Safety, Tolerability, and Pharmacokinetics of Multiple Rising Oral Doses of BI 1015550 in Patients With Idiopathic Pulmonary Fibrosis (IPF) on no Background Anti-fibrotic Therapy.
Phase: PHASE1
Conditions: Idiopathic Pulmonary Fibrosis
Sponsor: Boehringer Ingelheim

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Clinical Trial Protocol
TITLE PAGE
Document Number:
c17703547-05
EudraCT No.:
BI Trial No.:
2017-002736-16
1305-0012
BI Investigational
Product:
BI 1015550
Title:
Safety, tolerability, and pharmacokinetics of multiple rising oral doses
of BI 1015550 in patients with idiopathic pulmonary fibrosis (IPF) on 
no background anti-fibrotic therapy. 
Lay title:
This study tests different doses of BI 1015550 in patients with 
idiopathic pulmonary fibrosis (IPF). The study tests how BI 1015550 
is taken up by the body and how well it is tolerated. 
Clinical Phase:
Ic
Clinical Trial Leader:
Phone:
Co-ordinating 
Investigator:
Phone:
Status:
Final Protocol (Revised protocol (based on Global Amendment 4 ))
Version and Date:
Version: 5.0
Date: 27 Mar 2019
Page 1 of 111
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CLINICAL TRIAL PROTOCOL SYNOPSIS
Name of company:
Tabulated
Trial Protocol
Boehringer Ingelheim
Name of finished product:
Not applicable
Name of active ingredient:
BI 1015550
Protocol date:
Trial number:
Revision date:
27 Mar 2019
02 Nov 2017
1305-0012
Title of trial:
Safety, tolerability, and pharmacokinetics of multiple rising oral doses of BI 1015550 
in patients with idiopathic pulmonary fibrosis (IPF) on no background anti-fibrotic 
therapy. 
Co-ordinating 
Investigator:
Phone: 
Trial site(s):
Multi-Centre study
Clinical phase:
Ic
Objectives:
Multiple Rising Dose (MRD)
The primary objective is to investigate safety and tolerability of BI 1015550 in 
patients with IPF.
The secondary objectives are to investigate the effect of BI 1015550 on
 
he pharmacokinetics (PK) of BI 1015550.
Methodology:
Double-blind, randomised within dose groups, placebo-controlled, parallel-group 
design
No. of patients: 
total entered:
N= 24
each treatment:
DG 1A*: 9 (6 on active drug and 3 on placebo) plus additional 6 (4 on active drug and 
2 on placebo)
DG 1B*: 9 (6 on active drug and 3 on placebo)
* Additional patients may be entered to allow for testing of additional doses within the planned 
dose range on the basis of experience gained during the trial conduct (e.g. preliminary PK 
data), i.e. the actual number of patients entered may exceed 18
Diagnosis:
Idiopathic Pulmonary Fibrosis
Main criteria
for inclusion:
Patients with IPF ages ≥40 years, who have not been treated with nintedanib or 
pirfenidone within 30 days of visit 1 and not planning to be initiated on nintedanib or 
pirfenidone for the duration of the study.
Test product:
BI 1015550 as tablet formulation (TF 1 containing 6mg of BI 1015550)
dose:
Starting dose of 18mg b.i.d

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Name of company:
Tabulated
Trial Protocol
Boehringer Ingelheim
Name of finished product:
Not applicable
Name of active ingredient:
BI 1015550
Protocol date:
Trial number:
Revision date:
27 Mar 2019
02 Nov 2017
1305-0012
mode of admin.:
Oral
Reference Product
Matching placebo as tablet formulation
dose:
Not applicable
mode of admin.:
Oral
Duration of treatment: 4 weeks
Criteria for 
pharmacokinetics:
Secondary endpoint:
BI 1015550
Day 1: AUCτ,1 and Cmax
Day 14: AUCτ,ss and Cmax,ss
Criteria for safety:
Primary endpoint
To assess safety and tolerability of BI 1015550 by the number (%) of patients with 
drug-related adverse events (AEs) on-treatment.                    
Further criteria of interest: Treatment emergent AEs (TEAEs) (including clinically 
relevant findings from the physical examination), safety laboratory tests (including 
testing for fecal occult blood and fecal calprotectin, urinalysis for hematuria), 12-lead 
electrocardiogram (ECG), vital signs (blood pressure (BP), pulse rate (PR), 
respiratory rate (RR), oral body temperature and body weight), and suicidality 
monitoring.
Statistical methods:
Descriptive statistics will be calculated for all endpoints.

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FLOW CHART
Flow chart 1A: Overview
Trial Period
Screening
Treatment
End of 
Trial
Visit
1
2
31
4
5
6
7
81
9/ 
EOT
17
End of 
Trial
Day
-28 to -2
-1
1
2
4
± 1
7
± 1
10
± 1
13
14
28
± 4
+7
+3
Visit type
O
O
I
O
O
O
O
V
O
C2
O
Informed consent
X
Demographics3
X
Body Weight
X
X
X
X
Medical History
X
X
Physical Examination
X
X
X
X
X
Vital Signs4
X
X
X
X
X
X
X
X
X
X
X
Safety Laboratory test5
X
X6
X
X
X
X
X
X
X
Fecal Occult blood/ 
Fecal Calprotectin
X
X
X
X
X
X
X
Drug Screen/ Alcohol 
breath test
X
ECG
X
X
X
X
X
X
X
X
X
X
Suicide Questionnaire8
X
X
X
X
X
HRCT9
X
Review of
in/exclusion criteria
X
X
Randomisation
X
BI 1015550 dispensed
X
X
X
X
X
X
X
BI 1015550 
administration in 
clinic
X
10
X
10
X
11
X
11
X 
11
X
11
X 10
BI 1015550 returned 
X
X
X
X
X
Compliance Check
X
X
X
X
X
Dispense diary
X
X
X
X
X
Review diary
X
X
X
X
X
PK Plasma: BI 
1015550
X
12
X    
13
X
13
X
13
X
13
X 12
X 13
Concomitant therapy
X
X
X
X
X
X
X
X
X
X
X
X
Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
O= Outpatient visits; I= Inpatient visit with monitored overnight stay; V= Overnight stay either inpatient or nearby facility; C telephone call follow-up

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Footnotes Flow chart 1A
1. Please refer to flow chart 1B and flow chart 1C for specifics pertaining to these visits. 
2. Daily phone calls between study visits to assess and collect AE and confirm compliance 
until Day 14, with weekly phone calls between study visits thereafter until end of 
treatment (EOT).
3. Demographics (including determination of height, smoking status and alcohol history)
4. Vital signs include BP, PR, RR, body temperature.
5. Safety laboratory tests to be taken pre morning dose.
6. Safety laboratory tests to be taken and to be medically evaluated within 3 days prior to 
first administration of study drug at visit 3; this safety laboratory can be omitted, if the 
screening examination is performed on Days -3 or -2
7. DLCO is required at screening to confirm eligibility. For scheduling reasons, DLCO 
may be performed during or shortly following visit 1, providing results are available for 
review at visit 2.
8. Prospective suicidality monitoring, will be performed throughout this trial using the 
Columbia Suicidal Severity Rating scale (C-SSRS). Refer to section 5.2.5.3 and 
appendix 10.1 for additional details.
9. IPF diagnosis may be confirmed using a historical HRCT scan. If a historical scan taken 
within the past 12 months is not available, or an available scan fails to meet the required 
image acquisition specification, an HRCT may be performed after consent to determine 
eligibility. All HRCT scans will be sent to a central vendor for review and confirmation 
of IPF diagnosis, prior to randomization. HRCT should not be repeated for eligibility if 
previous scan was taken within the past 3 months. 
10. All applicable doses to be administered in clinic
11. Morning dose to be administered in clinic
12. On day 1 and day 14, PK sample for BI 1015550 to be taken pre morning dose and at 
0.5, 1, 1.5, 2, 4, 6, 8, 12h post dose; 12 h sample should be immediately prior to the 
evening dose.
13. PK sample for BI 1015550 to be taken pre morning dose in the morning on Days 2, 4, 
10, and day 13. At day 28, PK sample to be taken ~12h post day 27 evening dose.  
17. EOT visit is required for all patients, including patients who discontinue treatment early. 

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Flow chart 1B: Visit 3
Visit
Day
Planned time (relative to first drug 
administration 
[h:min]
Approximate clock time  of actual 
day [h:min]
Event and comment
Safety laboratory
BI 1015550 PK blood 
Fecal occult blood and fecal
calprotectin testing
12-lead ECG
Vital signs 
Questioning for AEs and 
concomitant therapy 
Other trial procedures 6
3
1
-2:00
6:00-
8:00
Randomization
x1
x1, 5
x1
x1
x
-0:30
07:30
Breakfast
0:00
08:00
First study drug 
administration
x
0:30
08:30
x
1:00
09:00
x2
x5
x
x
1:30
09:30
x
2:00
10:00
240 mL fluid 
intake 2
x
x5
x
x
4:00
12:00
240 mL fluid 
intake, thereafter 
lunch2
x
x5
x
x
6:00
14:00
x2
x5
x
x
8:00
16:00
Snack 
(voluntary)2
x
x5
x
x
10:00
18:00
Dinner
12:00
20:00
Study drug 
administration
x2,
3
x3,5
x3
x
2
23:30
7:30
Breakfast2
x
x
x
x5
x
x
24:00
08:00
Study drug 
administration
28:00
12:00
240 mL fluid 
intake, thereafter 
lunch2
x
x
x
34:00
18:00
Dinner
36:00
20:00
Study drug 
administration
38:00
22:00
Discharge from 
trial site
x
x
x

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Flow chart 1C: Visit 8
Footnotes (flow chart 1B and 1C)
1.
The time is approximate; the respective procedure is to be performed and completed 
within 2 h prior to drug administration. Allocation to treatment may be performed at 
any time following enrolment but must be completed prior to (first) drug 
administration.
2.
If several actions are indicated at the same time point, venipuncture should be the last 
of the measurements and the intake of meals will be the last action.
3.
Samples will be taken just before administration of dose.
4.
Fecal occult blood and fecal calprotectin testing for visit 8 may be taken within 3 days 
of day 14 (i.e day 12-14). 
5.
The ECG recording has to be performed as triple at these time points. At baseline (i.e. 
Day 1, prior to drug administration) 3 triplicate ECGs are recorded within 
approximately one hour. The recordings should be separated by at least 15 minutes.
6.
Other trial procedures to be performed during the visit as outlined in flow chart 1A.
Visit
Day
Planned time (relative to 
first drug administration 
[h:min]
Approximate clock time  of 
actual day [h:min]
Event and comment
BI 1015550 PK blood 
Fecal occult blood and fecal
calprotectin testing
12-lead ECG5
Vital signs 
Questioning for AEs and 
concomitant therapy 
Other trial procedures 6
8
14
311:30
07:30
Breakfast2
x3
x4
X
x
X
x
312:00
08:00
Study drug 
administration
X
312:30
08:30
x
313:00
09:00
x2
X
x
X
313:30
09:30
x
314:00
10:00
240 mL fluid intake2
x
X
x
X
316:00
12:00
240 mL fluid intake, 
thereafter lunch2
x
X
x
X
318:00
14:00
x
X
x
X
320:00
16:00
Snack (voluntary)2
x
X
x
X
322:00
18:00
Dinner
324:00
20:00
Study Drug
administration
x2,3
x3
x3
X

