.
The primary analysis will be performed on the FAS. Patients will be analyzed 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 randomization and is 
therefore consistent with regulatory guidance.
A treatment policy estimand will be used for primary analysis (i.e., all available data from the 
FAS in each active treatment arm and the placebo arm within the first 52 weeks will be used, 
including baseline and data retrieved post treatment discontinuation for patients who 
prematurely discontinued randomized treatment and after use of antifibrotic (rescue) therapy 
for patients not on AF therapy). 
7.2.3.1
Sensitivity Analyses
Sensitivity analysis will be performed to assess whether background therapy status influences 
the primary efficacy analysis. This will use the same primary analysis model with an 
additional covariate of antifibrotic treatment at baseline, treatment, and visit interaction.
MMRM analyses assume that data are missing at random (MAR). For the primary outcome, 
tipping point analyses will assess how robust the primary analysis is against deviations from 
the MAR assumption by imposing a penalty for missing data. The tipping point analysis for 
the longitudinal FVC data will be based on the Multiple Delta Adjustment Method. A delta 
adjustment, dependent on a shift parameter and the weeks between visits, will be added to 
each imputed value. Shift parameters will be selected by arm covering plausible and 
implausible cumulative changes of FVC values at Week 52.
Additional sensitivity analyses based on different missing data imputation scheme as detailed 
in Section 7.3.1 will be conducted.
On-treatment, while-compliant-to-protocol analyses and models with modified sets of 
covariates will be conducted as further sensitivity analyses.
Further details will be specified in the TSAP.
7.2.3.2
Subgroup Analyses
Subgroup analyses will include at least gender, age and antifibrotic treatment at baseline. A 
complete list of subgroup analyses will be specified in the TSAP.

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7.2.3.3
Supplementary Analyses
Further details will be specified in the TSAP.
7.2.4
Secondary objective analyses
7.2.4.1
Analysis of key secondary endpoint
The key secondary endpoint of time to first acute IPF exacerbation, first hospitalization for 
respiratory cause or death will be analyzed with a Cox proportional hazards model using data 
over the whole trial, i.e., including data beyond 52 weeks. The equality of the hazard rates 
will be tested by the Wald test for the treatment effect at a two-sided significance level
deemed for test in each step as specified in Section 7.1. The model will include the treatment 
effect, intake of AF treatment, age (continuous), FVC % predicted and DLCO % predicted 
(corrected for hemoglobin) at baseline as covariates. Breslow’s method for handling ties will 
be used. Kaplan-Meier plots by treatment group will be presented. In addition, percentage of 
patients with event at Week 52 will be presented both descriptively and by Kaplan-Meier 
estimates.
In general, for all time-to-event endpoint, the time to the event of interest will be computed as 
(event date – first drug intake date) +1. All events observed after first drug intake date until 
trial termination will be included in the analysis except for events occurring after a lung 
transplantation as outlined in Section 7.2.2. Patients who do not have an event during the trial 
period will be censored at the individual day of trial completion or the last day that the patient 
was known to be free of the event, whichever is earlier. The time to censoring will be 
computed as (individual day of trial completion or the last day known to be free of the event 
– first drug intake date) + 1. For patients who have more than one event during the trial, the 
time to the first event will be considered for the analysis.
Same as for the primary endpoint, the primary analysis will be performed on the FAS using a 
treatment policy estimand listed in Section 7.2.2.
On-treatment, while-compliant-to-protocol analyses and models with modified sets of 
covariates will be conducted as further sensitivity analyses. In addition, handling change of 
background antifibrotic therapy or treatment discontinuation will also be evaluated by 
hypothetical approach (censored) and composite approach (addition of antifibrotic therapy 
considered as event).
Further details will be specified in the TSAP.
7.2.4.2
Analysis of other secondary endpoints
Absolute change from baseline in the various Living with Pulmonary Fibrosis (L-PF) 
(domain) scores at Week 52 will be analyzed by a restricted maximum likelihood (REML) 
estimation based approach using a mixed-effect model with repeated measurements 
(MMRM) analysis comparing the change from baseline in respective L-PF (domain) Score at 
Week 52 between treatment groups. The analysis will include the fixed, categorical effects of 
treatment at each visit, intake of AF treatment at baseline, and the fixed continuous effects of 
baseline at each visit. 

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In general, for all time-to-event endpoints, the time to the event of interest will be computed 
as (event date − first drug intake date) +1. All events observed after first drug intake date
until trial termination will be included in the analysis except for events occurring after a lung 
transplantation as outlined in Section 7.2.2. Patients who do not have an event during the trial 
period will be censored at the individual day of trial completion or the last day that the patient 
was known to be free of the event, whichever is earlier. The time to censoring will be 
computed as (individual day of trial completion or the last day known to be free of the event 
– first drug intake date) + 1. For patients who have more than one event during the trial, the 
time to the first event will be considered for the analysis.
Time to event secondary efficacy endpoints will be analyzed using a Cox proportional 
hazards model using data from the whole trial i.e. including data beyond 52 weeks. The 
equality of the hazard rates will be tested by the Wald test for the treatment effect at the two-
sided 5% significance level. The model will include the treatment effect and intake of AF 
treatment, age (continuous), FVC % predicted and DLCO % predicted (corrected for 
hemoglobin) at baseline as covariates . Breslow’s method for handling ties will be used. 
Kaplan-Meier plots by treatment group will be presented. In addition, percentage of patients 
with event at Week 52 will be presented both descriptively and by Kaplan-Meier estimates.
Any p-values presented for the other secondary endpoints will be considered nominal in 
nature and no adjustment for multiplicity will be made.
7.2.5
Further objective analyses
All further endpoints will be considered exploratory in nature. The analysis of further 
endpoints over 26 or 52 weeks will be performed with the same models and procedures as 
described for the primary and secondary endpoints.
Restricted maximum likelihood estimation based on a random slope and intercept model will 
be used to compare the adjusted annual rate of decline in FVC [mL/year] as measured over 
52 weeks between treatment groups. This model will include fixed effects for time, treatment, 
baseline, intake of AF treatment at baseline, as well as treatment-by-time and baseline-by-
time interactions. Random effects for time and intercept will be included for each patient.
Further time to event endpoints will be assessed using similar analysis models as respective 
secondary time to event endpoints (e.g. Cox regression models, Kaplan-Meier plots).
The annualized rate of hospitalization due to respiratory cause over the whole trial will be 
analyzed using negative binomial regression with logarithm of the exposure as an offset. The 
analyses will include the treatment effect, intake of AF treatment at baseline, and other key 
covariates of interest with more detail to be provided in the TSAP. The mean number of 
events per patient year by treatment arm, the rate ratio, and corresponding 95% confidence 
interval will be presented.
7.2.6
Safety analyses
All safety assessments described below will focus on data collected within the first 52 weeks 
and additional safety analyses will be repeated to include data over the whole trial.

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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.
Kaplan-Meier plots will be produced for the time to premature treatment discontinuation and 
for the time to first treatment interruption.
Statistical analysis and reporting of adverse events will concentrate on treatment-emergent 
adverse events, i.e. all adverse events occurring between start of treatment and end of the 
REP. Adverse events that start before first drug intake and deteriorate under treatment will 
also be considered as ‘treatment-emergent’.
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 analyzed both quantitatively as well as qualitatively. The latter will 
be done via comparison of laboratory data to their reference ranges. Values outside the 
reference range as well as values defined as clinically relevant will be 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.
Summary tables will be produced for the adjudication results of MACE and deaths.
Further details will be specified in the TSAP
7.2.7
Other Analyses
7.2.7.1
Pharmacokinetic Methods
In the Clinical Trial Report, plasma concentrations of BI 1015550 will be tabulated with 
descriptive statistics. A population PK analysis may be performed on BI 1015550 plasma 
concentrations. If so, a separate population PK analysis plan will be written, and results will 
be reported separately.
7.2.8
Interim analyses
An interim analysis to assess futility of the 9 mg bid dose will be performed when 
approximately 300 patients (100 patients per arm) in the trial have completed 12 weeks of 
treatment taking also into account the safety data from trial 1305-0023. Specific details of 
timing of the interim, futility criteria and analysis plan will be detailed in the DMC charter or 

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TSAP as appropriate. The DMC will review the results and make a recommendation to the 
sponsor on continuation or stoppage of the 9 mg bid dose arm. If the 9 mg dose is considered 
futile, the patients on that treatment arm will be re-assigned to the 18 mg dose in a blinded 
manner (see Section 4.1.5.1) at their next scheduled visit.
Full details will be provided in the DMC charter.
7.3
HANDLING OF MISSING DATA
7.3.1
Efficacy endpoints
In the primary analysis of primary endpoint, missing data will not be imputed except for 
death, where a poor outcome will be assigned, see Table 7.3.1: 1. The mixed effect model 
will handle missing data based on a likelihood method under the "missing at random 
assumption". 
A tipping point analysis is planned as sensitivity analysis, see Section 7.2.3.1. The effect of 
missing data on the primary endpoint will be further investigated using other multiple 
imputation techniques.
These four subsets of patients will be used in sensitivity analyses to estimate the treatment 
effect under differing assumptions around the persistence of efficacy after withdrawal of trial 
medication.
1. Patients with an FVC result at Week 52 who received trial medication until Week 52. 
2. Patients with an FVC result at Week 52 who prematurely discontinued trial 
medication prior to Week 52.
3. Patients without an FVC result at Week 52 who were alive at Week 52.
4. Patients without an FVC result at Week 52 who died prior to Week 52.
Table 7.3.1: 1 describes the planned sensitivity analyses for handling missing primary 
endpoint data. Sensitivity analyses 1 and 2 will only be performed if there are at least 
10 patients included in patient subset 2 in each treatment group.
Table 7.3.1: 1
Sensitivity analyses for handling missing primary endpoint data
Analysis
Patient subset 3: No FVC result 
but alive at Week 52
Patient subset 4: No FVC result 
but died Week 52
Handling of 
missing FVC
Underlying 
assumption
Handling of 
missing FVC
Underlying 
assumption
Primary 
analysis
Missing data 
handled by 
model
Assumes 
missing at
random. 
Discontinued
patients would 
have
behaved 
similarly to
Impute based on 
10th percentile1
of all observed 
values (change 
from baseline) 
in each
treatment arm at 
each visit
Patients who 
died before
Week 52 would 
have expected a 
poor outcome

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Analysis
Patient subset 3: No FVC result 
but alive at Week 52
Patient subset 4: No FVC result 
but died Week 52
Handling of 
missing FVC
Underlying 
assumption
Handling of 
missing FVC
Underlying 
assumption
patients who 
did not
discontinue.
Sensitivity
analysis 1
Retrieve 
dropout:
based on the
point estimates 
for drug and 
placebo in 
patient subset 
2.
Patients without 
a result would 
have behaved 
similarly to 
discontinued 
patients with a 
result who are 
in the same 
treatment group
Impute based on 
10th percentile1
of all observed 
values (change 
from baseline) 
in each
treatment arm at 
each visit
Patients who 
died before
Week 52 would 
have expected a 
poor outcome.
Sensitivity
analysis 2
Follow 
reference:
based on the
point estimates 
for all placebo 
patients in
patient subset 1 
& 2.
Patients without 
a result would 
have behaved 
similarly to all 
patients in the 
placebo arm
1 selected based on pooled INPULSIS I/II data to reflect a negative outcome, while retain estimation efficiency by avoiding 
extreme values.
In the analysis of all other 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". 
In the primary analysis of time-to-event endpoints, missing or incomplete data will be 
handled using standard survival analysis techniques (i.e. censoring), except for death which 
will be handled as event.
Additional details on the handling of missing data and sensitivity analysis will be specified in 
the TSAP prior to unblinding. 
7.3.2
Safety endpoints
Missing or incomplete AE dates will be imputed according to BI standards. Other missing 
safety data will not be imputed.

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7.4
RANDOMIZATION
Patients will be parallel randomized in blocks to double-blind treatment. The randomization
will be stratified by intake of AF treatment at baseline (Yes/No), within the IRT system. 
Approximately equal numbers of patients will be randomized to BI 101550 18 mg bid, 
BI 1015550 9 mg bid and placebo in a 1:1:1 ratio. For patients to be enrolled and randomized
after a potential futility stop of the low dose level (9 mg; see Section 7.2.8), the 
randomization ratio will be 1:1 (BI 1015550 18 mg bid vs. Placebo).
BI will arrange for the randomization and the packaging and labelling of trial medication. 
The randomization list will be generated using a validated system, which involves a pseudo-
random number generator so that the resulting treatment will be both reproducible and non-
predictable. The block size will be documented in the Clinical Trial Report. Access to the
codes will be controlled and documented.
7.5
DETERMINATION OF SAMPLE SIZE
Results from the Phase II trial 1305-0013 show substantial improvement of BI 1015550 over 
placebo in FVC change from baseline to Week 12. Given the uncertainty of whether a similar 
progressive patient population will be recruited in the current trial, for trial 1305-0014 in IPF 
patients, a target treatment effect of 110 mL in FVC decline at Week 52 compared to 
Placebo, as seen in the pooled INPULSIS trials is assumed for patients receiving BI 1015550 
and not on antifibrotic background therapy.
No data on the treatment effect beyond 12 weeks on top of antifibrotics is available. 
However, the maximum treatment effect on top of antifibrotics is limited by the natural age-
related decline in FVC. Therefore, assuming FVC decline at 52 weeks is 110 mL in the 
placebo arm for patients on antifibrotic background therapy, a lower treatment effect of
65 mL is assumed for BI 1015550 in patients on background antifibrotic therapy. 70% of 
patients are expected to be on background antifibrotic treatment.
Additionally, 25% of Placebo patients not on antifibrotic treatment, are expected to initiate 
antifibrotic therapy on average at Week 26 and 12.5% of BI 1015550 patients not on AF 
treatment expected to switch AF treatment after 26 weeks. Under the linearity assumption of 
FVC decline assumed treatment effect at Week 52 in patients not on background treatment 
will be reduced by 12.5%. Based on all above-mentioned assumptions, a treatment effect of 
74 mL for BI 1015550 vs. placebo in FVC change from baseline at Week 52 is expected for 
trial 1305-0014. A common adjusted standard deviation (SD) of FVC change of 280 mL is 
assumed based on estimates from INPULSIS trials.
An effective sample size of 310 patients per group, will detect a treatment effect of 74 mL 
with 91% power under two-sided alpha of 5% for one active BI 1015550 dose arm vs. 
placebo. With 310 patients per arm and a two-sided type I error rate of 0.05, a treatment 
effect size of 90, 65, 55, and 45 can be detected for each of the primary endpoint with 98%, 
82%, 69%, and 52% power respectively.
Calculations were performed using R Version 4.0.2.

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For the key secondary endpoint time to first acute IPF exacerbation, first hospitalization for 
respiratory cause or death, assumptions for the power calculations are derived from the 
pivotal INPULSIS trials (1199-0032 and 1199-0034) and patients with UIP-like fibrotic 
pattern from the INBUILD trial (1199-0247). The proportion of Placebo patients with at least 
one event of the composite outcome observed until Week 52 was 17.5% for pooled 
INPULSIS patients and was estimated as 18.3% for patients with a UIP-like fibrotic pattern
in INBUILD. In order to reflect potential differences in the trial population of 1305-0014, 
scenarios including 15%, 17.5%, and 20% are presented in the power calculations. As the 
treatment effect on the key secondary endpoint is unknown, the power was evaluated for 
hazard ratios in the range of 0.60 to 0.75 for the treatment effect of BI 1015550 vs. placebo 
over the duration of the trial. Accrual time for 1305-0014 is expected to be 15 to 18 months
with a follow-up period of 12 months. Table 7.5: 1 provides power calculations for time to 
first acute IPF exacerbation, first hospitalization for respiratory cause or death on different 
combined scenarios. Power calculations assuming a 1:1:1 randomization for an effective 
sample size of 310 patients per arm with linear accrual rate have been performed based on a 
two-sided Log-rank test comparing BI 1015550 18 mg bid vs. placebo, with a significance 
level of 5%. No correction for dropouts has been incorporated into the power calculation for 
the key secondary endpoint.

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Table 7.5: 1 Power evaluation for secondary endpoint based on a two-sided, two-sample 
Log-rank test with a significance level of 5% considering different effect sizes, 
event rates and accrual time
52 week event rate 
for key secondary 
endpoint (placebo)
Hazard Ratio
Accrual time in 
months
Expected number 
of events/Local 
Power1
15%
0.75
15
127/37%
15%
0.70
15
124/51%
15%
0.65
15
120/66%
15%
0.60
15
117/79%
17.5%
0.75
15
147/42%
17.5%
0.75
18
157/44%
17.5%
0.70
15
144/57%
17.5%
0.70
18
153/60%
17.5%
0.65
15
140/72 %
17.5%
0.65
18
149/75%
17.5%
0.60
15
136/85%
17.5%
0.60
18
144/87%
20%
0.75
15
167/46%
20%
0.70
15
163/62%
20%
0.65
15
159/77%
20%
0.60
15
154/89%
1 numbers reflecting comparison between one active dose arm and placebo arm
Based on the range of plausible assumptions and hazard ratios considered, local power of the 
key secondary ranges from 37%-46% for a hazard ratio of 0.75 to around 79%-89% for a 
hazard ratio of 0.6 as often targeted in pivotal trials.
Calculations were performed using “rpact” package version 3.0.4 in R version 4.0.2.  
As a graphical testing procedure is used for the hypothesis tests in this Phase III trial and the 
controlled one-sided type I error rate for each hypothesis test depends on the result of other 
endpoints, it is very complicated, if not impossible, to derive the mathematical formula for 
the power of each efficacy endpoints considered in the graphical testing procedure. As a 
result, we conducted simulations to approximate the power for each efficacy endpoint (i.e. the 
probability of rejecting each null hypothesis) using the graphical testing procedure under five 
different scenarios of the effect size for each efficacy endpoint and dose level with the 
proposed graph. 310 effective patients per arm, two-sided family-wide type I error rate of 
0.05, and 0.4 correlation among efficacy endpoints. The probability of rejecting at least one 
dose in primary endpoint, namely  or , as well as the probability of rejecting both 
primary and secondary endpoint for high dose are calculated.

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Simulation results as presented in Table 7.5: 2 suggest that with 310 effective sample size per 
arm, there is at least 93% power to detect an effect size of 74 mL in FVC change from 
baseline at Week 52 for at least one dose is significant (Scenario #1). Regardless of effect 
size of the 9 mg bid arm, probability of detecting a significant FVC effect of 74 mL in the 
18 mg bid arm is between 89% to 90%. Furthermore, if 18 mg bid arm has an effect of 74 mL 
in primary endpoint and HR of 0.6 in key secondary endpoint, the probability of rejecting 
both   and  is between 65% to 74% depending on relative effect size of the 9 mg bid 
arm. The simulation results also show a well controlled type-I error under the null hypothesis 
(Scenario #5) with the proposed testing strategy. 
Additional simulation results, which are not displayed here, also show that the transition 
weight from  to  ranging from 0.5 to 0.7 does not impact the marginal power for the 
primary and key secondary efficacy endpoints much. Hence we choose 0.5 as the transition 
weight given desirable success probabilities of 88%-93% for primary endpoint and 65% to 
74% for key secondary endpoint 18 mg bid arm under various conditions.
In summary with 310 effective patients per arm, simulation results show satisfactory
operational characteristics of the proposed graphical testing procedure under Scenarios #1-5
which are considered plausible for this Phase III trial.
Table 7.5: 2 Multiplicity adjusted probabilities of success for each hypothesis and positive 
study under different scenarios of effect sizes from simulations.
18 mg bid 
FVC [mL] 
change from 
baseline at 
Week 521
9 mg bid 
FVC [mL] 
change from 
baseline at 
Week 521
18 mg bid 
time-to resp 
hosp. or 
exac. or 
death2
9 mg bid 
time-to resp 
hosp. or 
exac. or 
death2
Scenario #1
(both doses achieve 
target effect)
74
74
0.6
0.6
Probability of rejecting 
each hypothesis
90%
87%
75%
63%
Probability of rejecting at 
least one dose primary 
endpoint
94%
Scenario #2
(low dose approx. 70% 
of high dose)
74
52
0.60
0.72
Probability of rejecting 
each hypothesis
90%
60%
71%
30%

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18 mg bid 
FVC [mL] 
change from 
baseline at 
Week 521
9 mg bid 
FVC [mL] 
change from 
baseline at 
Week 521
18 mg bid 
time-to resp 
hosp. or 
exac. or 
death2
9 mg bid 
time-to resp 
hosp. or 
exac. or 
death2
Probability of rejecting at 
least one dose primary 
endpoint
90%
Scenario #3
(low dose approx. 50% 
of high dose)
74
37
0.60
0.80
Probability of rejecting 
each hypothesis
89%
35%
69%
11%
Probability of rejecting at 
least one dose primary 
endpoint
90%
Scenario #4
(low dose no effect)
74
0
0.60
1
Probability of rejecting 
each hypothesis
89%
3.5%
65%
0.2%
Probability of rejecting at 
least one dose primary 
endpoint
89%
Scenario #5
(null effect)
0
0
1
1
Probability of rejecting 
each hypothesis
4.1%
1.3%
0.1%
<0.1%
Probability of rejecting at 
least one dose primary 
endpoint
4.8%
Probability calculated based on 50 000 simulation iterations. Total alpha-level = 0.05 (two-sided), 1:1:1 randomization ratio 
with 310 patients per arm. 
[1] For FVC change from baseline at Week 52, SD assumed to be 280 mL. 
[2] For composite endpoint: placebo event rate at 52 weeks = 17.5%, accrual period = 15 months, no dropout, correlation 
between endpoints for each dose = 0.4.
Calculations were performed using “rpact” package version 3.0.4 in R version 4.0.2.  

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Based on the proportions of early treatment discontinuation, patients with missing data and 
missing data patterns as observed in our Phase II trial 1305-0013 and INBUILD trial, we 
project 20% patients will prematurely terminate treatment in our Phase III trial. Since BI will 
take every measure to collect all data at planned visits from early dropout, we anticipate 75% 
of these dropouts will have efficacy outcome collected after treatment termination and can be 
used for analysis. Based on these estimations, we assume a 5% rate for missing data. 
Furthermore, an information content of 0.34 estimated from pivotal INPULSIS trials, which 
provides average amount of information by a non-completing patient is assumed. Based on 
these estimations, we apply a 3.3% correction for missing data in sample size calculation for 
this Phase III trial. This gives the total number of 963 randomized patients, with 
321 randomized patients in each treatment arm.
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 or delegate immediately of any urgent safety 
measures taken to protect the trial patients against any immediate hazard, as well as of any 
serious breaches of the protocol or of ICH GCP.
The Boehringer Ingelheim transparency and publication policy can be found on the following 
web page: trials.boehringer-ingelheim.com. The rights of the investigator and of the Sponsor
with regard to publication of the results of this trial are described in the investigator contract. 
As a rule, no trial results should be published prior to finalisation of the Clinical Trial Report.
The certificate of insurance cover is made available to the investigator and the patients and is
stored in the ISF.
8.1
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED CONSENT
This trial will be initiated only after all required legal documentation has been reviewed and 
approved by the respective Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC) and competent authority (CA) according to national and international regulations). The 
same applies for the implementation of changes introduced by amendments.
Prior to patient participation in the trial, written informed consent must be obtained from 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-

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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. 
The patient must be given sufficient time to consider participation in the trial. The 
investigator or delegate obtains written consent of the patient’s own free will with the 
informed consent form after confirming that the patient understands the contents. The 
investigator or 
delegate must sign (or place a seal on) and date the informed consent form. 
If a trial collaborator has given a supplementary explanation, the trial collaborator also signs 
(or places a seal on) and dates the informed consent. Re-consenting may become necessary 
when new relevant information becomes available and should be conducted according to the 
sponsor’s instructions.
The consent and re-consenting process should be properly documented in the source 
documentation.
8.2
DATA QUALITY ASSURANCE
A risk-based approach is used for trial quality management. It is initiated by the assessment 
of critical data and processes for trial subject protection and reliability of the results as well as 
identification and assessment of associated risks. An Integrated Quality and Risk 
Management Plan or alternative plan, in line with the guidance provided by ICH Q9 and 
ICH-GCP E6, for fully outsourced trials, documents the rationale and strategies for risk 
management during trial conduct including monitoring approaches, vendor management and 
other processes focusing on areas of greatest risk.
Continuous risk review and assessment may lead to adjustments in trial conduct, trial design 
or monitoring approaches. 
A quality assurance audit/inspection of this trial may be conducted by the sponsor, sponsor’s 
designees, or by IRB/IEC or by regulatory authorities. The quality assurance auditor will 
have access to all medical records, the investigator’s trial-related files and correspondence, 
and the informed consent documentation of this clinical trial.
8.3
RECORDS
CRFs for individual patients will be provided by the sponsor. See Section 4.1.5.2 for rules 
about emergency code breaks. For drug accountability, refer to Section 4.1.8.
8.3.1
Source documents
For adverse events, an end date may not always be available (e.g. due to hospital discharge 
and later recovery, or change in treating physician), but should be recorded in the source if 
known.
For eCRF all data need to be derived from source documents, which need to be available on-
site (this could be for example physician’s notes in patient files, printouts, patient diaries).