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TABLE OF CONTENTS
TITLE PAGE ......................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS ................................................2
FLOW CHART...................................................................................................4
TABLE OF CONTENTS ...................................................................................8
ABBREVIATIONS.......................................................................................... 12
1.
INTRODUCTION.................................................................................... 15
1.1
MEDICAL BACKGROUND............................................................................15
1.2
DRUG PROFILE...............................................................................................15
1.2.3
Toxicology..............................................................................................16
1.2.5
Clinical experience in humans.............................................................18
1.2.5.1
Clinical Safety..........................................................................18
1.2.5.1.1 Single-Rising Dose (SRD) Study (1305.1)............................................18
1.2.5.1.2 Multiple-Rising Dose (MRD) study (1305.2)........................................19
1.2.5.1.3 SRD and MRD study (1305-0011) (completed) [c22991937-01].........19
1.2.5.1.4 Food Effect (1305-0020) (completed) ...................................................21
1.2.5.1.5 Clinical experience with other PDE4 inhibitors ....................................21
1.2.5.2
Clinical pharmacokinetics........................................................22
1.2.5.2.2 Multiple-rising dose trial (1305.2 and 1305.11, part 2).........................23
1.2.5.2.3 Food effect trial (1305.20) [c20307414-01] ..........................................24
1.2.5.2.4 Prediction of human therapeutic dose range..........................................24
1.2.6
Drug product.........................................................................................25
2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT ......................................................................................... 26
2.1
RATIONALE FOR PERFORMING THE TRIAL........................................26
2.2
TRIAL OBJECTIVES.......................................................................................26
2.3
BENEFIT - RISK ASSESSMENT ...................................................................26
2.3.1
Procedure-related risks ........................................................................27
2.3.2
Drug-related risks and safety measures..............................................28
2.3.3
Safety measures.....................................................................................29
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.............. 31
3.1
OVERALL TRIAL DESIGN AND PLAN ......................................................31
3.1.1
Administrative structure of the trial...................................................34
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP..........................................................................................35

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3.3
SELECTION OF TRIAL POPULATION ......................................................36
3.3.1
Main diagnosis for study entry............................................................36
3.3.2
Inclusion criteria...................................................................................36
3.3.3
Exclusion criteria ..................................................................................37
3.3.4
Removal of patients from therapy or assessments.............................38
3.3.4.1
Removal of individual patients................................................38
3.3.4.2
Stopping criteria for dose escalation........................................39
3.3.4.3
Discontinuation of the trial by the sponsor..............................40
3.3.5
Replacement of patients .......................................................................40
4.
TREATMENTS........................................................................................ 41
4.1
TREATMENTS TO BE ADMINISTERED....................................................41
4.1.1
Identity of BI investigational product and comparator product......41
4.1.2
Method of assigning patients to treatment groups ............................41
4.1.3
Selection of doses in the trial................................................................42
4.1.3.1
Maximum acceptable systemic exposure, and exposure 
multiples of selected doses.......................................................42
4.1.4
Drug assignment, dispensing and administration of doses for 
each patient............................................................................................44
4.1.4.1
Drug Assignment .....................................................................44
4.1.4.2
Dispensing of medication ........................................................44
4.1.4.3
Administration of Doses ..........................................................45
4.1.5
Blinding and procedures for unblinding ............................................46
4.1.5.1
Blinding....................................................................................46
4.1.5.2
Procedures for (emergency) unblinding...................................46
4.1.6
Packaging, labelling, and re-supply ....................................................47
4.1.7
Storage conditions.................................................................................47
4.1.8
Drug accountability ..............................................................................47
4.2
CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE 
TREATMENT....................................................................................................48
4.2.1
Rescue medication, emergency procedures, and additional 
treatments ..............................................................................................48
4.2.1.1
Management of acute IPF exacerbations.................................48
4.2.2
Restrictions............................................................................................48
4.2.2.1
Restrictions regarding concomitant treatment .........................48
4.2.2.2
Restrictions on diet and life style.............................................49
4.3
TREATMENT COMPLIANCE.......................................................................50
5.
VARIABLES AND THEIR ASSESSMENT ......................................... 51
5.2
SAFETY..............................................................................................................52

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5.2.1
Endpoints of safety................................................................................52
5.2.2
Assessment of adverse events...............................................................52
5.2.2.1
Definitions of adverse events...................................................52
5.2.2.2
Adverse event collection and reporting ...................................55
5.2.3
Assessment of safety laboratory parameters......................................57
5.2.4
Electrocardiogram................................................................................60
5.2.4.1
12-lead resting ECG.................................................................60
5.2.5
Assessment of other safety parameters...............................................62
5.2.5.1
Vital signs ................................................................................62
5.2.5.2
Medical examinations..............................................................62
5.2.5.3
Suicidal risk assessed by the C-SSRS......................................63
5.4
APPROPRIATENESS OF MEASUREMENTS.............................................63
5.5
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS..................................................................................64
5.5.1
Pharmacokinetic endpoints..................................................................64
5.5.1.1
Secondary endpoints................................................................64
5.5.2
Methods of sample collection...............................................................65
5.5.2.1
Plasma sampling for pharmacokinetic analysis.......................65
5.5.3
Analytical determinations ....................................................................66
5.5.3.1
Analytical determination of plasma concentrations.................66
6.
INVESTIGATIONAL PLAN.................................................................. 70
6.1
VISIT SCHEDULE............................................................................................70
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS ................70
6.2.1
Screening and run-in period(s)............................................................70
6.2.2
Treatment period ..................................................................................71
6.2.3
Follow-up period and end of trial........................................................72
7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE......................................................................................... 73
7.1
STATISTICAL DESIGN – MODEL ...............................................................73
7.1.1
Objectives...............................................................................................73

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7.2
NULL AND ALTERNATIVE HYPOTHESES ..............................................73
7.3
PLANNED ANALYSES....................................................................................73
7.3.1
Primary analyses...................................................................................73
7.3.2
Secondary analyses ...............................................................................74
7.3.3
Safety analyses.......................................................................................75
7.3.4
Interim analyses ....................................................................................76
7.3.5
Pharmacokinetic analyses ....................................................................77
7.4
HANDLING OF MISSING DATA ..................................................................78
7.4.1
Safety......................................................................................................78
7.4.2
Plasma drug concentration - time profiles..........................................78
7.4.3
Pharmacokinetic parameters...............................................................78
7.5
RANDOMISATION ..........................................................................................78
7.6
DETERMINATION OF SAMPLE SIZE ........................................................78
8.
INFORMED CONSENT, DATA PROTECTION, TRIAL
RECORDS ................................................................................................ 80
8.1
STUDY APPROVAL, PATIENT INFORMATION, AND INFORMED 
CONSENT ..........................................................................................................80
8.2
DATA QUALITY ASSURANCE .....................................................................80
8.3
RECORDS..........................................................................................................81
8.3.1
Source documents .................................................................................81
8.3.2
Direct access to source data and documents.......................................81
8.4
LISTEDNESS AND EXPEDITED REPORTING OF ADVERSE 
EVENTS..............................................................................................................81
8.4.1
Listedness...............................................................................................81
8.4.2
Expedited reporting to health authorities and IECs/IRBs................81
8.5
STATEMENT OF CONFIDENTIALITY.......................................................81
8.6
COMPLETION OF TRIAL..............................................................................82
9.
REFERENCES......................................................................................... 83
9.1
PUBLISHED REFERENCES...........................................................................83
9.2
UNPUBLISHED REFERENCES.....................................................................85
10. APPENDICES .......................................................................................... 87
10.1
COLUMBIA SUICIDAL SEVERITY RATING SCALE (C-SSRS) ............87
11. DESCRIPTION OF GLOBAL AMENDMENT(S).............................. 95

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ABBREVIATIONS
AE
Adverse event
AESI
Adverse events of special interest
ANCOVA
Analysis of Covariance
AUCτ,1
Area under the concentration-time curve of the analyte in plasma over a 
uniform dosing interval τ after administration of the first dose
AUCτ,ss
Area under the concentration-time curve of the analyte in plasma at steady 
state over a uniform dosing interval τ
BI
Boehringer Ingelheim
b.i.d.
twice daily
BLQ
Below limit of quantification
BP
Blood pressure
CA
Competent authority
CK
Creatine Kinase
C-SSRS
Columbia-suicide severity rating scale
CTR
Clinical trial report 
Cmax,ss
Maximum measured concentration of the analyte in plasma at steady state 
over a uniform dosing interval τ
Cmax
Maximum measured concentration of the analyte in plasma
CML
Local clinical monitor
CNS
Central nervous system 
COPD
Chronic obstructive pulmonary disease

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CRA
Clinical research associate
CRF
Case report form
CRP
C-reactive protein
CTP
Clinical trial protocol
CTR
Clinical trial report
DILI
Drug induced liver impairment
ECG
Electrocardiogram
EDC
Electronic data capture 
EDTA
Ethylenediaminetetraacetic acid
EOT
End of treatment
FC
Fecal Calprotectin
GI
Gastro-intestinal
gMean
Geometric mean
HPLC-MS/MS
High performance liquid chromatography with tandem mass spectrometry
HRCT
High-resolution computed tomography 
HR
Heart rate
ICH-GCP
ICH Harmonised Tripartite Guideline for Good Clinical Practice
IEC
Independent Ethics Committee
IPF
Idiopathic Pulmonary Fibrosis
IRB
Institutional Review Board
IRT
Interactive Response Technology
ISF
Investigator Site file
MedDRA
Medical Dictionary for Drug Regulatory Activities 
MetID
A blank sample for metabolic analysis 
MRD
Multiple-rising dose
NC
Not calculated
NIMP
Non-investigational medicinal product
nM
Nanomolar
NOA
Not analysed
NOAEL
No observed adverse effect level
NOR
No valid result
NOS
No sample available
PD
Pharmacodynamic(s)
PDE4 B
Phosphodiesterase 4 B
PK
Pharmacokinetic(s)
PKS
Pharmacokinetic set/ parameter analysis set
PR
Pulse rate
PV
Pharmacovigilance
q.d.
once daily