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In accordance with regulatory requirements, the investigator should prepare and maintain 
adequate and accurate source documents and trial records that include all observations and 
other data pertinent to the investigation on each trial patient. Source data as well as reported 
data should follow the “ALCOA principles” and be attributable, legible, contemporaneous, 
original and accurate. Changes to the data should be traceable (audit trail).
Data reported on the CRF must be consistent with the source data or the discrepancies must 
be explained.
The current medical history of the patient may not be sufficient to confirm eligibility for the 
trial and the investigator may need to request previous medical histories and evidence of any 
diagnostic tests. In this case, the investigator must make at least one documented attempt to 
retrieve previous medical records. If this fails, a verbal history from the patient, documented 
in their medical records, would be acceptable.
Copies of source documents necessary for evaluation of adverse events will be provided to
the adjudication committee members or the pharmacovigilance department. 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)

Medication history

Adverse events and 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, i.e. chest 
HRCT or biopsy reports, DLCO report with proper documented medical evaluation (in 
validated electronic format, if available)

Patient-reported outcome forms and C-SSRS questionnaire if done on paper

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.

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For the spirometry, electronic patient-reported outcomes and C-SSRS questionnaire data will 
be transferred to the data base from the respective vendor and the electronic records are 
regarded as source documents.
8.3.2
Direct access to source data and documents
The investigator / institution will allow site trial-related monitoring, audits, IRB / IEC review 
and regulatory inspections. Direct access must be provided to the CRF and all source 
documents / data, including progress notes, copies of laboratory and medical test results, 
which must always be available 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 or delegate will also monitor compliance with the protocol and GCP.
8.3.3
Storage period of records
Trial sites:
The trial sites must retain the source and essential documents (including ISF) according to 
contract or the local requirements valid at the time of the end of the trial (whatever is longer).
Sponsor:
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 trial participant data in accordance with the principles 7 and 12 of the WHO 
GCP handbook. 
To ensure confidentiality of records and personal data, only pseudonymised data will be 
transferred to the sponsor by using a patient identification number instead of the patient’s 
name. The code is only available at the site and must not be forwarded to the sponsor. In case 
patient’s records will be forwarded e.g. for SAE processing or adjudication committees, 
personal data that can identify the patient will be redacted by the site prior to forwarding. 
Access to the patient files and clinical data is strictly limited: 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.
A potential data security breach will be assessed regarding the implications for rights and 
privacy of the affected person(s). Immediate actions as well as corrective and preventive 
actions will be implemented. Respective regulatory authorities, IRBs / IECs and patients will 
be informed as appropriate.

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8.5.1
Collection, storage and future use of biological samples and corresponding 
data 
Measures are in place to comply with the applicable rules for the collection, biobanking and 
future use of biological samples and clinical data, in particular

Sample and data usage have to be in accordance with the 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

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).

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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 Steering Committee (SC) consisting of independent experts and sponsor representatives 
will be established to support the Coordinating Investigator who will be the chair of the SC. 
The composition of the SC will be documented in the TMF. The tasks and responsibilities 
will be agreed in contracts between the SC members and the sponsor and summarised in a SC 
charter.
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 safety data on a regular basis and perform the interim analysis. 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.
An independent adjudication committee will review all fatal cases and adjudicate all deaths
due to cardiac or respiratory causes. The adjudication committee will a will also review all 
adverse events categorized as major adverse cardiovascular events (MACE). A separate 
independent adjudication committee will review all events suspicious for vasculitis.
Relevant documentation on the participating (Principal) Investigators (e.g. their curricula 
vitae) will be filed in the ISF.
The investigators will have access to the BI web portal Clinergize to access documents 
provided by the sponsor.
BI has appointed a Clinical Trial Leader 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.
Data Management and Statistical Evaluation will be done by BI according to BI SOPs.
Tasks and functions assigned in order to organise, manage, and evaluate the trial are defined 
according to BI SOPs. A list of responsible persons and relevant local information can be 
found in the ISF.
A central laboratory service, a central images service, a central ePRO service, a central 
spirometry service, a central patient and site engagement service and an IRT vendor will be 
used in this trial. Details will be provided in the respective vendor specific instruction 
manuals as applicable,  in the ISF.

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9.
REFERENCES
9.1
PUBLISHED REFERENCES
P11-07084
Raghu G, et al. ATS/ERS/JRS/ALAT Committee on Idiopathic Pulmonary 
Fibrosis. An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary 
fibrosis: evidence-based guidelines for diagnosis and management. Am J Respir 
Crit Care Med 2011;183(6):788-824.
P12-03241
King TE, Pardo A, Selman M. Idiopathic pulmonary fibrosis. Lancet 
2011;378(9807):1949-1961.
P15-07362
Raghu G, et al. ATS, ERS, JRS, and ALAT. An official ATS/ERS/JRS/ALAT 
clinical practice guideline: treatment of idiopathic pulmonary fibrosis: executive 
summary: an update of the 2011 clinical practice guideline. Am J Respir Crit 
Care Med 2015;192(2):238-248.
P16-06899
Collard HR, Ryerson CJ, Corte TJ, et al. Acute exacerbation of idiopathic 
pulmonary fibrosis: an international working group report. American Journal of 
Respiratory and Critical Care Medicine, Article in press, published on 14-June-
2016, doi: 10.1164/rccm.201604-0801CI; 2016. p. 265-275.
P22-03204
Raghu G, Remy-Jardin M, Richeldi L, et al. American Thoracic Society, 
European Respiratory Society, Japanese Respiratory Society, Asociacion 
Latinoamericana de Torax. Idiopathic pulmonary fibrosis (an update) and 
progressive pulmonary fibrosis in adults: an official ATS/ERS/JRS/ALAT 
clinical practice guideline. Am J Respir Crit Care Med 2022;205(9):e18-e47.
R06-0638
Wang SK, Tsiatis AA. Approximately optimal one-parameter boundaries for 
group sequential trials. Biometrics 1987;43,193-199.
R06-2002
Macintyre N, Crapo RO, Viegi G, et al. Standardisation of the single-breath 
determination of carbon monoxide uptake in the lung. Eur Respir J 
2005;26(4):720-735.
R10-1559
Giembycz MA. Life after PDE4: overcoming adverse events with dual-
specificity phosphodiesterase inhibitors. Curr Opin Pharmacol 2005;5:238-244.
R12-1920
Herdman M, Gudex C, Lloyd A, et al. Development and preliminary testing of 
the new five-level version of EQ-5D (EQ-5D-5L). Qual Life Res 2011;20:1727-
1736.
R16-4473
Bretz, F., Maurer, W., Brannath, W. and Posch, M. A graphical approach to 
sequentially rejective multiple test procedures. Statistics in Medicine (2009). 28, 
586–604.
R17-2617
Winthrop KL, Novosad SA, Baddley JW, et al. Opportunistic infections and 
biologic therapies in immune-mediated inflammatory diseases: consensus 
recommendations for infection reporting during clinical trials and postmarketing 
surveillance. Ann Rheum Dis 2015;74:2107-2116.
R17-2947
Maurer W, Bretz F. Multiple testing in group sequential trials using graphical 
approaches. Stat Biopharm Res 2013;5(4):311-320.

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R17-4075
Lynch DA, Sverzellati N, Travis WD, et al. Diagnostic criteria for idiopathic 
pulmonary fibrosis: a Fleischner Society White Paper. Lancet Respiratory 
Medicine, Published online November 15, 2017, doi: 10.1016/S2213-
2600(17)30433-2; 2017.
R18-2794
Raghu G, Remy-Jardin M, Myers JL, 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 
2018;198(5):e44-e68.
R20-2419
Graham BL, Steenbruggen I, Miller MR, et al. American Thoracic Society, 
European Respiratory Society. Standardization of spirometry 2019 update: an 
official American Thoracic Society and European Respiratory Society technical 
statement. Am J Respir Crit Care Med 2019;200(8):e70-e88.
R22-1856
Stern, A. F. The Hospital Anxiety and Depression Scale. Occup Med-c 64 2014, 
393–394.
R22-1857
Aronson, K. I. et al. Patient-centered Outcomes Research in Interstitial Lung 
Disease: An Official American Thoracic Society Research Statement. Am J 
Resp Crit Care 204 2021, e3–e23.
R96-2382
EuroQol - a new facility for the measurement of health-related quality of life. 
Health Policy 1990;16:199-208.
9.2
UNPUBLISHED REFERENCES
c02094779
Investigator’s Brochure 1305.P03. BI 1015550.
c37065416
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. 1305-0013.
c37934954
Population Pharmacodynamic Model for Forced Vital Capacity during 
BI 1015550 Treatment in Patients with Idiopathic Pulmonary Fibrosis.

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10.
APPENDICES
10.1
SPIROMETRY: BRONCHODILATOR WASHOUT 
RECOMMENDATIONS 
Based on ATS/ERS 2019 guidelines [R20-2419] for the conduct of spirometry, the following 
washout of bronchodilators is recommended before spirometry (see Table 10.1: 1). 
According to the ongoing treatment, the investigator should advise the patient on the washout 
on/before the days of the onsite spirometry and document it in the source documents.
Table 10.1: 1
Minimal washout timeframes for bronchodilators before spirometry
Bronchodilator Medication
Withholding Time
SABA (e.g., albuterol or salbutamol)
4-6 hours
SAMA (e.g., ipratropium bromide)
12 hours
LABA (e.g., formoterol or salmeterol)
24 hours
Ultra-LABA (e.g., indacaterol, vilanterol, or olodaterol)
36 hours
LAMA (e.g., tiotropium, umeclidinium, aclidinium, or glycopyrronium)
36-48 hours

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10.2
PATIENT-REPORTED OUTCOMES
10.2.1
Living with Pulmonary Fibrosis Symptoms and Impact Questionnaire (LPF)

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10.2.2
EuroQol 5-Dimensional quality of life Questionnaire (EQ-5D)
This trial uses the English version for the United Kingdom [R12-1920].

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10.2.3
Hospital Anxiety and Depression Scale (HADS)

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10.2.4
Patient’s Global Impression of Severity (PGIS) for Cough, Shortness of 
Breath, and Fatigue
Cough
Shortness of breath
Fatigue
10.3
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.

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The C-SSRS interview may be administered by any type of physician, psychologist, clinical 
social worker, mental health counsel, 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/baseline 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.
All positive reports during trial treatment are treatment-emergent adverse events (AEs).
The results of further medical, including psychiatric examinations, should be documented as 
adverse events where appropriate.
The original Columbia Suicidal Severity Rating scales used in this trial are attached in the 
following appendix sections.

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10.3.1
Visit 1 – Screening/baseline version

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10.3.2
C-SSRS – since last visit

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10.4
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.

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10.4.1
Strong CYP3A4 inhibitors
Strong CYP3A4 inhibitors:

boceprevir

ceritinib

clarithromycin

cobicistat

conivaptan

diltiazem

idelalisib 

indinavir

itraconazole

ketoconazole oral administration

LCL161

mifepristone

mibefradil

nefazodone

nelfinafir

posaconazole

ribociclib

ritonavir

saquinavir

telaprevir

telithromycin

troleandomycin

VIEKIRA PAK2

voriconazole
Combinations of CYP3A4 inhibitors:

danoprevir/ritonavir

elvitegravir/ritonavir

indinavir/ritonavir

lopinavir/ritonavir

paritaprevir/ritonavir/ombitasvir/dasbuvir

saquinavir/ritonavir

tipranavir/ritonavir

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10.4.2
Equivalent doses of corticosteroids
Table 10.4.2: 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
10.4.3
Restricted PDE inhibitors
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 
Tofisopam (highest affinity for PDE4, 10, 3, 2) 
(Emandaxin, Grandaxin) 
Anxiety 

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Compound
Indication 
Dipyridamole (highest affinity for PDE8, 1, 3, 2, 
adenosine deaminase and ENT1) (Persantine) 
Post-operative thromboembolism 
PDE3 with potential PDE4-cross reactivity
Milrinone (Primacor, Corotrope) 
Congestive heart failure 
Amrinone (Inamrinone, Inocor) 
Congestive heart failure 
Enoximone (Perfan) 
Congestive heart failure 
Pimobendan (Acardi) 
Heart failure 
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 
10.5
OPPORTUNISTIC INFECTIONS 
These include Pneumocystis jirovecii, BK virus disease including polyomavirus-associated 
nephropathy (PVAN), Cytomegalovirus (CMV), post-transplant lymphoproliferative disorder 
(Epstein–Barr virus [EBV]), progressive multifocal leucoencephalopathy, bartonellosis 
(disseminated only), blastomycosis, toxoplasmosis, coccidioidomycosis, histoplasmosis, 
aspergillosis (invasive only), candidiasis (invasive or pharyngeal), cryptococcosis, other 
invasive fungi (mucormycosis (zygomycosis, rhizopus, mucor, lichtheimia), 
Scedosporium/Pseudallescheria boydii, fusarium), legionellosis, Listeria monocytogenes
(invasive only), tuberculosis, nocardiosis, non-tuberculous mycobacterium, salmonellosis 
(invasive only), HBV reactivation, herpes simplex (invasive only), herpes zoster, 
strongyloides (hyperinfection syndrome and disseminated forms only), paracoccidioides, 
Penicillium marneffei, Sporothrix schenckii, cryptosporidium species (chronic only), 
microsporidiosis, leishmaniasis (visceral only), Trypanosoma cruzi infection (Chagas’ 
disease) (disseminated only), campylobacteriosis (invasive only), shigellosis (invasive only), 
vibriosis (invasive due to vibrio vulnificus), HCV progression [R17-2617].
10.6
ELIGIBILITY CONFIRMATION OF IPF DIAGNOSIS
Eligible are Patients with a clinical diagnosis of IPF based on the 2022 guideline Idiopathic 
Pulmonary Fibrosis (an Update) and Progressive Pulmonary Fibrosis in Adults: An Official 
ATS/ERS/JRS/ALAT Clinical Practice Guideline as confirmed by the investigator based on 
chest HRCT scan taken within 12 month of Visit 1 and, if available, surgical lung biopsy or 

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transbronchial lung cryobiopsy (TBLC), as well as a “UIP” or “Probable UIP” HRCT pattern 
consistent with the clinical diagnosis of IPF, as confirmed by central review prior to Visit 2. 
If the HRCT finding is “Indeterminate”, the clinical diagnosis of IPF may be confirmed 
locally by (historical) surgical lung biopsy or TBLC demonstrating a “UIP” or “Probable 
UIP” histopathology pattern.  If the HRCT findings are “suggestive of an alternative 
diagnosis”, the clinical diagnosis of IPF may be confirmed locally by (historical) surgical 
lung biopsy or TBLC demonstrating a “UIP” histopathology pattern.
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 [P22-03204].
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 of “Indeterminate for UIP”
require historical (i.e., not taken for the purpose of this trial) surgical lung biopsy or TBLC,
which will be reviewed locally (by the investigator/local histopathologist). In these patients, 
specific combinations of HRCT patterns and histopathology patterns may still allow a 
diagnosis of IPF based on the 2022 ATS/ERS/JRS/ALAT Guideline, i.e., an HRCT pattern of 
"indeterminate for UIP" in combination with a surgical lung biopsy or TBLC with a 
histopathologic pattern of “UIP or probable UIP” could qualify for inclusion.
Patients clinically suspected to have IPF with an HRCT pattern “suggestive of an alternative 
diagnosis” require historical (i.e., not taken for the purpose of this trial) surgical lung biopsy 
or TBLC which will be reviewed locally (by the investigator/local histopathologist).  In these 
patients, specific combinations of HRCT patterns and histopathology patterns may still allow 
a diagnosis of IPF based on the 2022 ATS/ERS/JRS/ALAT Guideline, i.e., an HRCT pattern 
of “alternative diagnosis” in combination with a surgical lung biopsy or TBLC with a 
histopathology pattern of “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.
In case the HRCT does not meet eligibility criteria of 1305-0014, patient is allowed to be re-
screened in the 1305-0023 trial if an alternative clinical ILD diagnosis is reached and the 
patient fulfils the respective inclusion & exclusion criteria.

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Table 10.6: 1
Idiopathic Pulmonary Fibrosis diagnosis based upon chest HRCT and 
biopsy patterns
IPF suspected1
Histopathology pattern
UIP
Probable UIP
Indeterminate 
for UIP or 
biopsy not 
performed
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
Indeterminate3
Non-IPF dx
Non-IPF dx
dx = diagnosis; HRCT = high-resolution computed tomography; IPF = idiopathic pulmonary 
fibrosis; UIP = usual interstitial pneumonia.
(adapted from Figure 9 in [P22-03204])
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:

Moderate-to-severe traction bronchiectasis and/or bronchiolectasis (defined as mild 
traction bronchiectasis and/or 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 remains indeterminate
With an adequate biopsy may be reclassified to a more specific diagnosis after 
multidisciplinary discussion and/or additional consultation.
10.7
TRIAL PARTICIPANT FEEDBACK
Optional Trial Participant Feedback Questionnaires:
This trial will include an option for participants to complete anonymized questionnaires, 
‘Trial Participant Feedback Questionnaire’, to provide feedback on their clinical trial 
experience. Individual participant level responses will not be reviewed by investigators. 
Responses will be used by the sponsor to understand where improvements can be made in the 
clinical trial process. These questionnaires will not collect data about the participant’s 
disease, symptoms, treatment effect, or AEs and therefore will not be part of the trial data or 
clinical trial report. The questionnaires will be implemented after local regulatory approval 
and after consent of the trial participant. Providing feedback is optional and not required for 
participation in the trial.

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Optional Caregiver Feedback Questionnaires:
If applicable, this trial will include an option for caregivers to complete anonymized 
questionnaires, ‘Caregiver Feedback Questionnaire’, to provide feedback on the clinical trial 
experience. Individual caregiver level responses will not be reviewed by investigators. 
Responses will be used by the sponsor to understand where improvements can be made in the 
clinical trial process. These questionnaires will not collect data about the participant’s 
disease, symptoms, treatment effect, or AEs and therefore will not be part of the trial data or 
clinical trial report. The questionnaires will be implemented after local regulatory approval 
and after consent of the caregiver. Providing feedback is optional and not required for 
participation in the trial.

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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
11.1
GLOBAL AMENDMENT 1
Date of amendment
26 Jul 2022
EudraCT No.
2022-001091-34
BI Trial No.
1305-0014
BI Investigational 
Medicinal Product
BI 1015550 
Title of protocol
A double blind, randomized, placebo-controlled trial 
evaluating the efficacy and safety of BI 1015550 over at 
least 52 weeks in patients with Idiopathic Pulmonary 
Fibrosis (IPF)
Global Amendment due to urgent safety reasons
Global Amendment (non-substantial changes)
X
Section to be changed
Flow chart (number of days for visit assignment)
Description of change
The number of days for Visit 4 was changed from 35 to 43. 
The number of days for Visit 7 was changed from 169 to
183.
Rationale for change
Changed to correct the calculated number of days for visit 
assignments based on the conversion of trial weeks into 
days.
Section to be changed
Flow chart (footnote ** on ESR collection)
Description of change
Updated wording in footnote: Central laboratory will may
not provide the material for ESR collection to some 
countries. Instead, material from local site has to be used 
to perform the test locally. ESR should also be measured in 
case of potential vasculitis.
Rationale for change
Clarification that material for ESR collection may be 
provided to some countries by central laboratory.
Section to be changed
Flow chart (footnote 11)
Description of change
Addition of sentence: More frequent pregnancy testing 
may be done if required.
Rationale for change
Clarification on pregnancy tests.

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Section to be changed
Section 1.4.2 Risks
Description of change
Addition of Psychiatric disorders to Table 1.4.2: 1 
Overview of trial related risks.
Rationale for change
Correction as this row was unintentionally missing in this 
table to maintain consistency with information in the IB.
Section to be changed
Description of change
Rationale for change
Section to be changed
Section 3.2 Discussion of trial design including the choice 
of control group(s)
Description of change
Deleted information on continuing, adding, or changing 
treatment with immunosuppressive and immunomodulatory 
drugs.
Rationale for change
Correction as immunosuppressive drugs are not indicated 
for treatment of IPF, where no other underlying disease is 
present as per definition.
Section to be changed
Section 3.3.4.1 Discontinuation of trial treatment
Description of change
Deleted last part of the sentence: Ideally, the patient should 
attend all remaining visits after treatment discontinuation. 
For those patients who are unable to complete the scheduled 
visits, at least phone contacts should occur at the scheduled 
visit time points and FVC measurement at Week 52 should 
be collected.
Rationale for change
Clarification as in case of a phone contact, FVC 
measurements cannot be performed. 
Section to be changed
Section 5.1.1 FVC
Description of change
Deletion of phone call: During the treatment phase, the 
iSpiro device and respective phone with the App will be 
provided to the patient upon decision of the investigator in 
order to perform an assisted (via phone or video call) home 
spirometry either at unscheduled visits or as a fallback 
solution if the patient is unable to get to the site for the 
scheduled visit.
Rationale for change
Clarification as the provided device does not offer the 
facility to have a phone call without video connection.