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QT
Time between start of the Q-wave and the end of the T-wave in an 
electrocardiogram
QTc
QT interval corrected for heart rate using the method of Fridericia (QTcF) 
or Bazett (QTcB)
REP
Residual effect period
RR
Respiratory Rate
SAE
Serious adverse event
SOP
Standard operating procedure
SRD
Single-rising dose
SUSAR
Suspected Unexpected Serious Adverse Reaction
TEAEs
Treatment emergent adverse events
t.i.d.
three times daily
TMF
Trial master file
TDMAP
Trial Data Management and Analysis Plan
TSAP
Trial statistical analysis plan
ULN
Upper limit of normal

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1.
INTRODUCTION
BI 1015550 is a selective inhibitor of the Phosphodiesterase 4 B (PDE4 B) with broad anti-
inflammatory and anti-fibrotic activities. It is under development for the treatment of 
idiopathic pulmonary fibrosis (IPF). 
1.1
MEDICAL BACKGROUND
Idiopathic Pulmonary Fibrosis is a specific form of chronic, progressive fibrosing interstitial 
pneumonia of unknown cause, occurring primarily in older adults, limited to the lungs, and 
associated with the histopathologic and/or radiologic pattern of usual interstitial pneumonia 
[P11-07084]. IPF is the most common of the 7 idiopathic interstitial pneumonias. It is a rare 
and fatal disease, with a median survival time of 2 to 3 years following diagnosis [R12-5527], 
[P11-07084]. The natural history of IPF is variable and unpredictable [R11-2587]. Disease 
progression is manifested by increasing respiratory symptoms, worsening pulmonary function 
test results, acute respiratory decline, and death.
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 [P15-07539]. Despite the availability of these 
drugs, the medical need remains high in this devastating disease.
BI 1015550 is a selective inhibitor of the PDE4 B with broad anti-inflammatory and anti-
fibrotic activities. Based on its mode of action, BI 1015550 is hypothesized to have
complementary activity to current therapies in IPF, as well as improved tolerability compared
to other marketed PDE-4 inhibitors due to lower affinity for PDE4 D.
For further information, please refer to the Investigator’s Brochure [c02094779-03].
1.2
DRUG PROFILE
For details on nonclinical pharmacology, refer to section 5.1 in the IB [c02094779-03].

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1.2.3
Toxicology
The toxicology data support administration of BI 1015550 to women of non-child bearing 
potential and to men for up to 13 weeks.
The toxicity profile for BI 1015550 has been assessed in safety pharmacology studies, genetic
toxicology studies, and repeat dose toxicity studies in the rat and minipig of up to 13 weeks
including:

Repeat dose toxicity studies in the rat
o
4 weeks (dose groups 0.2-6/12 mg/kg/day), and 13 weeks (dose groups 3-9
   mg/kg/day) with 4 weeks recovery

Repeat dose toxicity studies in the minipig
o
2 weeks (3-30 mg/kg/day, 2 week recovery) and 13 weeks (3-20 mg/kg/day, 4
   week recovery)
Overall, vasculopathy and mortality secondary to vasculopathy are the primary findings 
defining the no observed adverse effect level (NOAEL) in the rat and minipig and are 
consistent with findings from other known PDE4 inhibitors [R10-1559]. Vasculopathy in 
toxicology species is thought to be a consequence of vascular tone dysregulation and 
subsequent inflammatory response [R17-0158]. Areas affected by vasculopathy are 
dependent on the nonclinical species tested. The GI tract/mesentery has been shown to be 
affected in multiple species (rats, minipigs, monkey) after administration of PDE4 inhibitors, 
including marketed compounds apremilast and roflumilast [R17-0915], [R17-0916], [R17-
0919]. Additional target organs/tissues of PDE4 inhibitors include heart, liver, lung, thymus, 
and pancreas, and PDE4 inhibitors effects have been noted in male and female reproductive 
tracts of nonclinical species such as the mouse, rat, hamster, dog and monkey. Vasculopathy 
is considered reversible, as demonstrated in a longitudinal study performed in mice with 
apremilast, which showed the recovery of PDE4 inhibitor-related vasculopathy following 
repeated administration over 90 days [R17-0919].
 
Moreover, despite the observed effects in nonclinical species, two PDE4 inhibitors are 
used clinically and vascular injury has not been documented in humans.

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PDEi-related effects on the testes and uterus have been reported for previously marketed PDE 
inhibitors [R17-0915], [R17-0919]. 
 
 
 
Both marketed PDE4 inhibitors have demonstrated adverse effects in preclinical reproductive 
toxicity studies that include embryotoxicity or fetotoxicity and are labelled accordingly [R17-
0915], [R17-0919]. Specific studies to evaluate the potential for BI 1015550 to affect male 
and female fertility and developmental toxicity have not yet been conducted. Therefore, 
adequate contraception as detailed in Section 3.3.3 is required.
For further information please refer to the IB [c02094779-03]

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1.2.5
Clinical experience in humans
1.2.5.1
Clinical Safety
Four clinical trials have been completed with BI 1015550 in healthy male volunteers:

a single rising dose First-in-Men trial (1305.1) [U13-1792-01]

a multiple rising dose trial (1305.2) [c02191718-02]

a single rising dose/multiple rising dose trial (1305.11)

a food effect trial (1305.20) [c20307414-01]
1.2.5.1.1
Single-Rising Dose (SRD) Study (1305.1)
BI 1015550 (0.02 mg, 0.06 mg, 0.2 mg, 0.6 mg, 2 mg, 4 mg, 8 mg, 16 mg and 24 mg dose
levels) has been tested in 70 healthy male subjects. Sixteen subjects received placebo and 54 
received BI 1015550. There were no notable differences between the dose groups with 
respect to safety and tolerability.
A total of 41 treatment emergent adverse events (TEAEs) were reported by 27 (39%) subjects. 
Five of these subjects (31%) received placebo. Nine subjects (12.9%) reported TEAEs that 
were considered drug-related by the investigator. These include drug-related diarrhea (N=3), 
abdominal pain (N=3), headache (N=2), and nausea/vomiting/fatigue/oral herpes in 1 subject.
There was no correlation of the administered drug-dose and the number of subjects reporting 
at least 1 TEAE. Four of the subjects (including one subjects on placebo) reported moderate 
TEAEs. All subjects were reported to have recovered from TEAEs by the end-of-study 
examination.

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There were no suspected unexpected serious adverse reaction (SUSAR), nor any significant 
(based upon ICH E3), severe, serious or fatal AEs. No subject was discontinued due to AEs.
In addition, no clinically relevant laboratory, vital signs and ECG changes were observed 
following administration of single doses of BI 1015550.
Further details can be found in IB [c02094779-03].
1.2.5.1.2
Multiple-Rising Dose (MRD) study (1305.2)
BI 1015550 (1 mg and 6 mg b.i.d. for two weeks) has been tested in 24 healthy male subjects. 
Six subjects received placebo and 18 received BI 1015550.
 
 
A total of 10 TEAEs were reported by 6 (25%) patients, 1 patient in the placebo group, 4 
patients in the 1 mg group and 1 patient in the 6 mg group. The most frequent TEAEs, all of 
mild intensity, occurred within the CNS and GI organ classes. Reported TEAEs included 
headache, mild diarrhea, abdominal pain, aphtous stomatitis, mild constipation and 
abdominal pain. There were no GI TEAE reported in the placebo group.
Two patients were discontinued, one for personal reasons in the 1 mg b.i.d. group and one 
due to TEAEs in the 6 mg b.i.d. group. The latter discontinuation occurred on study Day 12 
because of adverse events that were considered drug-related by the investigator. All TEAEs 
in this patient were of mild intensity, with the exception of C-reactive protein (CRP) increase 
which was of moderate intensity. Apart from the CRP increase of moderate intensity, 
described above, no clinically relevant laboratory findings or clinically relevant changes in 
vital signs or ECGs were observed following administration of repeated doses of BI 1015550.
There were no TEAEs of severe intensity, SUSARS, severe, serious or fatal AEs.
1.2.5.1.3
SRD and MRD study (1305-0011) (completed) [c22991937-01]
This partially randomized within dose groups, placebo-controlled trial investigated the safety, 
tolerability, and pharmacokinetics of single and multiple rising oral doses of BI 1015550 as 
tablet formulation and is an extension of the previous trials 1305.1 and 1305.2. The 
investigation of single (36 mg and 48 mg) and multiple (6 mg b.i.d. and 12 mg b.i.d) rising 
doses of BI 1015550 beyond the doses tested in the previous two trials is supported by new 
toxicological investigations of BI 1015550. In Part 1, BI 1015550 (36 mg and 48 mg single 
dose levels) was tested in 18 healthy male subjects in a partially randomised, placebo-
controlled within dose groups design. Following completion of the SRD part, BI 1015550 (6 
mg and 12 mg b.i.d. for two weeks) was tested in 24 healthy male subjects in a randomised, 
double-blind, placebo-controlled within dose groups study.

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For further details, see ‘Investigator’s Brochure’ [c02094779-03].
1.2.5.1.4
Food Effect (1305-0020) (completed)
This open-label, randomized two-sequence, two-period crossover trial investigated the 
relative bioavailability of BI 1015550 following oral administration of 24 mg BI 1015550 
under fed and fasted conditions. Twelve (12) healthy male subjects were entered. 
 
[c20307414-01]. 
1.2.5.1.5
Clinical experience with other PDE4 inhibitors
Selective PDE4 inhibitors have been approved for chronic obstructive pulmonary disease 
(COPD) with chronic bronchitis and a history of exacerbations (roflumilast), and for 
moderate to severe plaque psoriasis and active psoriatic arthritis (apremilast). Roflumilast has 
been tested in Phase III studies for asthma and apremilast in Phase III studies for active 
Behcet’s disease. No PDE4 inhibitor has been tested in IPF, yet.
Cilomilast
Cilomilast was the first selective PDE4 inhibitor developed for the maintenance of lung 
function (forced expiratory volume in one second (FEV1)) in patients with COPD but failed 
to demonstrate efficacy to support approval of the drug. Cilomilast nonclinical findings 

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include mesenteric arteritis in rats. In the clinical program the frequency of GI AEs was high. 
Fecal occult blood testing was benign with unremarkable colonoscopy findings in the few 
patients with blood in the stool. Lack of approval was based on inadequate evidence of 
efficacy rather than any safety concern [P06-08316].
Roflumilast
This PDE4 inhibitor (Daxas® in EU, Daliresp® in US) got approved for treatment of COPD.
More than 5,000 patients with COPD were included in the “COPD Safety Pool”. The most 
frequently reported AEs associated with roflumilast treatment were GI events (diarrhea, 
weight loss, nausea, abdominal pain) and headache followed by insomnia, dizziness and 
decreased appetite. There was an increased incidence of neuropsychiatric adverse reactions 
such as insomnia, anxiety, nervousness and depression; in rare instances suicidal ideation 
behavior (including completed suicide). Atrial fibrillation as SAE was reported more often in 
patients treated with
roflumilast. Among the AEs leading to death, cardiac arrest was reported in a higher number 
of patients who received roflumilast [R10-1555]. Clinical manifestation of mesenteric 
vasculitis, an adverse effect that has been a concern with PDE4 inhibition in general, was not 
reported in these clinical studies.
Apremilast
One PDE4 inhibitor for treatment of active psoriatic arthritis (Otezla®) has been approved by 
the FDA for moderate to severe plaque psoriasis. Otezla® has been evaluated in 1493 patients 
with active psoriatic arthritis in three randomized placebo-controlled studies [R17-1427]
Access date 29, March 2017.). The most common adverse reactions were diarrhea, headache 
and nausea, followed by vomiting, upper respiratory tract infection, nasopharyngitis and 
abdominal pain. The product information of Otezla® recommends the close monitoring of 
patient’s body weight and its cautious use in patients with history of depression and/or 
suicidal thoughts or behavior [R14-1795].