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Section to be changed
Section 5.3.1 Assessment of pharmacokinetics
Description of change
Updated wording: PK sampling will be performed at the 
time points indicated in the flow chart. Visits 4, 5, and 7.
Rationale for change
Clarification to keep text consistent with the flow chart
Section to be changed
Section 6.2.2.2 Conduct of a fallback visit (remote/home 
visit)
Description of change
Added sentence: Trial medication may be shipped from 
the site directly to the patient (if acceptable according to 
local laws and regulations).
Rationale for change
Clarification on the fallback visit
Section to be changed
Section 6.2.2.2 Conduct of a fallback visit (remote/home 
visit)
Description of change
Added bullet point to assessments that can be done 
remotely:

Urine dipstick pregnancy test performed by the 
patient at home
Rationale for change
The possibility of urine pregnancy testing done during 
remote visits was missing.
Section to be changed
Section 6.2.2.2 Conduct of a fallback visit (remote/home 
visit)
Description of change
Updated wording: If blood and urine sampling for central 
lab at the patient’s home is not possible, safety lab analyses 
including the routine safety lab tasks as per Table 5.2.3.1: 1 
should be performed at a local lab.
Rationale for change
Clarification on safety lab analyses during home visits.
Section to be changed
Section 7.5 Determination of sample size
Description of change
Deletion of asterisks for 2 footnotes in Table 7.5: 2:
*  Probability calculated based on 50,000 simulation 
iterations. Total alpha-level = 0.05 (two-sided), 1:1:1 
randomization ratio with 336 patients per arm
**  multiplicity adjusted for interim analysis using group 
sequential design with Wang-Tsiatis alpha spending 
function (delta = 0.25)
Rationale for change
Clarification as these notes refer to the whole table.
Section to be changed
Section 10.6  Eligibility confirmation of IPF diagnosis
Description of change
Reference related to HRCT scans changed
Rationale for change
Corrected to reference number of updated 
ATS/ERS/JRS/ALAT guideline
Section to be changed
Throughout the CTP
Description of change
Typographical errors and minor formatting issues amended
Rationale for change
To increase readability

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11.2
GLOBAL AMENDMENT 2
Date of amendment
10 May 2023
EudraCT No.
2022-001091-34
BI Trial No.
1305-0014
BI Investigational 
Medicinal Product
BI 1015550 
Title of protocol
A double blind, randomized, placebo-controlled trial 
evaluating the efficacy and safety of BI 1015550 over at 
least 52 weeks in patients with Idiopathic Pulmonary 
Fibrosis (IPF)
Global Amendment due to urgent safety reasons
Global Amendment (substantial changes)
X
Section to be changed
Flow Chart (screening period)
Description of change
The minimum period for screening was reduced to 1 week
Rationale for change
Provide more flexibility for randomizations
Section to be changed
Flow Chart (lab tests)
Description of change
The erythrocyte sedimentation rate (ESR) test was removed.
Rationale for change
Local workup is crucial for the reliability of the results, but 
sites are not familiar with the sample handling and 
procedures. Therefore test results are often inconclusive.
Section to be changed
Flow Chart (temporary discontinuation of trial treatment)
Description of change
Footnote #2 was modified as follows:
In case of premature discontinuation of trial medication, 
the End of Treatment (EOT) visit should only be done in 
cases of premature trial medication if the discontinuation is 
permanent, and with a Follow-up (FU) visit is to be 
performed 7 days (+3 days) after end of treatment. If the
patient discontinued the trial medication more than a 
week prior to the EOT visit, this FU visit is not required. 
A scheduled visit may be missed if EOT or FUollow-up
visit occurs within 4 weeks prior to scheduled visits. After 
the premature EOT, every effort should be made to collect 
data until the end of the trial.
Rationale for change
Clarification of procedures in case of temporary vs.
permanent discontinuation of trial treatment. 
Section to be changed
Flow Chart (patient-reported outcomes)

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Description of change
Addition to Footnote #3:
At the latest, the patients’ questionnaires must be 
completed prior to the pulmonary function tests.
Rationale for change
Clarification of the timing of the patients’ questionnaires 
(consistent with the change in Section 6.2)
Section to be changed
Flow Chart (pregnancy tests)
Description of change
Footnote #11 was modified as follows:
Women of childbearing potential only. Serum pregnancy 
test to be performed at V1; urine dipstick pregnancy test 
to be performed at V2 and following visits (if positive, 
urine dipstick test to be followed by serum test for 
confirmation). More frequent pregnancy testing may be 
done if required.
Rationale for change
The type and timing of the pregnancy tests were clarified.
Section to be changed
Flow Chart (design of the extension trial)
Description of change
Footnote #17 was updated to remove the design of the 
extension trial (“open-label”) and clarify when a follow-up 
visit is needed.
Rationale for change
The extension trial design is not finalized and might also 
contain a double-blind start until the decision about the final 
intended marketed dose.
The follow-up visit can be skipped if the following regular 
visit after the end of treatment is planned at 7-21 days after 
the last dose was administered.
Section to be changed
Section 1.2 Drug profile
Description of change
Sentence added to the drug-drug interaction subsection:
In a clinical drug-drug interaction study with 
midazolam (sensitive CYP3A4 substrate), BI 1015550 
was not shown to have a clinically relevant CYP3A 
induction.
Subsection on the data from non-clinical toxicology studies 
updated to reflect the fact that the toxicology summary 
remained applicable when considering the data from the 
39-week study in monkeys and sentence added:
A sporadic menstrual cycle prolongation was observed 
in the 39-week study in female monkeys receiving 
≥10 mg/kg/day, i.e., at approximately 4-fold human 
exposure at 18 mg bid.
Rationale for change
Addition of data from a recent drug-drug interaction study 
with midazolam

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Addition of data from a recent 39-week oral (gavage) 
toxicity and toxicokinetic study in Cynomolgus monkeys 
with a 8-week recovery period
Section to be changed
Section 1.4.2 Risks (Table 1.4.2: 1, PK interaction with 
strong CYP34A inhibitors)
Description of change
Mitigation strategy updated as follows:
This is also applicable for Paxlovid in the treatment of 
Covid-19: iIf short-term treatment with Paxlovid potent 
CYP3A4 inhibitor is needed, trial medication needs to be 
paused
Rationale for change
Application of the mitigation strategy to all potent CYP3A4 
inhibitors, not just Paxlovid.
Section to be changed
Section 1.4.2 Risks (Table 1.4.2: 1, Vasculitis)
Description of change
Summary of data updated to reflect the fact that vasculitis 
was not observed following oral administration of 
BI 1015550 in 13- or 39-week studies in monkeys
Rationale for change
Addition of data from a recent 39-week oral (gavage) 
toxicity and toxicokinetic study in Cynomolgus monkeys 
with a 8-week recovery period
Section to be changed
Section 1.4.2 Risks (Table 1.4.2: 1, Severe infections)
Description of change
Patients with active tuberculosis are excluded from the trial.
Rationale for change
Mitigation strategy updated to reflect the change in EC23 
(Section 3.3.3)
Section to be changed
Section 1.4.2 Risks (Table 1.4.2: 1, Reproductive toxicity)
Description of change
Summary of data updated as follows:
In monkeys, a sporadic prolongation in menstrual 
cycles was observed at approximately ≥4-fold human 
exposure at 18 mg BI 1015550 bid.
Efficacy of oral hormonal contraceptives can be 
impacted by potential BI 1015550 related CYP3A 
induction
Mitigation strategy on reproductive toxicity updated as 
follows:
Women of childbearing potential (WOCBP) need to use 
a highly effective method of contraception. Of note, oral 
hormonal contraceptives are not considered a highly 
effective method due to potential drug interactions.
WOCBP taking oral contraceptives (OCs) also have 
to ensure the use of one barrier method during sexual 
intercourse with their partner, e.g., condom to 

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account for the risk of potentially reduced efficacy of 
the OCs in the event of severe vomiting and diarrhea
In case of vomiting or diarrhea, instructions in the 
label of the OC should be followed
In case of prolonged (>48h) or repeated 
vomiting/diarrhea, the use of an alternative highly 
effective contraceptive measure should be considered
Rationale for change
The potentially reduced efficacy of OCs from potential 
CYP3A induction by BI 1015550 was ruled out by a drug-
drug interaction trial on the PK of midazolam, a 
recommended substrate of CYP3A4.
Based on these results, OCs are now allowed as highly 
effective measure of contraception in WOCBP, associated 
with one barrier method to prevent the risk of potentially
reduced efficacy of the OCs in case of severe vomiting and 
diarrhea.
Section to be changed
Section 3.2 Discussion of trial design (participants and 
caregivers questionnaires)
Description of change
The following paragraph was added:
This trial will include an option for participants and 
participant caregivers to complete anonymized 
questionnaires to provide feedback on their clinical trial 
experience. Providing this feedback is not required for 
trial participation, and information collected from these 
questionnaires will not be analyzed as part of the clinical 
data for the trial (see Section 10.7).
Rationale for change
To identify where improvements can be made in the clinical 
trial process, the sponsor wants to collect the participants’ 
and caregivers’ feedback on their clinical trial experience.
Section to be changed
Section 3.3.1 Main diagnosis for trial entry
Description of change
Eligibilty criteria for patients with an “alternative diagnosis” 
HRCT finding added:
Patients with an “Alternative diagnosis” HRCT finding 
are eligible if a clinical diagnosis of IPF can be 
confirmed locally based on (historical) surgical lung 
biopsy or cryobiopsy demonstrating a “UIP” 
histopathology pattern
Cross references to Table 10.6: 1 were also added in this 
section.
Rationale for change
Patients with an “alternative diagnosis” HRCT finding are 
considered for eligibility (also see Section 10.6).
Section to be changed
Section 3.3.2 Inclusion criteria (IC6, also in synopsis)
Description of change
Inclusion criterion 6 was updated as follows:

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DLCO corrected for Hemoglobin (Hb) [Visit 1] ≥25% and 
<90% of predicted of normal corrected for hemoglobin 
(Hb) at Visit 1.
Rationale for change
The upper limit for DLCO was deleted since it is not 
relevant as an exclusion criterion. Exclusion criteria 
regarding lung function are sufficiently covered by the 
criteria based on FVC (EC5).
The wording regarding the correction for Hb of predicted 
value of DLCO was clarified.
Section to be changed
Section 3.3.2 Inclusion criteria (IC7)
Description of change
Inclusion criterion 7 was updated as follows:
Women of childbearing potential (WOCBP) must be ready 
and able to use highly effective methods of birth control. Of 
note, oral hormonal contraceptives are not considered a 
highly effective method due to potential drug-drug 
interactions WOCBP taking oral contraceptives (OCs) 
also have to use one barrier method; please refer to 
Section 4.2.2.3.
Rationale for change
Based on the results of a drug-drug interaction trial on the 
PK of midazolam, OCs are now allowed as highly effective 
measure of contraception in WOCBP, associated with one 
barrier method to prevent the risk of potentially reduced 
efficacy of the OCs in case of severe vomiting and diarrhea
(also see change to Section 1.4.2).
Section to be changed
Section 3.3.3 Exclusion criteria (EC1, also in synopsis)
Description of change
Exclusion criterion 1 was updated as follows:
Relevant airways obstruction (pPrebronchodilator 
FEV1/FVC <0.7) at Visit 1
Rationale for change
Any FEV/FVC ratio <0.7 should be avoided as the risk of 
emphysema and obstruction is high and would influence 
efficacy endpoint measurements. This criterion was 
therefore simplified.
Section to be changed
Section 3.3.3 Exclusion criteria (EC10)
Description of change
Exclusion criterion 10 was updated as follows:
Patients with underlying chronic liver disease cirrhosis
(Child Pugh A, B, or C hepatic impairment).
Rationale for change
Clarification following a question from a site (as Child Pugh 
only refers to liver cirrhosis, not chronic liver disease).
Section to be changed
Section 3.3.3 Exclusion criteria (EC23)
Description of change
Exclusion criterion 23 was updated as follows:
Patients with positive active tuberculosis (TB) test at Visit 
1 unless they have completed treatment for active or latent 
tuberculosis in line with local guidelines.

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Rationale for change
No negative effect of BI 1015550 on latent tuberculosis is
expected based on new preclinical data (immunophenotype 
in a 39-week monkey study). The TB diagnosis was 
simplified, relying on the site's expertise.
Section to be changed
Section 3.3.3 Exclusion criteria (EC27 - new)
Description of change
Exclusion criterion 27 was added:
History of stem cell therapy for the treatment of 
pulmonary fibrosis.
Rationale for change
The effect on the lung of such treatment in the longer term 
is currently unknown.
Section to be changed
Section 3.3.4.1 Discontinuation of trial treatment
Description of change
The following paragraph was updated as follows:
All patients who prematurely discontinue trial medication 
will need to complete an End of Treatment (EOT) visit at 
the time of discontinuation, and The End of Treatment 
(EOT) visit activities will be performed when a patient 
discontinues trial medication permanently.
aA premature Follow-up (FU) visit is to be performed 
7 days (+3 days) 1 week later after end of treatment. If 
the patient discontinued the trial medication more than 
a week prior to the EOT visit, this FU visit is not 
required. Patients who prematurely discontinue trial 
medication will be asked to remain in the trial and to return 
to all regularly scheduled visits until the end of the trial.
Ideally, the patients who permanently discontinue trial 
medication should attend all remaining visits after 
treatment discontinuation.
Rationale for change
The procedures in case of temporary vs. permanent 
discontinuation of trial treatment were clarified.
Section to be changed
Section 4.1.4 Drug assignment and administration 
(supervision and timing)
Description of change
The need for supervision during administration was 
clarified:
The patient will receive either active treatment at a dose of 9 
mg, 18 mg, or placebo. The first dose of BI 1015550 or 
placebo will be administered to the patient at the end of 
Visit 2 (Day 1) under direct supervision of the 
investigator or designee. On the day of any further clinic 
visits, supervision of administration is not required but 
the treatment will preferably be administered to the patient 
during the visit.
The timing of administration was clarified to say that the 
trial medication should be taken at the same time every day 

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(±30 mins), ideally between 6:00 and 11:00 in the morning 
and between 18:00 and 23:00 in the evening, and that if 
taken around the same time (approximately within an 
hour), pPatients on nintedanib background should take trial 
medication first, followed by the antifibrotic background 
medication after some minutes.
Rationale for change
Supervision remains mandatory during the first 
administration but is not mandatory for any of the following 
administrations including further clinic visits. Simplified for 
facilitation of scheduling the visits.
The timing of administration was clarified due to questions 
on the timeframe, e.g. when a baseline patient visit ends at 
12:00.
The order of administration would only have an influence in 
case intake of antifibrotic and BI 1015550 is close to each 
other timewise (potential effect of side effects like 
vomiting).
Section to be changed
Section 4.1.5.1 Blinding and procedures for unblinding
Description of change
The following sentence was added:
If the 9 mg dose is considered futile based on the 
respective interim analysis (see Section 7.2.8), the 
patients will be re-assigned to the 18 mg dose in a 
blinded manner and the 18 mg dose will be given at the 
next scheduled visit.
Rationale for change
The management and handling of patients and data in case 
the dose of 9 mg bid is considered as futile were clarified.
Section to be changed
Section 4.2.2.1 Restrictions regarding concomitant 
treatment (Table 4.2.2.1: 1, about prednisone)
Description of change
The restrictions regarding prednisone prior to the study were 
updated from not permitted to permitted. As indicated in the 
footnote of the table, this is referring to ‘historical episodes 
of intake’ (i.e. treatment should not be ongoing at Visit 1). 
It was clarified in the text that prednisone >15 mg/day or 
equivalent should not be started for respiratory 
indications during the screening or treatment period. 
However, prednisone >15 mg/day or equivalent can be 
prescribed during the treatment period in case of 
(suspected) acute IPF exacerbation.
Rationale for change
Clarification of restrictions regarding historical episodes of 
intake, and introduction in case of exacerbations
Section to be changed
Section 4.2.2.1 Restrictions regarding concomitant 
treatment (CYP3A4 inhibitors)

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Description of change
Restrictions regarding potent CYP3A4 inhibitors were 
updated to clarify that, if any short-term treatment with 
potent CYP3A4 inhibitor is needed, IMP should be 
temporarily discontinued and a cross-reference to 
Section 3.3.4.1 was added about the conditions to 
re-introduce the IMP.
A footnote was also added to Table 4.2.2.1.
Rationale for change
The sentence was added to be consistent with Table 1.4.2: 1 
(about trial-related risks) and with Section 3.3.4.1 (about 
temporary discontinuation of trial treatment).
Section to be changed
Section 4.2.2.1 Restrictions regarding concomitant 
treatment (including Table 4.2.2.1: 1, about stem cell 
therapy)
Description of change
The following restriction was added:
Stem cell therapy for the treatment of pulmonary 
fibrosis is not allowed.
Rationale for change
The effect on the lung of such treatment in the longer term 
is currently unknown (also see addition of EC 27).
Section to be changed
Section 4.2.2.2 Restrictions on diet and lifestyle
Description of change
The restriction regarding the consumption of 
methylxanthine-containing drinks or food was lifted:
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 from drinking grapefruit 
juice during the duration of the trial.
Rationale for change
Caffeine, theobromine, and theophylline are the most well-
known compounds of the family of methylxanthines. They 
are predominantly metabolized by CYP1A2. Since 
BI 1015550 is not a CYP1A2 substrate and also does not 
modulate CYP1A2, an interaction between BI 1015550 and 
methylxanthine-containing drinks or food is not expected.
Section to be changed
Section 4.2.2.3 Contraception requirements

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Description of change
The following sentence was deleted:
Of note, oral hormonal contraceptives are not considered 
highly effective due to a potential CYP3A4 drug interaction 
of BI 1015550 in the gastrointestinal tract. Non-oral 
hormonal contraception is permissible as described below.
And the following was added to the list of acceptable highly 
effective methods of contraception:
• Oral hormonal contraceptives together with one 
barrier method (e.g. condom) to account for the risk of 
potentially reduced efficacy of the OCs in the event of 
severe vomiting and diarrhea. In case of vomiting or 
diarrhea, instructions in the label of the OC should be 
followed in addition. In case of prolonged (>48h) or 
repeated vomiting/diarrhea, the use of an alternative 
highly effective contraceptive measure should be 
considered
Rationale for change
Based on the results of a drug-drug interaction trial on the 
PK of midazolam, OCs are now allowed as highly effective 
measure of contraception in WOCBP, associated with one 
barrier method to prevent the risk of potentially reduced 
efficacy of the OCs in case of severe vomiting and diarrhea
(also see change to Section 1.4.2).
Section to be changed
Section 5.1.1 FVC
Description of change
Addition of the following sentence:
In case unacceptable results for FVC/FEV1 at V1 or 
FVC at V10 are obtained after the review, the patient 
must be reassessed.
Rationale for change
These instructions are in the spirometry guidance document 
but it was considered important to emphasize to the sites.
Section to be changed
Section 5.1.5.3 Patient’s Global Impression of Severity 
(PGIS) of Cough, Shortness of Breath, and Fatigue (also 
Section 5.1.5)
Description of change
The description of the questionnaire assessing the severity 
of the patient’s fatigue was added (the actual questionnaire 
was added in Appendix 10.2.4).
Rationale for change
The assessment of fatigue severity will be implemented in 
all countries where the setup is completed and translated 
questionnaire available.
Section to be changed
Section 5.1.6 DLCO
Description of change
The section was updated to clarify that the correction for Hb 
was applied to predicted DLCO values. It was also clarified 
that the site has to enter the unadjusted predicted DLCO 
result without Hb correction in the eCRF.

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The first formula (one for each gender) was for predicted 
DLCO corrected for Hb (and not percent predicted DLCO 
corrected for Hb) and the unit of Hb was clarified (g·dL-1)
A second formula was added for percent predicted DLCO 
corrected for Hb:
Percent predicted DLCO corrected for Hb = (Mean 
value of two DLCO measurements, expressed in
mmol/min/kPa) / Predicted DLCO corrected for Hb) * 
100
DLCO should always must be performed after spirometry 
on the same day.
Rationale for change
Clarification of the correction of predicted DLCO for Hb 
and revision/addition of formulas to calculate 1) predicted 
DLCO corrected for Hb, and 2) percent predicted DLCO 
corrected for Hb.
Clarification of the timing of DLCO relative to spirometry.
Section to be changed
Section 5.2.3 Safety laboratory parameters
Description of change
The ESR test was removed from the routine safety lab test 
panel (Section 5.2.3.1) and the test for cryoglobulins was 
removed from the vasculitis lab test panel (Section 5.2.3.3).
Note: the mention of ESR test in Section 5.2.6.1.4 (Adverse 
Events of Special Interest) was also removed.
Rationale for change
Local workup is crucial for the reliability of the results, but 
sites are not familiar with the sample handling and 
procedures. Therefore test results are often inconclusive.
Section to be changed
Section 5.2.3.1 Routine safety lab tests (Table 5.2.3.1: 1)
Description of change
The type and timing of the pregnancy tests were clarified. 
At screening (V1), a serum pregnancy test is to be 
performed (no IMP taken at that time) whereas at V2 (and 
following visits), urine dipstick pregnancy test is to be 
performed (if positive, urine dipstick test should be 
followed by serum test for confirmation).
Rationale for change
The use of “Day -1” in the table was confusing; visit 
numbers were used instead. 
Section to be changed
Section 5.2.3.2 Infection serology
Description of change
Wording was updated as follows:
In case of positive TB test Screening Test, further 
diagnostic work up to confirm/exclude the diagnosis of 
latent or active is needed (documentation on respective 
eCRF page).
Rationale for change
Clarification that further diagnostic work up to 
confirm/exclude the diagnosis of latent or active TB is to be 
done for any positive TB test (not just at screening)

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Section to be changed
Section 5.2.3.3 Immunological vasculitis markers
Description of change
Addition of the following paragraph:
Due to stability matter during storage, ANCA markers 
(MPO-ANCA and PR3-ANCA) from Visit 2 and Visit 10 
are analyzed upon receipt, but investigators will not 
receive these results as it could influence their 
judgement regarding a suspected vasculitis. The rest of 
the analysis of immunological vasculitis markers is 
performed if an unscheduled “Vasculitis event” is 
collected. In this situation, the site will receive the result 
for all vasculitis markers previously performed (from 
V2 and V10 if already done) and from the unscheduled 
“Vasculitis event” kit. These results are shared by the 
trial team to the site via the CRA.
Rationale for change
The timing and conditions of analysis of ANCA markers 
and communication of results to the site were clarified due 
to stability matter during storage.
Section to be changed
Section 5.2.6.3 Independent safety monitoring and adverse 
events with additional information collection
Description of change
Wording was updated as follows:
Additional details (on top of standard AE and SAE 
reporting) will be collected in the eCRF for the adverse 
event ‘Diarrhea/gastrointestinal events’, the adverse events 
in the Standard MedDRA Query (SMQ) ‘vasculitis’ and in 
case of positive TB tests tuberculosis screening (see 
Section 5.2.3.2).
Rationale for change
Clarifications that additional details should be collected in 
the eCRF for any positive TB test (not just at screening).
Section to be changed
Section 5.6.1 Chest HRCT assessment (repetition of HRCT)
Description of change
The following sentence was deleted:
HRCT should not be repeated for eligibility if previous scan 
was taken within the past 3 months.
Rationale for change
The possibility to repeat the HRCT for eligibility and the 
allowed timeframe between scans will be left up to the 
investigator’s decision, based on local guidance.
Section to be changed
Section 6.1 Visit Schedule
Description of change
The following sentence was amended:
The patient will be randomized at Visit 2 if all inclusion 
criteria (including positive HRCT review and acceptable 
spirometry measurements) and none of the exclusion 
criteria (lab exclusion criteria referring to Visit 1 results) are 
fulfilled.

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Rationale for change
The conditions for randomization were clarified (also see 
the change in Section 5.1.1)
Section to be changed
Section 6.2 Details of trial procedures at selected visits
Description of change
The following edits were made:
Regarding patients’ questionnaire: At the latest, the 
patients’ questionnaires must be completed prior to the 
pulmonary function tests
Regarding the pulmonary function tests: FVC (spirometry) 
should must be performed before DLCO
Regarding IRT call and IMP dosing/dispensing: IRT call 
and IMP dosing/dispensing should always be done as the 
last procedure after all visit assessments, except at Visit 1 
where the IRT call may be done earlier during the 
patient’s visit.
Rationale for change
The order of procedures was clarified.
Section to be changed
Section 6.2.1 Screening period
Description of change
Sentence amended:
If a patient is re-screened and there are valid screening 
determinations from patient’s previous participation in the 
trial, like for example safety labs, performed within 28 days
8 weeks prior to randomization (Visit 2), these do not need 
to be repeated.
Rationale for change
This is to align the timeframe with the regular allowed 
screening phase of 8 weeks without repetition of V1 
laboratory tests.
Section to be changed
Section 6.2.2.1 Conduct of a regular site visit
Description of change
The need for supervision during administration was 
clarified:
Each patient will receive the first dose of BI 1015550 or 
placebo at the end of Visit 2 (Day 1) under direct 
supervision of the investigator or designee. Patients will 
take trial medication twice daily (bid) orally from that 
timepoint onwards. On the day of any furtherAt clinic 
visits, supervision of administration is not required but 
trial medication will preferably be administered to the 
patient during the visit (as the last procedure, see 
Section 6.2) taken under direct supervision of the 
investigator or
designee.
Rationale for change
Supervision remains mandatory during the first 
administration but is not mandatory for any of the following 
administrations including further clinic visits. Simplified for 
facilitation of scheduling the visits.
Section to be changed
Section 6.2.3 Follow-up period and trial completion