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1.2.5.2.2
Multiple-rising dose trial (1305.2 and 1305.11, part 2)
Pharmacokinetics of BI 1015550 was investigated in healthy male volunteers given multiple 
oral doses of 1 mg and 6 mg b.i.d. with solution formulation in a fasted condition (Study 
1305.2) and 6 and 12 mg bid with tablet formulation in a fed condition (Study 1305.11). 

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1.2.5.2.3
Food effect trial (1305.20) [c20307414-01]
A two-way crossover, single dose, food effect study (24 mg, N=12) was performed. 
1.2.5.2.4
Prediction of human therapeutic dose range
Observed target engagement data in the previous clinical trials [U13-1792-01] and
[c02191718-02] supported by population pharmacokinetic-pharmacodynamic (PK-PD)
modelling predicts a human therapeutic dose range of 12 mg - 24 mg BI 1015550 b.i.d. The 

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estimated exposure at these doses range from free maximum measured concentration of the 
analyte in plasma at steady state over a uniform dosing interval τ (free Cmax,ss_ of 81.1 nM and 
free AUC0-24,ss of 1072 nM∙h at the 12 mg bid dose to free Cmax,ss of 193 nM and free AUC0-
24,ss of 1983 nM∙h at 24 mg b.i.d., respectively). These exposures are below the target 
maximum exposure margin for humans of 277 nM (free Cmax,ss) and 2284 nM∙h (free AUC0-
24,ss) based on the 13-week rat study (section 4.1.3.1).
1.2.6
Drug product
BI 1015550 is a non-hygroscopic, white to off-white to light yellow powder. It is a poorly 
soluble compound with high permeability.
For further details, see ‘Investigator’s Brochure’ [c02094779-03].

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2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT
2.1
RATIONALE FOR PERFORMING THE TRIAL
Based on the limitations of the current therapy of IPF there is a medical need to slow or halt 
the progression of this disease (see section 1.1). BI 1015550 is a selective PDE4 B inhibitor 
with a pleiotropic and broad mode of action (MoA) that has the potential to offer improved 
efficacy and/or tolerability as add-on to registered anti-fibrotics or as a mono therapy in IPF.
As the planned doses to be tested fall within the estimated therapeutic range and based on the 
safety profile of this class of compound, the safety, tolerability and PK of rising doses of BI 
1015550 will be evaluated in IPF patients.
 
The current design will provide essential information for clinical development of BI 1015550 
as a treatment for IPF with the aim of determining the optimal dose of BI 1015550 based on 
PK, safety and tolerability. 
2.2
TRIAL OBJECTIVES
Description of the endpoints to be determined, and the observations along with specific 
information as how to collect the data for that information, is provided in section 5.
The primary objective is to investigate safety and tolerability of BI 1015550 in patients with 
IPF. The secondary objectives are to 
 
 evaluate the pharmacokinetics (PK) of BI 1015550 in patients 
with IPF.
2.3
BENEFIT - RISK ASSESSMENT
Experiments have shown that BI 1015550 affects the fibrotic pathway and the effects may be 
complementary and synergistic to those of nintedanib. It is postulated that BI 1015550 may 
provide therapeutic benefit to patients with lung fibrosis, but this has not yet been shown 
clinically [c02094779-03]. Patient participation in the study is of major importance to 
investigate the safety, tolerability and PK profile of BI 1015550.

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Based on study 1305.11 using indirect target engagement in healthy volunteers at single 
doses up to 48 mg q.d., therapeutic efficacy might be expected from  12 mg b.i.d but may not 
plateau at that dose.  Given the morbidity associated with IPF, dose escalation within the 
therapeutic range in a patient population rather than healthy subjects is considered acceptable 
to also assess target engagement in the relevant population. Given the morbidity associated 
with IPF, dose escalation within the therapeutic range in a patient population rather than 
healthy subjects is considered acceptable.  The expected exposure at the planned doses of 18 
mg b.i.d and 24 mg b.i.d fall within range of the estimated therapeutic range and are below 
the pre-defined maximal acceptable human systemic exposure limit. As such, the benefit-risk 
of these doses in a patient population is considered positive. Accordingly, dose escalation 
within the current protocol starting with administration of 18 mg b.i.d will be assessed in IPF 
patients. Evaluation of the 12 mg b.i.d dose, which has been evaluated in healthy volunteers
(1305.11), will only be performed in this study if the safety and tolerability of the 18 mg b.i.d 
dose is not supported. 
Furthermore, given the potential overlap in tolerability profile between BI 1015550 and the 
currently approved standard of care for IPF, dose escalation will be performed on no 
background therapy in order to adequately evaluate the tolerability and safety profile of the 
compound. To mitigate potential risk associated with a placebo controlled study in this 
patient population, only patients not currently treated with anti-fibrotic or not planned to be 
treated within 4 weeks of Visit 3 will be targeted for participation. Initiation of treatment for 
management of acute deterioration will be allowed at any time during the study at the 
discretion of the treating physician.
The patients are exposed to the risks of the study procedures and the risks related to the 
exposure to the trial medication (see section 2.3.1).
It is hypothesized that BI 1015550 will ultimately lead to improved efficacy and an 
acceptable tolerability profile, resulting in a positive benefit/risk profile. 
2.3.1
Procedure-related risks
The use of an indwelling venous catheter for the purpose of blood sampling may be
accompanied by mild bruising and also, in rare cases, by transient inflammation of the wall of
the vein. In addition, in rare cases a nerve might be injured while inserting the venous
catheter, potentially resulting in paresthesia, reduced sensibility, and/or pain for an indefinite
period. The same risks apply to venipuncture for blood sampling.
ECG electrodes may cause local and typically transient skin reactions.
The total volume of blood withdrawn during the entire study will not exceed 400 mL per 
patient over the duration of the trial. This is less than the volume of a normal blood donation 
(500 mL). No health-related risk to the patients is expected from this blood withdrawal.

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2.3.2
Drug-related risks and safety measures
There are no listed adverse events or expected events defined for BI 1015550 based on the
available data.
BI 1015550 is considered a low risk compound for the purpose of this trial based on the 
following observations:
BI 1015550 has been used in humans before (although in lower doses) and was 
considered safe and well-tolerated
BI 1015550 is not a first in class compound. Other PDE4-inhibitors have been 
previously evaluated by other companies and two are approved (see section 1.2.5.1.5)
Both rat and minipig are considered relevant species for BI 1015550 with toxicology 
data showing the rat as the most sensitive species [c02094779-03].
The nature of the target and the mechanism of action of BI 1015550 are well 
understood [c02094779-03].
Below is a summary of the known safety profile for the PDE4 class of compounds:
Vasculopathy: Vasculopathy is a typical side effect of PDE4 inhibitors in rats. 
 
 
The predicted exposure for the 
doses to be tested in the current study falls below the maximum tolerable limit set based on 
the NOAEL. 
As there are no validated biomarkers for vasculitis, routine monitoring of surrogate markers
as performed in previous PDE-4 programs will be done as part of standard safety assessment 
including:

Hematology panel (to detect changes by bleeding or inflammation)

Inflammation markers (hsCRP, fibrinogen, erythrocyte sedimentation rate (ESR), 
fecal calprotectin)

Immunochemical based fecal occult blood test as a sensitive method to detect occult 
blood in the stool

Urinalysis (dipstick to detect hematuria followed by urine microscopy in case of 
positive results)
Of note, safety monitoring as described above was suggestive of an inflammatory process in 
the GI tract of one subject in trial 1305.2, where moderate elevation in CRP was observed. At 
the same time, the subject developed mild GI-AEs (section 1.2.5.1.2). The subject was 
therefore discontinued from study drug administration.
Safety monitoring continued showing normalization within days and the subject recovered.
Emesis and further GI adverse events:
 
 Based on the two completed clinical trials [U13-1792-01] and 
[c02191718-02] BI 1015550 was generally well tolerated at the doses tested with only mild to 
moderate GI side effects.

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Depression and Suicidality: Apremilast and roflumilast, two of the currently marketed PDE4 
inhibitors, are associated with increased risk of depression with some patients reporting 
suicidal ideation and attempts and also reported cases of completed suicide. Accordingly, 
symptoms of depression and suicidality will be monitored using the Columbia-suicide 
severity ranking score (C-SSRS). If a patient exhibits serious suicidality in the clinical 
judgment of the investigator or according to the C-SSRS, assessment the patient will be 
discontinued (for details refer to section 3.3.4.1 and appendix 10.1).
Reproductive toxicity: PDEi-related effects on the testes have been shown nonclinically for 
the marketed compounds ampremilast and roflumilast (section 1.2.5.1.5).
 
 
 
Developmental and reproductive studies have not yet been conducted; therefore the effect of
sub therapeutic concentrations of BI 1015550 or its metabolites with regards to embryofetal 
risk has not been explored. In order to address this risk, patients will be informed accordingly 
and be required to use adequate contraception as detailed in section 3.3.3.
2.3.3
Safety measures
Although rare, a potential for drug-induced liver injury is under constant surveillance by 
sponsors and regulators. Therefore, this study requires timely detection, evaluation, and 
follow-up of alterations in selected liver laboratory parameters to ensure patients’ safety. See 
also section 5.2.2.1, adverse events of special interest.
The following precautionary measures will be taken in this study in order to minimize the
risk for patients:

Careful dose selection as described in section 4.1.3. For each group, patients will be 
divided into two cohorts. The first cohort will consist of 3 patients (2 on active and 1 
on placebo), the second of 6 patients (4 on active, 2 on placebo). Within each dose 
level, the two cohorts will be separated by at least 72 hours (between 1st patients of 
each cohort)

A maximum acceptable human exposure has been defined based on toxicity findings
(see section 4.1.3.1).

Dose escalation will be guided by measurements of BI 1015550 (free Cmax and free 
AUC0-24,ss). Prior to each dose escalation, the estimated systemic exposure of the next 
higher dose group will be calculated using PK data from the preceding dose group to 
ensure that the estimated exposure does not exceed the pre-defined maximum 
acceptable human exposure limit.

Decision for dose escalation will be made after blinded review of the data by the 
safety review committee (see section 3.1.1 and section 4.1.5.2), in a documented 
Safety Review meeting which will take place after all patients in the first dose group 

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(18mg b.i.d, group 1A) have completed 14 days of treatment. Dose escalation to 24 
mg b.i.d. is only permitted if both safety/tolerabilty (from all 9 patients) and PK 
projections (from a minimum of 4 patients on active treatment) are acceptable and if 
none of the pre-specified stopping criteria are met (section 3.3.4). The minimum time 
interval between last patient completing dosing at day 14 in the first cohort of a given 
dose group and the first dosing in the next higher dose group is 7 days. For details see 
section 3.1 and section 3.3.4.

Safety laboratory examinations including surrogate markers of inflammation/
vasculitis will be performed as described in section 2.3.2.

Repeated single and triple 12-lead ECGs during inpatient PK visits will be performed. 

During inpatient visits, the patients will be under medical observation and thoroughly 
monitored for both expected and unexpected adverse events. 

Male Subjects have to use adequate contraception as detailed in section 3.3.3 and 
female subjects of childbearing potential are not eligible to participate. 
After completing the first 14 days of treatment, the appropriateness of the patients to remain 
and continue treatment will be done by PI or delegate based on continued assessment of 
benefit-risk profile for each patient. 

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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN AND PLAN
This study will test multiple doses of BI 1015550. For a schematic overview, refer to figure 
3.1:1.
Figure 3.1:1
1305-0012 Study Design Overview
This trial is double-blind, randomised, and placebo-controlled within parallel dose groups. A
total of 18 male and female patients with IPF are planned to participate in 2 sequential groups 
consisting of 9 patients per group. However, additional patients may be entered to allow 
testing of additional doses within the planned dose range on the basis of results obtained from 
the 1305-0011 trial as well as experience gained during trial conduct (e.g. preliminary PK 
data), provided the planned and approved highest dose will not be exceeded. Thus, the actual 
number of patients entered may exceed 18, but will not exceed 30 patients entered. Such 
changes may be implemented via non-substantial clinical trial protocol (CTP)
amendments**. 
Within each dose group, 6 patients will receive the active drug and 3 will receive placebo. 
Only one dose is tested within each dose group. Each dose group will consist of 2 cohorts 
which will be treated subsequently for safety reasons as outlined in section 2.3.3. 
**An additional 6 patients (4 on active, 2 on placebo) will be entered in dose group 1A 
(18mg bid)
The first 36 hours of drug administration will be done in an inpatient setting to monitor for 
any acute reaction. Patients will then be treated outpatient with daily follow up by study 

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personnel by telephone, and interim clinic visits for monitoring during the first 14 days. 
Thereafter, patients will be contacted weekly by telephone, for monitoring with interim clinic 
visits until 4 weeks.  This monitoring schedule was selected in order to optimize feasibility 
and based on known safety profile of this class of compound which are primarily limited to 
GI tolerability in clinical studies.  
For a schematic overview of design and decision points, refer to figure 3.1:2.
Figure 3.1:2 
Design and decision point
The dose groups to be evaluated are outlined in Table 3.1: 1. Patients will take medication 
twice daily, for the duration of the trial.
Table 3.1: 1
Dose groups
Dose Group
1A
1B*
Dose Level
0
-1
1
Daily Dose (mg) 
36
24
48
Dose Regimen
18 mg b.i.d
12 mg b.i.d
24 mg b.i.d
Number of patients
9
6**
9
9
Patients receiving placebo
3
4
3
3
Patients receiving active drug
6
2
6
6
*The daily dose for group 1B may be reduced to 24 mg delivered as 12 mg b.i.d dosing regimen, if the safety, tolerability or PK profile of 
the 18 mg b.i.d dose is determined to be unacceptable.
** An additional 6 patients (4 on active, 2 on placebo) will be entered in dose group 1A 
(18mg bid). A documented safety review meeting will take place to review the full 18mg bid 
group data (9 + 6 patients), prior to dose escalation.

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The dose groups (group 1A and group 1B) will be investigated consecutively, maintaining a 
time interval of at least 7 days between the last patient completing dosing at day 14 in the 
previous dose group and the first drug administration of the subsequent dose group. 
A documented safety review meeting will take place prior to dose escalation. The decision to 
escalate the dose will be made by the sponsor after consultation with the safety review 
committee (see section 3.1.1) based on in-depth analysis of all available safety data, 
especially SAEs (if occurred), AEs and out-of-range laboratory results (if considered 
clinically significant) and PK data (from a minimum of 4 patients on active treatment).  
Safety Reviews may be conducted face-to-face or by video/telephone conference. The 
clinical trial leader is responsible for organization and minutes of the reviews. A summary
will be filed in the ISF at each site and in trial master file (TMF). 

The dose will be escalated to 24 mg b.i.d if no safety concerns arose in the preceding 
dose group (i.e. no dose-limiting events occurred) and if none of the pre-specified 
trial-specific stopping criteria were met (refer to section 3.3.4.2). 

In the event the 18 mg b.i.d dose is found to have acceptable safety but an 
unacceptable PK projection for 24 mg, the second dose group 1B will be cancelled. 

In the event the 18 mg b.i.d dose is determined to have unacceptable safety or 
tolerability, the dosing of group 1B will be reduced to 12 mg b.i.d and the patients 
continuing with extended treatment in the 18 mg b.i.d group 1A will be stopped. The 
12 mg b.i.d dose will be used to confirm the safety and tolerability of the 12 mg b.i.d 
dose previously tested in healthy volunteers, in the target patient population, as well 
as to evaluate disease specific biomarkers over 12 weeks.
An unscheduled safety review meeting can be requested anytime for any reasonable cause by 
the coordinating investigator or the sponsor of the study, e.g. because of any unforeseen 
adverse events, etc. 
The minimum data set for safety review consists of the following data:

AEs in the current and preceding dose group (including clinically relevant findings 
from ancillary safety testing listed below) (Note: AEs may be ongoing at the time of 
Safety Reviews and AE information may be subject to change prior to Database Lock)

Results from 12-lead EGG in the current and preceding dose groups.

Vital signs in the current and preceding dose groups

Clinical laboratory tests in the current and preceding dose groups

Preliminary PK data for selected time as per section 7.3.4. 

Check of criteria for stopping patient treatment as per section 3.3.4.1
The sponsor is allowed to alter the scheduled dose levels (e.g. add an intermediate dose level) 
within the planned dose range on the basis of experience gained during the study. This may 
include PK data suggesting an exposure close to or just above predefined thresholds or initial 
safety signals with open causality (not dose limiting), providing the planned and approved 

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highest dose is not exceeded. In this case, the total number of patients in this trial might 
increase. The sponsor should stop dose escalation in case the safety evaluation leads to 
concerns that would not allow higher dosing.
An overview of all relevant activities is provided in the Flow Charts 1A, 1B, and 1C. For visit 
schedules and details of trial procedures at selected visits, refer to sections 6.1 and section 
6.2, respectively.
The trial will terminate after all patients have completed the scheduled study visits or 
discontinue study treatment, whichever comes first.
3.1.1
Administrative structure of the trial
The trial will be conducted in approximately 20 sites in Europe.
A safety review committee will be responsible for blinded review of safety and PK data in 
order to guide decisions pertaining to dose used in subsequent treatment groups. The safety 
review committee will be composed of representatives from the sponsor, the coordinating 
investigator as well as an external expert not otherwise involved in the trial. The committee 
will retain the ability to unblind patients(s) as required (refer to section 4.1.5.2). This is not 
expected to cause bias with regards to data assessment or analyses. Following each data 
safety review meeting, a meeting will be held with trial investigators to review the blinded 
data and discuss the recommendation from the safety review committee.
A coordinating investigator is responsible to coordinate investigators at the different sites 
participating in this trial. The coordinating investigator (or appropriately qualified delegate) 
will participate in safety review meetings and will be involved in the discussions to escalate 
the dose.
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 standard 
operating procedure (SOP),

direct the clinical trial team in the preparation, conduct, and reporting of the trial

ensure appropriate training and information of local clinical monitors (CML) , clinical
research associate (CRA), and participating trial sites.
The trial medication will be provided by the Clinical Trial Supplies Unit, BI Pharma GmbH 
& Co. KG, Biberach, Germany. 
On-site monitoring will be performed by BI or a contract research organisation appointed by 
BI.
Safety laboratory tests will be performed by a central laboratory appointed by BI. 
The analyses of 
BI 1015550
 in plasma will be 
performed at BI or a suitable contract research organization (CRO).

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The digitally recorded 12-lead ECGs will be sent to a specialized contract research
organization for evaluation.
Data management and statistical evaluation will be done by BI or by a suitable contract 
research organization (CRO) under the responsibility of BI and according to BI SOPs.
Tasks and functions assigned in order to organize, 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.
The trial is sponsored by Boehringer Ingelheim Pharma GmbH & Co. KG, Germany.
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP
For multiple-rising dose trials, the design described in section 3.1 is viewed favourable under 
the provision not to expose the patients involved to undue risks since the main study 
objective is to investigate safety and tolerability of BI 1015550.
A double blind design is appropriate to reduce observer bias and evaluate safety and 
tolerability. 
Given the morbidity associated with IPF, and potential differences regarding fibrotic status 
dose escalation within the therapeutic range in a patient population for 4 weeks rather than 
healthy subjects is considered acceptable.  The expected exposure at the planned doses of 18 
mg bid and 24 mg bid fall within range of the estimated therapeutic range and are below the 
pre-defined maximal acceptable human systemic exposure limit. As such, the benefit-risk of 
evaluating of these doses in a patient population is considered positive. Accordingly, within 
the current protocol dose escalation starting with administration of 18 mg b.i.d is planned in 
IPF patients to minimize exposure of patients to sub-therapeutic doses and build on the data 
already obtained in healthy volunteers at 12 mg for 2 weeks. Evaluation of the 12 mg b.i.d 
dose for 4 weeks is only planned in this trial if the safety and tolerability of the 18 mg b.i.d 
dose is not supported. 
It is standard in Phase 1 trials to include a placebo group as control for the evaluation of 
safety and tolerability. Each dose group consists of 9 patients with 6 on active treatment, and 
3 on placebo**. The placebo control group includes all patients of all dose groups treated 
with placebo. 6 patients per active treatment group are in general considered as sufficient for 
the exploratory evaluation of pharmacokinetics.
** An additional 6 patients (4 on active, 2 on placebo) will be entered in dose group 1A 
(18mg bid).
Non clinical toxicology data currently supports studies up to 12 weeks of durations. The
treatment duration of 4 weeks is sufficient to capture safety and tolerability of a PDE4 
inhibitor in support of longer term studies, evaluate PK and exploration of induction 
potential,
. 