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Description of change
Specification about the design of the extension trial (“open-
label”) was removed (also applied in Section 3.1).
The procedures in case of temporary vs. permanent 
discontinuation of trial treatment were aligned with the 
changes made in Section 3.3.4.1.
It was clarified that the abnormal values to monitor are 
those collected at the last study visit (EOS).
Rationale for change
The extension trial design is not finalized and might also 
contain a double-blind start until the decision about the dose 
that could be given as an open-label treatment is taken.
Alignment of procedures in case of temporary vs.
permanent discontinuation of trial treatment with 
Section 3.3.4.1.
Section to be changed
Section 7.2.1 General considerations (and Sections 7.2.3 
and 7.2.4)
Description of change
Addition of the Full Analysis Set (FAS) as the primary 
population for the efficacy analysis, and modification of the 
definition of the Treated Set (TS), which will be the primary 
population for the safety analysis (but not the efficacy 
analysis).
Inclusion of the analysis strategy in the definition of the 
analysis sets.
Deletion of the following sentence: For efficacy and safety 
analyses, patients will be analysed according to their 
planned treatment group.
Deletion of the Per Protocol Set (PPS).
Sections 7.2.3 and 7.2.4 were updated to reflect the fact that 
the FAS will be the efficacy set.
Rationale for change
Efficacy and safety analyses will be conducted with 
different analysis strategy. Patients will be analyzed as 
randomized in the efficacy analysis, whereas they will be 
analyzed as treated in the safety analysis.
The PPS was deleted as post-randomization events will be 
handled via estimands (based on ICH E9 addendum), as 
described in the TSAP.
Section to be changed
Section 7.2.1 General considerations (important protocol 
deviations)
Description of change
The sentence was updated as follows:

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Specifications for Definitions and handlings of important 
protocol deviations (IPDs) leading to exclusion from PPS 
will be provided in the trial Integrated Quality and Risk 
Management Plan (IQRMP) included in the DV domain 
specifications and will be stored within the trial master 
file (TMF) in the electronic document management 
system (EDMS). All potential important protocol 
deviations will be discussed during trial oversight 
meetings and report planning meetings. and aAll final
decisions concerning IPDs will be made before un-blinding.
Rationale for change
Clarification on handling, documentation and review of 
IPDs.
Section to be changed
Section 7.2.3.1 Sensitivity analyses
Section 7.2.4.1 Analysis of key secondary endpoint
Description of change
Sentence amended:
On-treatment analyses, while-compliant-to-protocol
analyses in the PerProtocol Set and models with modified 
sets of covariates will be conducted as further sensitivity 
analyses
Rationale for change
Deletion of the PPS.
Section to be changed
Section 7.2.4.1 Analysis of key secondary endpoint
Section 7.2.4.2 Analysis of other secondary endpoints
Description of change
For all time-to-event endpoints, the start date considered 
when calculating the time to event of interest (and the time 
to censoring) was changed from ‘randomization date’ to 
‘first drug intake date’.
Rationale for change
There may be a few days gap between the randomization 
date and the first drug intake date. For the purpose of 
time-to-event analyses, the actual time at risk starts with the 
first drug intake.
Section to be changed
Section 7.2.8 Interim analyses (and synopsis)
Description of change
The following sentences were added:
If the 9 mg dose is considered futile, the patients on that 
treatment arm will be re-assigned to the 18 mg dose in a 
blinded manner (see Section 4.1.5.1) at their next 
scheduled visit.
A shorter version of this new paragraph was added to the 
synopsis.
Rationale for change
The management and handling of patients and data in case 
the dose of 9 mg bid is considered as futile were clarified.
Section to be changed
Section 7.2.8 Interim analyses (and synopsis)
Description of change
The description of the interim analysis to detect early signs 
of substantial efficacy was adjusted:

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[…] an interim analysis for efficacy will may be performed 
by the DMC.
This interim analysis is planned to may be conducted when 
a minimum of 450 patients (150 patients per arm) have 
reached the Week 52 FVC assessment approximately 
52 weeks after 450 patients (150 patients per arm) have 
started treatment and 26 weeks after the last patient has 
started treatment.
Rationale for change
The previous wording excluded patients who died or who 
were lost to follow-up from the count of 450 because these 
patients would not reach the Week 52 FVC assessment. The 
new wording does include the patients who died or who 
were lost to follow-up in the count of 450.
The exact timing of this analysis remains to be confirmed.
Section to be changed
Section 7.4 Randomization (futility analysis)
Description of change
The following sentence was added:
For patients to be enrolled and randomized after a 
potential futility stop of the low dose level (9 mg; see 
Section 7.2.8), the randomization ratio will be 1:1 
(BI 1015550 18 mg bid vs. Placebo).
Rationale for change
The randomization ratio in case the dose of 9 mg bid is 
considered as futile were clarified.
Section to be changed
Section 7.5 Determination of sample size
Description of change
Sentence deleted: This leads to the same overall treatment 
effect of 74 mL overall.
Rationale for change
The treatment effect is already stated further below in that 
section.
Section to be changed
Section 10.1 Spirometry: Bronchodilator Washout 
Recommendations
Description of change
The title of table was amended to clarify that the washout 
timeframes presented were minimal timeframes
Rationale for change
Washout timeframes for bronchodilators before spirometry 
may be longer than those presented in the table.
Section to be changed
Section 10.2.4 Patient’s Global Impression of Severity 
(PGIS) for Cough, Shortness of Breath, and Fatigue
Description of change
Addition of the questionnaire on fatigue severity
Rationale for change
See change to Section 5.1.5.3
Section to be changed
Section 10.6 Eligibility confirmation of IPF diagnosis
Description of change
Eligibilty criteria for patients with an “alternative diagnosis” 
HRCT finding were clarified with the following:
If the HRCT findings are “suggestive of an alternative 
diagnosis”, the clinical diagnosis of IPF may be 

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confirmed locally by (historical) surgical lung biopsy or 
TBLC demonstrating a “UIP” histopathology pattern.
[…]
Patients clinically suspected to have IPF with an HRCT 
pattern “suggestive of an alternative diagnosis” require 
historical (i.e., not taken for the purpose of this trial) 
surgical lung biopsy or TBLC which will be reviewed 
locally (by the investigator/local histopathologist).  In 
these patients, specific combinations of HRCT patterns 
and histopathology patterns may still allow a diagnosis 
of IPF based on the 2022 ATS/ERS/JRS/ALAT 
Guideline, i.e., an HRCT pattern of “alternative 
diagnosis” in combination with a surgical lung biopsy or 
TBLC with a histopathology pattern of “UIP” could 
qualify for inclusion.
Rationale for change
Patients with an “alternative diagnosis” HRCT finding are 
considered for eligibility (also see Section 3.3.1).
Section to be changed
Section 10.7 Trial participant feedback
Description of change
This new section describes the conditions of implementation 
of the optional participant and caregiver feedback 
questionnaires.
Rationale for change
To identify where improvements can be made in the clinical 
trial process, the sponsor wants to collect the participants’ 
and caregivers’ feedback on their clinical trial experience.
Section to be changed
Throughout the CTP
Description of change
Typographical errors and minor formatting issues amended
Rationale for change
To increase readability
11.3
GLOBAL AMENDMENT 3
Date of amendment
20 September 2023
EudraCT number
2022-001091-34
BI Trial number
1305-0014
BI Investigational 
Medicinal Product
BI 1015550 
Title of protocol
A double blind, randomized, placebo-controlled trial 
evaluating the efficacy and safety of BI 1015550 over at 
least 52 weeks in patients with Idiopathic Pulmonary 
Fibrosis (IPF)
Global Amendment due to urgent safety reasons
Global Amendment (substantial changes)
X
Section to be changed
Synopsis

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Description of change
A paragraph was deleted, and a new paragraph added to the 
statistical methods:
An interim analysis for a potentially earlier regulatory 
submission may be conducted approximately 52 weeks after 
450 patients (150 patients per arm) have started treatment 
and 26 weeks after the last patient has started treatment in 
order to detect early signs of substantial efficacy. The 
interim analysis will be implemented within a group 
sequential design with the aim to decide whether or not 
efficacy of BI 1015550 can be claimed early on in a 
confirmatory manner. Once the last randomized patient 
completes the Week-52 assessment, the main analysis of 
the trial will be carried out by the sponsor, who will be 
unblinded to assess the benefit-risk of the two doses of 
BI 1015550 compared with placebo. Patients will remain 
on their randomized blinded treatment until the sponsor 
has reviewed the efficacy and safety data from the main
analysis and communicated the end of the trial. Once 
this trial ends, a final analysis based on all data will be 
carried out.
Rationale for change
1) To reflect that the efficacy interim analysis will not be 
conducted, which was decided by the sponsor before the 
futility analysis. The sponsor’s decision was based on
Health Authority feedback and shifting trial timelines with 
fast recruitment, which make the time advantage in 
conducting the interim analysis limited
2) To specify the main analysis and the final analysis
Section to be changed
Flow chart
Description of change
The following footnotes were revised:
(1) Following completion of V10 patients will continue to 
have study visits every 12 weeks until the start of EoT 
visits is announced. The global study will be completed 
after all patients have performed the EoT visit and the 
EoS visit (if not continuing in the separate extension 
trial)the last patient randomized has reached Week 52. If 
the patient will complete EOT at 52 weeks (study 
completion phase), V10 is replaced by the EOT visit.
(8) Assisted home spirometry will be offered at selected 
centres where every patient should have a training and 
measurement with the device ideally at Visits 2 or 3. If the 
requirement to use the iSpiro appears later in the trial, 
then this timepoint can be shifted. Remote measurement 

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can be performed as per investigator’s judgement but 
should not replace the on-site FVC measurement.
Rationale for change
1) Clarification 2) To allow flexibility in training of iSpiro
Section to be changed
Section 3.1 Overall trial design
Description of change
The following paragraphs were added or revised:
The main analysis of this study will be performed once 
the last randomized patient reaches the Week-52 visit 
(Visit 10 at the end of Part A). At that time, a first 
database lock (DBL1; Figure 3.1: 1) will occur and all 
data will be unblinded to the sponsor. Efficacy and 
safety analyses will be performed on the data from Part 
A of the trial to assess the benefit-risk of BI 1015550
over 52 weeks. In addition, data collected in Part B of 
the trial (after 52 weeks) and available at the time of 
data cut-off for the main analysis will be reported 
together with data from Part A (i.e. over the whole 
trial).
Trial 1305-0014 Part B, will continue until all patients 
have completed the EOT visit and the EOS visit as 
applicable. A final database lock (DBL2; Figure 3.1: 1) 
will then occur and a final analysis based on the data 
over the whole trial will be carried out.
Depending on the results of the evaluation based on 
DBL1 and determination of the BI 1015550 dose with 
the more favorable benefit-risk profile, patients 
receiving trial medication until the end of Part B will be 
eligible for open-label treatment with BI 1015550 in a 
separate extension trial.
Around the time the last randomized patient reaches 52 
weeks of treatment, After review of the efficacy and 
safety data available at DBL1, the sponsor will 
communicate the end of the trial and all patients still on 
blinded study treatment will perform an End of Treatment
(EOT) visit and an End of Study (EOS) visit if applicable. 
The trial ends when all patients complete these visits.
Details on follow-up and rollover to the extension trial are 
given in Section 6.2.3.
“Figure 3.1: 1 Trial design overview at patient level 
(upper panel) and trial level (lower panel)” was updated 
according to the revised text.
Rationale for change
To specify the main analysis and the final analysis