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Disease specific biomarkers and pulmonary function outcomes would require longer than 4 
weeks. Recent disease specific biomarker data from the INMARK study (1199-0227) suggest 
that effects in disease specific biomarkers would require much larger sample size and with 
longer duration, even beyond 12 weeks to gain a robust evaluation of disease specific 
biomarkers. Four weeks data allows first generation of normative data on BI 1015550. 
3.3
SELECTION OF TRIAL POPULATION
It is planned that 18 male and female patients with a confirmed diagnosis of IPF will enter the 
study. The actual number of patients entered may exceed the total of 18 if additional 
intermediate doses will be tested (see section 3.1). 
Only male patients and postmenopausal or surgically sterilised female patients will be 
included into the study because hitherto no data on reproductive toxicology are available.
A log of all patients enrolled into the study (i.e. having given informed consent) will be 
maintained in the investigator site file (ISF) at the investigational site irrespective of whether 
they have been treated with investigational drug or not.
Reasons for screen failures will be collected in the electronic Case Report Form (eCRF). The 
re-screening of screen failed patients may be permitted in certain cases after discussion with 
the trial team. A patient will not be permitted to re-screen more than one time and must meet 
inclusion/exclusion to be eligible for randomization. For patients re-screened, a new informed 
consent should be signed and the patient will be assigned a new unique patient number.
3.3.1
Main diagnosis for study entry 
Patients diagnosed with IPF and who comply with eligibility requirements may qualify for 
participation in the trial. 
3.3.2
Inclusion criteria
Patients will only be included into the trial, if they meet the following criteria:
1. Signed and dated written informed consent prior to admission to the study in accordance 
with ICH Harmonised Tripartite Guideline for Good Clinical Practice (ICH-GCP) and 
local legislation
2. Male or female patients aged ≥40 years at visit 1. 
3. A clinical diagnosis of IPF based on ATS/ERS/JRS/ALAT 2011 guideline (P11-07084)
within the previous 5 years as confirmed by the investigator based on chest high-
resolution computed tomography (HRCT) scan taken within 12 months of visit 1 and 
confirmed by central review prior to visit 2. 
4. Forced Vital Capacity (FVC) ≥50% of predicted normal at visit 1
5. Diffusion capacity of the lung for carbon monoxide (DLCO) (corrected for haemoglobin 
[Hb] [Visit 1]): > 30% of predicted  normal at visit 1
  

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3.3.3
Exclusion criteria
Patients will not be allowed to participate if any of the following general criteria apply:
1. Patients with a significant disease or condition other than IPF 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. 
2. Any laboratory value outside the reference range that the investigator considers to be of 
clinical relevance.
3. Surgery of the GI tract that could interfere with PK of the trial medication (except 
appendectomy).
4. Diseases of the central nervous system (including but not limited to any kind of seizures 
or stroke), and other relevant neurological or psychiatric disorders including but not 
limited to mood disorders.
5. Evidence of active infection (chronic or acute) based on clinical exam or laboratory 
findings. 
6. History of allergy or hypersensitivity to the trial medication or its excipients 
7. Use of drugs within 30 days prior to administration of trial medication that are known to
influence the results of the trial including time between start of the Q-wave and the end of 
the T-wave in an electrocardiogram (QT) / QT interval corrected for heart rate using the 
method of Fridericia (QTcF) or Bazett (QTcB) (QTc)
8. A marked baseline prolongation of QT/QTc interval (such as QTc intervals that are 
repeatedly greater than 450 ms in males or repeatedly greater than 470 ms in females) or 
any other relevant ECG finding at screening
9. A history of additional risk factors for Torsades de Pointes (such as heart failure, 
hypokalemia, or family history of Long QT Syndrome) 
10. Participation in another trial where an investigational drug has been administered within 
30 days or less than 5 half-lives (whichever is greater) of the respective drug prior to 
planned administration of trial medication, or current participation in another trial 
involving administration of investigational drug.
11. Inability to refrain from smoking on trial days
12. Alcohol abuse (consumption of more than 20 g per day)
13. Active drug abuse
14. Blood donation of  more than 100 mL within 30 days prior to administration of trial 
medication or intended donation during the trial
15. Inability to comply with dietary regimen required for the trial

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16. Patient is assessed as unsuitable for inclusion by the investigator, for instance, because 
considered not able to understand and comply with study requirements, or has a condition 
that would not allow safe participation in the study 
17. Male patients who do not agree to minimize the risk of female partners becoming 
pregnant from first dosing day until two months after the study completion. Acceptable 
methods of contraception comprises barrier contraception and a medically accepted 
contraceptive method for the female partner (intra-uterine device with spermicide, 
hormonal contraceptive used for at least two months prior), true sexual abstinence (when 
this is in line with the preferred and usual lifestyle of the patient), or surgically sterilized,
including vasectomy. 
18. Females who are not surgically sterilised or who are not postmenopausal, defined as at 
least 1 year of spontaneous amenorrhea (in questionable cases a blood sample with 
simultaneous levels of Follicle-stimulating hormone (FSH) above 40 U/L and estradiol 
below 30 ng/L is confirmatory).
19. Relevant airways obstruction (i.e. pre-bronchodilator FEV1/FVC <0.7) at visit 1
20. Patients who have previously been treated with nintedanib or pirfenidone within 30 days 
of visit 1.
21. Positive fecal occult blood (no retest allowed),
22.
23. Positive testing for hematuria if confirmed by microscopic urine analysis (retest allowed)
24. Any lifetime history of suicidal behavior (i.e. actual attempt, interrupted attempt, aborted 
attempt, or preparatory acts or behavior)
25. Any suicidal ideation of type 2 to 5 on the C-SSRS in the past 12 months (i.e. active 
suicidal thought without method, intent or plan; active suicidal thought with method, but 
without intent or plan; active suicidal thought with method and intent but without specific 
plan; or active suicidal thought with method, intent and plan).
For study restrictions, refer to section 4.2.2.
3.3.4
Removal of patients from therapy or assessments
3.3.4.1
Removal of individual patients
An individual patient is to be removed from the trial if:
1. The patient withdraws consent, without the need to justify the decision
2. The patient needs to take concomitant drugs that interfere with the investigational  
product or other trial medication
3. The patient is no longer able to participate for other medical reasons (such as surgery, 
adverse events, or diseases)
4. An AE or clinically significant laboratory change or abnormality occurred that the 
investigator judges to warrant discontinuation of treatment. This may include cases of 
sustained symptomatic hypotension (BP <90/50 mmHg) or hypertension (BP >180/100 

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mmHg) or of clinically relevant changes in ECG requiring intervention as well as 
unexplained liver enzyme elevations at any time during the trial.
5. The patient shows an elevation of AST and/or ALT ≥3-fold upper limit of normal (ULN)
combined with an elevation of total bilirubin ≥2-fold ULN (measured in the same blood 
sample) and/or needs to be followed up according to the drug induced liver impairment 
(DILI) checklist provided in the case report form (CRF).
6. The subject exhibits serious suicidality, in the clinical judgment of the investigator or
according to the following criteria:
- any suicidal behavior (i.e. actual attempt, interrupted attempt, aborted attempt,
or preparatory acts or behaviour)
- any suicidal ideation of type 4 or 5 in the C-SSRS (i.e. active suicidal thought
with intent but without specific plan, or active suicidal thought with plan and intent)
In addition to these criteria, the physician may discontinue patients at any time based on his 
or her clinical judgment.
A patient can also be removed from the trial if eligibility criteria are being violated or if the 
patient fails to comply with the protocol (for instance, by non-adherence to dietary rules, or 
non-attendance at study assessments).
If a patient is removed from or withdraws from the trial after first administration of trial 
medication, this will be documented and the reason for discontinuation must be recorded in 
the CRF. In this case, the data will be included in the CRF/trial database and will be reported
in the clinical trial report (CTR). At the time of discontinuation a complete end of trial 
examination will be performed if possible and the information will be recorded in the CRFs. 
These discontinuations will be discussed in the CTR.
3.3.4.2
Stopping criteria for dose escalation 
Dose escalation will not proceed if 
1. More than 50% of the patients of one dose group on active drug show drug-related and 
clinically relevant adverse events of moderate or severe intensity during planned safety 
review. 
2. At least 2 subjects at one dose level on active drug showed relevant individual QT 
prolongation, i.e. a QTc increase of greater 60 ms from baseline in connection with 
absolute QT or QTc greater than 500 ms, which has been confirmed by a repeat ECG 
recording.
3. The measured gMean free Cmax or free AUC of one dose group increases above the 
following exposure thresholds or if the estimated gMean exposure of the next dose group 
is expected to exceed a free Cmax,ss of 277 nM or a free AUC0-24,ss of 2284 nM∙h. 
Estimation will be done at specified time points based on preliminary PK results of 
preceding dose groups as specified in section 7.3.4.

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3.3.4.3
Discontinuation of the trial by the sponsor
Boehringer Ingelheim reserves the right to discontinue the trial overall or at a particular trial 
site at any time for any of the following reasons:
1. New toxicological findings or serious adverse events (SAE) invalidate the earlier positive 
benefit-risk-assessment.
2. The trial will be terminated if at least one drug-related SAE is reported that is considered 
to be unacceptable.
3. The expected enrolment goals overall or at a particular trial site are not met
4. Violation of ICH-GCP, or the CTP, or the contract with BI by a trial site or investigator, 
disturbing the appropriate conduct of the trial
5. The sponsor decides to discontinue the further development of the investigational 
product.
The investigator / the trial site will be reimbursed for reasonable expenses incurred in case of 
trial termination (except in case of the fourth reason).
3.3.5
Replacement of patients
In case some patients do not complete the trial, the clinical trial leader together with the trial 
pharmacokineticist and the trial statistician are to decide if and how many patients will be 
replaced. A replacement patient will be assigned a unique study patient number, and will be 
assigned to the same treatment as the patient he or she replaces.

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4.
TREATMENTS
4.1
TREATMENTS TO BE ADMINISTERED
The investigational product has been manufactured by BI Pharma GmbH & Co. KG.
4.1.1
Identity of BI investigational product and comparator product
The characteristics of the test product are given below:
Substance:
BI 1015550 
Pharmaceutical formulation: Tablet Formulation (TF1)
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
6 mg
Posology:
Dose group 1A: 3-0-3
Dose group 1B: 2-0-2 or 4-0-4  
Route of administration:
p.o.
Duration of use:
28 days b.i.d. dosing
The characteristics of the reference product (placebo) are given below:
Substance:
Placebo matching in size and weight to 6 mg tablet
Pharmaceutical formulation: Tablet formulation
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
n.a.
Posology:
Dose group 1A: 3-0-3
Dose group 1B: 2-0-2 or 4-0-4
Route of administration:
p.o.
Duration of use:
28 days b.i.d. dosing
4.1.2
Method of assigning patients to treatment groups
At the screening visit, patients will be informed about the planned visit dates. The patients 
willing to participate will be recruited to groups according to their temporal availability
(group 1A vs group 1B). 

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At visit 3, eligible patients will be randomised to receive active drug or placebo. The 
randomisation will occur in a blinded fashion via Interactive Response Technology (IRT). 
The IRT system will assign the appropriate medication number based on the treatment 
allocated. The randomisation code will be controlled and documented. All instructions for use 
of the IRT system will be described in a user guide/ manual which will be available in the 
ISF. 
The randomisation procedure is described in section 7.5.
4.1.3
Selection of doses in the trial
Trial 1305-0012 is an extension of the previous multiple rising dose trial (1305-0011) and 
proceeds with dose escalation. The doses selected for this trial cover a lower estimated 
therapeutic range and fall below the maximum acceptable systemic exposure.
The recommended maximum target dose is based on an exposure multiple against the pre-
defined maximal acceptable human systemic exposure limit. This is calculated as a ratio of 
the maximal acceptable human exposure (see section 4.1.3.1) divided by predicted systemic 
exposure after single dosing based on the free fraction. 
A starting dose of 18 mg b.i.d. of BI 1015550 has been selected, based on safety, tolerability 
and PK data, as well as indirect target engagement data from the completed study 1305.11 
 and multiple doses 
up to 12 mg bid in healthy volunteers. These data will be provided through an annually 
updated IB. If supported by the safety and PK data from the 18 mg b.i.d. dose group, a 
second dose group will be initiated at the maximum targeted dose of 24 mg b.i.d. Based on 
simulations incorporating pre-clinical data and data from previously conducted clinical trials, 
it is expected that following escalation from 18 mg b.i.d. to 24 mg b.i.d., exposure will 
increase in a dose proportional manner. As such, this is the highest dose where the expected 
systemic exposure is within the therapeutic range and below the pre-defined human 
maximum acceptable exposure limit (Table 4.1.3.1: 1).
 
A b.i.d dosing allows administration of the same daily dose with an 
increased safety margin with regards to Cmax. Further, a lower Cmax following b.i.d. dosing 
compared to q.d dosing is also assumed to lead to fewer tolerability issues.
4.1.3.1
Maximum acceptable systemic exposure, and exposure multiples of selected 
doses
The maximal acceptable human systemic exposure limit is derived from the primary 
toxicological findings of vasculopathy and mortality observed in the rat and minipig (see 
section 1.2.3). 
 
 
 
 
 

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Table 4.1.3.1:1 shows the predicted maximum human exposure (AUC) for the planned doses 
to be tested in the current protocol, all of which fall below the pre-defined human maximum 
acceptable exposure limit.

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4.1.4
Drug assignment, dispensing and administration of doses for each patient
4.1.4.1
Drug Assignment
The treatments to be evaluated are outlined in Table 4.1.4.1: 1 below. The number of units for 
placebo corresponds to the number of units of the respective dose level.
Table 4.1.4.1: 1
BI 1015550 and placebo treatments, oral administration 
Dose
Substance
Pharmaceutical 
form
Unit strength
Number of units 
per administration
Total daily 
dose
1A
BI 1015550
Tablet
6mg 
3 tablets in the morning and 
evening
36 mg
1B
BI 1015550
Tablet
6mg 
2 or 4 tablets in the morning and 
evening
24 or 48 
mg
1A-1B
Placebo*
Tablet
--
Identical to active treatment
--
* Patients receiving placebo are equally distributed across dose groups
4.1.4.2
Dispensing of medication
Based on the treatment allocated at randomization, the IRT system will be used to dispense 
the appropriate medication kits at each visit. 
Medication is packaged in bottles containing 20 tablets. To ensure patients receive adequate 
supply of study medication, kits (bottles) will be dispensed at clinic visits in quantities as 
outlined in table 4.1.4.2: 1.

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Table 4.1.4.2: 1
Quantity of medication kits dispensed per visit
Visit
Day
Group 1A: 18mg b.i.d      
# bottles dispensed
Group 1B: 24mg b.i.d1           
# bottles dispensed
Group 1B: 12mg b.i.d1                  
# bottles dispensed
3
1
12
12
12
3
2
1
1
0
4
4
2
2
1
5
7
2
2
1
6
10
2
2
1
7
13
13
13
13
8
14
5
7
3
1. Dose tested in group 1B will be based on safety and PK result from dose group 1A.
2. Patients will retain bottle dispensed at day 1, when discharged at day 2.
3. Patients will retain bottle dispensed at day 13, when discharged at day 14.
4.1.4.3
Administration of Doses
Study Medication- BI 1015550
The first administration of trial medication will be in the clinic, at visit 3 (day 1). 
When in clinic, the trial medication will be administered to the patients, while in a standing 
position, as an oral dose together with about 240 mL of water under supervision of the 
investigating physician or an authorised designee. The so-called four-eye principle (two-
person rule) should be applied for administration of trial medication
During the first 2 h after drug administration, they are not allowed to lie down (i.e. no 
declination of the upper body of more than 45 degrees from upright posture except for 
medical examination), or to sleep. Patients will be kept under close medical surveillance from 
the morning of Day 1 to the evening of Day 2 and all day on Day 14. 
To ensure a dosing interval of 12 h, the administration of trial medication should take place at 
the same time every morning and evening.
While at home, the trial medication should be taken at approximately the same time each 
morning and evening, with one glass of water. 
Patients will be given a medication diary to record daily intakes of medication taken at home 
since the last clinic visit. 
For restrictions with regard to diet see section 4.2.2.2.

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4.1.5
Blinding and procedures for unblinding
4.1.5.1
Blinding
This trial is designed double-blind with regard to the patients and the investigators (as well as 
the research staff at the trial site) in order to eliminate observer or performance bias. This 
means avoiding systematic differences in assessments regarding the patient’s treatment 
(active or placebo). According to the trial design, the current dose level will be known to 
patients and investigators.
At the sponsor, access to the randomisation schedule is restricted to the Clinical Trial Support 
group, who generates the randomisation code and labels, and to the Pharmaceutics 
Department, where the packaging takes place. Access to the codes will be controlled and 
documented by a signed confidentiality statement, which will be stored in the TMF. 
Within the ECG laboratory, the staff involved with interval measurements and assessments 
will be blinded with respect to the treatment and also with regard to the recording date and 
time as well as the time points of the ECGs. The interval measurements for a given patient
will be performed in a random and blinded sequence by a single technician. No more than 
two different blinded readers will evaluate the ECGs of the study.
If an interim safety analysis of ECG data is required, a part of the staff of the ECG laboratory 
may be unblinded. This part of the staff is strictly separated from those parts of the staff, 
which is involved with interval measurements and assessments of single ECGs (blinded).
Prior to unblinding of the trial database, the randomisation codes may be provided to 
bioanalytical staff/trial pharmacokineticist to perform preliminary PK analyses. The Trial 
Bioanalyst and trial pharmacokineticist will sign a confirmation that the codes will be treated 
confidentially and results will only be shared in a blinded fashion.
The trial will only be unblinded after locking of the database.
4.1.5.2
Procedures for (emergency) unblinding
The safety review committee (except the coordinating investigator) will retain the ability to 
unblind patients(s) via IRT as required to review the trial specific stopping criteria based on 
active treatment (see section 3.3.4.2). By this the members of the review committee (except 
the coordinating investigator) will be unblinded but the unblinding information will not be 
distributed to other personnel involved in the study. The reason for unblinding must be 
documented in the minutes along with the date and initials of the person who broke the code.
Emergency unblinding will be available to the investigator/ pharmacist/ investigational drug 
storage manager via IRT. It must only be used in an emergency situation when the identity of 
the trial 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, along with the date and 
initials of the person who broke the code. 

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Due to the requirements to report SUSARs, it may be necessary for a representative from 
BI’s Pharmacovigilance (PV) group to assess the randomisation code for individual patients 
during trial conduct. The access to the code will only be given to authorised PV 
representatives and not shared further. 
4.1.6
Packaging, labelling, and re-supply
Drug supplies will be provided by Boehringer Ingelheim.. 
The investigational product will be packaged and labelled in accordance with the principles 
of Good Manufacturing Practice. Re-supply to the sites will be managed via an IRT system, 
which will also monitor expiry dates of supplies available at the sites. 
For details of packaging and the description of the label, refer to the ISF. 
The clinical trial supply will be packaged in bottles holding the trial medication (20 tablets 
per bottle), which are labelled with trial identification.
The sponsor and name, address and telephone number of the trial site are given in the patient
information form. The EudraCT number is indicated on the title page of this protocol as well 
as on the patient information and informed consent forms. Examples of the labels will be 
available in 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 (labelled) storage conditions. Where necessary, a 
temperature log must be maintained to make certain that the drug supplies are stored at the 
correct temperature. If the storage conditions are found to be outside the specified range, the 
local clinical monitor (as provided in the list of contacts) is to be immediately contacted.
4.1.8
Drug accountability
The investigator / pharmacist / investigational drug storage manager will receive the 
investigational drugs delivered by the sponsor when the following requirements are fulfilled:

Approval of the study protocol by the IRB / ethics committee

Availability of a signed and dated clinical trial contract between the sponsor and the 
principle investigator

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 or immediately imminent 
signing of the clinical trial protocol.
Only authorised personnel as documented in the form ‘Trial Staff List’ may dispense
medication to trial patients. The trial medication must be administered in the manner 
specified in the CTP. All unused trial medication must be returned to the sponsor. Receipt, 
usage and return must be documented on the respective forms. Account must be given for any 
discrepancies. 