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Section to be changed
Section 3.2 Discussion of trial design, including the choice 
of control group(s)
Description of change
The following sentences were added:
The additional data collected while patients remain on 
blinded treatment beyond 52 weeks will provide 
supportive long-term efficacy and safety data on the 
effect of BI 1015550 in a controlled manner. Due to the 
varying length of follow-up in Part B of the trial, the 
efficacy analyses incorporating data from Part A and 
Part B will focus on time-to-event endpoints.
Rationale for change
To add the rationale on conducting Part B
Section to be changed
Section 4.1.5.1 Blinding
Description of change
The following paragraphs were added or revised:
At the main analysis database lock (DBL1; see Section 
3.1), the sponsor will be unblinded to assess the benefit-
risk of both doses of BI 1015550 vs placebo and select 
the dose with the more favorable benefit-risk profile for 
the open-label extension trial. Patients, investigators, 
and other site personnel will remain blinded to the 
randomized treatment assignment until the end of the 
trial.
The trial medication is identified by a medication code 
number and packaging is identical. The color, size, and 
shape of the respective 9 mg and 18 mg BI 1015550 and the 
matching placebo tablets will be indistinguishable. The 
access to the randomization code will be kept restricted 
until its release for analysis at DBL1. Further details 
regarding the timepoint of unblinding the database for 
analysis is documented in the TSAP.
The randomization codes will be provided to bioanalytics 
before the last patient completed the trial DBL1 to exclude 
placebo or comparator samples from the PK analysis. 
Bioanalytics will not disclose the randomization code or the 
results of their measurements until the database lock DBL1.
A dedicated database snapshot (not a partial DBL) will 
be generated prior to DBL1, after all patients have 
completed the last PK visit (i.e. Week-26 visit), to allow 
for development and refinement of the population PK 
model (for “fast-track” PK analysis). Details of the 
analysis will be defined in the PK/PD analysis plan. In 
addition, the data will be used for front-loading of 
descriptive analysis for PK. Only personnel involved in 
the population PK and descriptive analyses will be 

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granted access to the unblinded PK data before DBL1, 
whereas the trial team and all other functions not 
involved in the population PK and PK descriptive 
analyses will remain blinded (details will be provided in 
a separate logistics and access plan). The analysis plan 
for the population PK analysis will be finalized and 
signed prior to this dedicated database snapshot. 
No formal interim report will be generated for the 
population PK analysis. The final PK and PK/PD 
analyses will be reported separately from the clinical 
trial report (CTR) after DBL1.
The external DMC will review unblinded data upon request 
and for the futility interim analyses analysis as described in 
Section 7.2.8, and only under conditions that ensure that 
patients, investigators, everyone involved in trial conduct or 
analysis, and anyone with any other participation in this 
double-blind trial will remain blinded. 
…
In case the interim analyses result in the recommendation 
for a preliminary report preparation, a respective team 
(“shadow team”) independent of the main trial team will be 
formed to conduct the necessary data cleaning, analysis, 
and reporting steps and ensure to maintain the blind and 
restrict access to the randomization codes from the main 
trial team. Details of data transfer, timelines and involved 
trial functions during this process will be described in a 
separate logistics plan which will also specify details on 
data access.
Rationale for change
1) To explain that unblinding of the sponsor will occur at 
the main analysis (DBL1); 2) To add that to front-load, 
personnel involved in the PK analyses will use unblinded 
PK data before DBL1; 3) To reflect that the efficacy interim 
analysis will not be conducted
Section to be changed
Section 4.2.2.1 Restrictions regarding concomitant 
treatment
Description of change
The following sentence was revised:
Treatment with non-selective PDE inhibitors as well as 
PDE1, PDE3, PDE4, and PDE10 inhibitors is not allowed.
“Table 4.2.2.1: 1 Restrictions regarding concomitant 
treatment” was updated according to the revised text. 
Rationale for change
To narrow restricted PDE inhibitors down to those that 
specifically interfere with PDE4

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Section to be changed
Section 5.1.1 FVC
Description of change
The following sentence was revised:
Training of the patients on the use of the iSpiro device and 
App should can be done at any visit, ideally at Visit 2 or 
Visit 3 together with a first recording.
Rationale for change
To allow flexibility in training of iSpiro
Section to be changed
Section 5.2.6.1.1 Adverse event
Description of change
The following paragraph was added:
Adverse event report for depression and anxiety
AE reporting based on the Hospital Anxiety and 
Depression Scale (HADS): new onset of moderate
depression, defined as HADS subscore of >10, has to be 
reported as AE; new onset of moderate anxiety, defined 
as HADS subscore of >10, has to be reported as AE. 
HADS subscore of ≤10 should only be reported as an AE 
if clinically relevant. See Section 5.2.6.1.4 for reporting 
of AESI based on HADS.
Rationale for change
To clarify AE reporting based on HADS
Section to be changed
Section 6.2.2.3 End of treatment visit
Description of change
The following sentence was revised:
As described in Section 3.1, around the time the last 
randomized patient reaches 52 weeks of treatment (Visit 
10)after the confirmation of the benefit-risk evaluation 
for a potential start of the extension trial based on the 
main analysis, all patients still on blinded study treatment
will perform an EOT visit. It will occur either at the regular 
timepoint of Visit 10 (52 weeks) if it falls within this 
timeframe (e.g. if patient is still in Treatment Period A) or 
at a convenient timepoint in this timeframe if the patient 
already had performed Visit 10 previously (e.g. if the 
patient had already started Treatment Period B).
The start of these EOT visits will be communicated when 
the last patient is randomized and thus, the timepoint of the 
anticipated last patient at 52 weeks visit is known.
Rationale for change
Clarification
Section to be changed
Section 7.1 Null and alternative hypotheses
Description of change
A paragraph was added:

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The hypothesis testing of the key secondary endpoint is 
based on data collected up to the main analysis (all data 
up to DBL1; see Figure 3.1: 1). A supplementary 
analysis of the key secondary endpoint using all data 
collected over the whole trial will be performed after 
DBL2.
The following sentence was deleted:
The tests for the primary endpoint comparing each dose vs. 
placebo within the graphical testing procedure will include 
one interim analysis for potential efficacy claim using a 
group sequential design. The alpha level at interim analysis 
and final analysis will be adjusted accordingly, see Section 
7.2.8.
Rationale for change
1) To clarify that the hypothesis testing of the key 
secondary endpoint will be done at the main analysis; 2) To 
reflect that the efficacy interim analysis will not be 
conducted
Section to be changed
Section 7.2.1 General considerations
Description of change
A paragraph was added:
All planned efficacy and safety analyses, including for 
the primary and key secondary endpoints will be 
carried out at DBL1 (Figure 3.1: 1) and the statistical 
hypotheses described in Section 7.1 will be tested. After 
DBL2, analyses of the efficacy endpoints defined as 
“over the duration of the trial” and all safety analyses
will be repeated to include all data collected until the 
end of the trial.
Rationale for change
To describe at a high level what will be analyzed at the 
main and the final analysis
Section to be changed
Section 7.2.3.3 Supplementary Analyses
Description of change
The following sentence was revised:
Further details will be specified in the TSAPNot 
applicable for this trial.
Rationale for change
Clarification
Section to be changed
Section 7.2.8 Interim analyses
Description of change
The following paragraphs were deleted:
To allow for the early initiation of marketing authorization 
applications in the case of a positive efficacy finding 
combined with a favorable safety profile which are 

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considered sufficient to conclude for a clearly positive 
benefit-risk balance, an interim analysis for efficacy may be 
performed by the DMC. This interim analysis will be 
implemented within a group sequential design with the aim 
to decide whether or not efficacy of BI 1015550 can be 
claimed early on in a confirmatory manner. This interim 
analysis may be conducted approximately 52 weeks after 
450 patients (150 patients per arm) have started treatment 
and 26 weeks after the last patient has started treatment. A 
Wang-Tsiatis type alpha spending approach [R06-0638] 
with a delta parameter of 0.25 will be used for the tests 
H_01 and H_02 of the primary endpoint comparing the 18 
mg bid and 9 mg bid dose vs. placebo, respectively. It is 
expected that at the time of the interim analysis around 70% 
of the events for the key secondary endpoint have been 
observed. The graphical testing procedure as defined in 
Section 7.1 will be followed with an extension to group 
sequential designs [R17-2947]. The secondary endpoint will 
not be tested at this interim analysis for either of the doses 
and all alpha propagated to secondary endpoint will be 
reserved for the final analysis as the trial will not be 
stopped.
In order to conclude that the trial met its primary endpoint 
for at least one dose, the following criteria must be met:
The p-value for the primary endpoint meets the required 
cut-offs for one dose based on the Wang-Tsiatis type alpha 
spending approach with a delta parameter of 0.25, e.g. for 
an interim at approximately 450 patients complete 52 week 
follow-up, planned at two-sided,  α_ia= 0.0103 for H_01 or 
α_ia= 0.0016 for H_02. 
If the interim analysis meets the primary endpoint, the 
DMC will take into account the totality of the data for the 
recommendation to the sponsor to unblind the trial by a 
team independent of the trial team with the task to prepare 
regulatory submission documents.
The interim analysis is expected to occur approximately 6 
months before the final analysis. Independent of the results 
the patients will be followed up until the planned End of 
Study.
The trial team, patients and investigators will remain 
blinded until the final data base lock. All measures taken 
will be directed to maintain the trial integrity. Details 
regarding the safeguards to keep patients, investigators and 
the trial team blinded will be provided in a logistics plan 
(Section 4.1.5).

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Rationale for change
To reflect that the efficacy interim analysis will not be 
conducted
Section to be changed
Section 7.3.1 Efficacy endpoints
Description of change
The following table reference was corrected:
In the primary analysis of primary endpoint, missing data 
will not be imputed except for death, where a poor outcome 
will be assigned, see Table 7.3.1: 1 Table 7.5: 1.
Rationale for change
Correction
Section to be changed
Section 7.5 Determination of sample size
Description of change
The following paragraphs were revised:
An effective sample size of 310 patients per group, will 
detect a treatment effect of 74 mL with 9091% power under 
two-stage group sequential design with Wang-Tsiatis alpha 
spending function (delta=0.25) and cumulative two-sided 
alpha of 5% for one active BI 1015550 dose arm vs. 
placebo. With 310 patients per arm and a two-sided type I 
error rate of 0.05, a treatment effect size of 90, 65, 55, and 
45 can be detected for each of the primary endpoint with 
98%, 8182%, 6769%, and 5052% power respectively.
Simulation results as presented in Table 7.5: 2 suggest that 
with 310 effective sample size per arm, there is at least 93% 
power to detect an effect size of 74 mL in FVC change 
from baseline at Week 52 for at least one dose is significant 
(Scenario #1). Regardless of effect size of the 9 mg bid arm, 
probability of detecting a significant FVC effect of 74 mL 
in the 18 mg bid arm is between 8889% to 90%. 
Furthermore, if 18 mg bid arm has an effect of 74 mL in 
primary endpoint and HR of 0.6 in key secondary endpoint, 
the probability of rejecting both  H_01 and H_03 is between 
65% to 74% depending on relative effect size of the 9 mg 
bid arm. The simulation results also show a well controlled 
type-I error under the null hypothesis (Scenario #5) with the 
proposed testing strategy.
“Table 7.5: 2 Multiplicity adjusted probabilities of success 
for each hypothesis, and positive study and interim success
under different scenarios of effect sizes from simulations” 
was revised to update the numbers without the efficacy 
interim analysis, to delete 5 lines with “probability of 
rejecting at least one dose primary endpoint at interim”, and 
to delete a footnote “Multiplicity adjusted for interim 

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analysis using group sequential design with Wang-Tsiatis 
alpha spending function (delta = 0.25).”.
Rationale for change
To reflect that the efficacy interim analysis will not be 
conducted
Section to be changed
Appendix 10.4.3 Restricted PDE inhibitors
Description of change
The table was revised to delete the lines of the following 
PDE inhibitors:
PDE1
Vinpocetine (Cavinton)
PDE3
Cilostazol (Pletal, Ekistol)
Olprinone (Coretec)
Anagrelide (also inhibits phospholipase A2) (Agrylin, 
Xagrid)
PDE10A
Papaverine (Pavabid, Pavagen)
Rationale for change
To narrow restricted PDE inhibitors down to those that 
specifically interfere with PDE4

 
 
 
 
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c39145241
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clinical-trial-protocol-1305-0014-version-04
A double blind, randomized, placebo-controlled trial evaluating the efficacy and
safety of BI 1015550 over at least 52 weeks in patients with Idiopathic Pulmonary
Fibrosis (IPF)
Approval-Clinical Program 
21 Sep 2023 13:29 CEST
Approval-Biostatistics
21 Sep 2023 13:29 CEST
Approval-Clinical Trial Leader
21 Sep 2023 15:20 CEST
Verification-Paper Signature
Completion
25 Sep 2023 11:31 CEST

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