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The investigator / pharmacist / investigational drug storage manager 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. 
These records will include dates, quantities, batch / serial numbers, expiry (‘use-by’) dates, 
and the unique code numbers assigned to the investigational products and trial patients. The 
investigator / pharmacist / investigational drug storage manager will maintain records that 
document adequately that the patients were provided the doses specified by the CTP, and that
reconcile all investigational products received from the sponsor. At the time of return to the 
sponsor (and/or) appointed CRO, the investigator / pharmacist / investigational drug storage 
manager 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
CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE 
TREATMENT
4.2.1
Rescue medication, emergency procedures, and additional treatments
There are no specific rescue drugs foreseen for the treatment of AEs. No special emergency 
procedures are to be followed. In case of adverse events in need of treatment, the investigator 
can authorise symptomatic therapy. In those cases, patients will be treated as necessary and, 
if required, kept under supervision at the trial site or transferred to a hospital until all medical 
evaluation results have returned to an acceptable level.
All concomitant or rescue treatment taken during the course of the trial must be recorded in 
the source document and on the CRF.
4.2.1.1
Management of acute IPF exacerbations
In case of acute IPF exacerbation or worsening in baseline condition, all treatment options 
considered adequate by the Investigator are allowed. Efforts should be made to keep the 
subject on study medication. Sponsor should be contacted prior to stopping study drug.
4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
All concomitant or rescue therapies will be recorded (including time of intake on study days) 
on the appropriate pages of the CRF.

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Table 4.2.2.1:1
Restricted medication
Medication
Prior to 
Study
Screening 
Period
PK Evaluation 
Period (Day 1-
14)
Extended 
treatment 
period      
(Day 15+)
Follow up 
period 
Potent p-gp 
inhibitor or inducer
Not permitted1
Not 
permitted
Not permitted
Not permitted
Permitted
Potent and 
moderate CYP3A 
inhibitors or 
inducers
Not permitted1
Not 
permitted
Not permitted
Not permitted
Permitted
Nintedanib
Refer to 
exclusion 20
Not 
permitted
Not permitted
Not permitted3
Permitted
Pirfenidone
Refer to 
exclusion 20
Not 
permitted
Not permitted
Not permitted3
Permitted
Other anti-fibrotic 
therapies
Not permitted1
Not 
permitted
Not permitted
Not permitted
Permitted
PDE inhibitors2
Not permitted1
Not 
permitted
Not permitted
Not permitted
Permitted
Sensitive substrate 
of CYP3A
Permitted
Permitted
Use with 
caution
Use with 
caution
Permitted 
Footnotes to restricted medication Table 4.2.2.1:1
1. Not permitted 30 days prior to randomization (visit 3)
2. Includes, for example: Sildenafil, tadalafil, vardenafil, roflumilast, apremilast.
3. Based on clinical status, standard of care treatment may be initiated prior to the end of 
4 weeks, but should be avoided where possible as the safety has not been previously 
assessed and interference with trial related endpoints cannot be excluded. To allow for 
assessment of disease relevant markers at 4 weeks, use of SOC should be limited 
where possible. 
4.2.2.2
Restrictions on diet and life style
While admitted to the trial site the patients are restricted from consuming any other foods or 
drinks than those provided by the staff. Standardised meals will be served at the time points 
described in the Flow Chart. No food is allowed for at least 4 h after drug intake.
On PK profile days (i.e., Day 1 and Day 14) liquid intake is restricted from 1 hour before
administration until lunch with exception of the fluid administered with the breakfast and the
drug, and ~240 mL of water at 2 and 4 hours post-dose (mandatory for all patients). From
lunch until 24 hours post-dose, water intake is restricted to 3000 mL. On PK profile days (i.e., 
Day 1 and Day 14), standardized meals will be served at 4, and 10 hours following drug 
administration. Snacks should be served at times as outlined in the flow chart. 
Grapefruits, Seville oranges (sour or bitter oranges) and their juices, and dietary supplements 
and products including St. John's wort (Hypericum perforatum) are not permitted starting 7 

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days before the first administration of trial medication until after the last PK sample is 
collected.
Alcoholic beverages are not permitted starting 7 days before the first administration of trial 
medication until after the last PK sample is collected at day 14. After day 14 the use of 
alcohol should be limited but is not prohibited. 
Smoking is not allowed during in-house confinement at the trial site.
Methylxanthine-containing drinks or foods (such as coffee, tea, cola, energy drinks, and 
chocolate) are not allowed from 24 h preceding the administration of trial medication and 
until the end of plasma PK sampling of the respective visit. 
Excessive physical activity (such as competitive sport) should be avoided starting 7 days 
before the first administration of trial medication until the end of trial examination. 
Direct exposure to the sun or exposure to solarium radiation should be avoided during the 
entire study.
4.3
TREATMENT COMPLIANCE
During visits, compliance will be assured by administration of all trial medication in the 
study centre under supervision of the investigating physician or a designee. The measured 
plasma concentrations will provide additional confirmation of compliance.
Patients are requested to bring all remaining trial medication, including empty bottles with 
them when attending visits. 
Based on tablet counts (unused), treatment compliance will be calculated as shown in the 
formula below. Compliance will be verified by the CRA authorised by the sponsor. 
Treatment compliance % = Number of tablets actually taken x 100
Number of tablets which should have been taken
If the number of doses taken is not between 80% and 120%, site staff will explain to the 
patient the importance of treatment compliance. 
Patients who are non-compliant (for instance, who do not appear for scheduled visits or 
violate trial restrictions) may be removed from the trial and the CRF will be completed 
accordingly (for further procedures, please see section 3.3.4.1). 

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5.
VARIABLES AND THEIR ASSESSMENT

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5.2
SAFETY
5.2.1
Endpoints of safety
The primary endpoint to assess safety and tolerability of BI 1015550 by the number (%) of 
patients with drug-related AEs on-treatment. 
Further endpoints:
Further criteria of interest: 

TEAEs (including clinically relevant findings from the physical examination)

Safety laboratory tests (including testing for fecal occult blood and fecal calprotectin 
and urinanalysis for hematuria)

12-lead ECG

Vital signs (blood pressure, pulse rate, respiratory rate, oral body temperature and 
body weight)

Suicidality monitoring
5.2.2
Assessment of adverse events
5.2.2.1
Definitions of adverse events
Adverse event
An adverse event (AE) is defined as any untoward medical occurrence, including an 
exacerbation of a pre-existing condition, in a patient in a clinical investigation who received a 
pharmaceutical product. The event does not necessarily have to have a causal relationship 
with this treatment.
Serious adverse event
A SAE is defined as any AE which fulfils at least one of the following criteria:

results in death, 

is immediately 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

requires prolongation of existing hospitalisation

results in persistent or significant disability / incapacity, or

is a congenital anomaly/birth defect, or 

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
is deemed serious for any other reason if it is an important medical event when based 
upon appropriate medical judgement which may jeopardise the patient and may 
require medical or surgical intervention to prevent one of the other outcomes listed in 
the above definitions.
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm, blood dyscrasias or convulsions that do not result in hospitalisation or 
development of dependency or abuse
AEs considered ‘Always Serious’
Cancers of new histology and exacerbations of existing cancer must be classified as a serious 
event regardless of the duration between discontinuation of the drug and must be reported as 
described in section 5.2.2.2, subsections ‘AE collection’ and ‘AE reporting to sponsor and 
timelines’.
In accordance with the European Medicines Agency initiative on Important Medical Events, 
Boehringer Ingelheim has set up a list of further AEs, which by their nature, can always be 
considered to be ‘serious’ even though they may not have met the criteria of an SAE as 
defined above.
The latest list of ‘Always Serious AEs’ can be found in the electronic data capture (EDC)
system. These events should always be reported as SAEs as described above.
Suicidal Risk assessed by the C-SSRS 
The C-SSRS is a semi-structured, investigator-rated interview, developed by clinical
experts in cooperation with the FDA, assessing both suicidal behavior and suicidal
ideation. It does not give a global score, but provides some categorical and some
severity information specifically for behavior and ideation.
The C-SSRS interview may be administered by any type of physician, psychologist,
clinical social worker, mental health counselor, nurse, or coordinator with C-SSRS
training. It has a typical duration of five minutes, and causes only a low burden on
subjects. 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 C-SSRS has been widely used in large multinational clinical trials. The C-SSRS will
be administered at the screening visit (using the ‘screening’ version) with the
aim to exclude subjects with active moderate or severe symptomatology within a
specified time prior to the screening or baseline visit. The life time history of suicidal
ideation and behavior will also be recorded.
After the screening/baseline visit the assessment ‘since last visit’ will be performed at each 
clinic visit (‘since last visit’ version).

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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 subject during the clinic visit and/or is to 
consult a psychiatrist. If the positive report is confirmed, appropriate actions for the subject’s 
safety have to be initiated. 
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’ 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. 
Adverse events of special interest (AESIs)
The term 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 PV Department within the same timeframe that 
applies to SAEs, please see above.
The following are considered as AESIs:

Hepatic injury
A hepatic injury is defined by the following alterations of hepatic laboratory 
parameters: 
o
an elevation of AST and/or ALT ≥3fold ULN combined with an elevation of 
total bilirubin ≥2fold ULN measured in the same blood sample, and/or
o
aminotransferase (ALT, and/or AST) elevations ≥10 fold ULN
These lab findings constitute a hepatic injury alert and the patients showing these lab 
abnormalities need to be followed up according to the DILI checklist provided in the eCRF. 
In case of clinical symptoms of hepatic injury (icterus, unexplained encephalopathy, 
unexplained coagulopathy, right upper quadrant abdominal pain, etc.) without lab results 
(ALT, AST, total bilirubin) available, the Investigator should make sure these parameters are 
analysed, if necessary in an unscheduled blood test. Should the results meet the criteria of 
hepatic injury alert, the procedures described in the DILI checklist should be followed.
Intensity (severity) of AEs
The intensity (severity) of the AE should be judged based on the following:
Mild:
Awareness of sign(s) or symptom(s) which is/are easily tolerated
Moderate:
Sufficient discomfort to cause interference with usual activity
Severe:
Incapacitating or causing inability to work or to perform usual activities

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Causal relationship of AEs
Medical judgment should be used to determine the relationship, considering all relevant 
factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge, 
confounding factors such as concomitant medication, concomitant diseases and relevant 
history. 
Arguments that may suggest that there is a reasonable possibility of a causal relationship 
could be:

The event is consistent with the known pharmacology of the drug 

The event is known to be caused by or attributed to the drug class.

A plausible time to onset of the event relative to the time of drug exposure.

Evidence that the event is reproducible when the drug is re-introduced

No medically sound alternative aetiologies that could explain the event (e.g. pre-
existing or concomitant diseases, or co-medications).

The event is typically drug-related and infrequent in the general population not 
exposed to drugs (e.g. Stevens-Johnson syndrome).

An indication of dose-response (i.e. greater effect size if the dose is increased, smaller 
effect size if dose is diminished).
Arguments that may suggest that there is no reasonable possibility of a causal relationship 
could be:

No plausible time to onset of the event relative to the time of drug exposure is evident 
(e.g. pre-treatment cases, diagnosis of cancer or chronic disease within days / weeks 
of drug administration; an allergic reaction weeks after discontinuation of the drug 
concerned)

Continuation of the event despite the withdrawal of the medication, taking into 
account the pharmacological properties of the compound (e.g. after 5 half-lives). Of 
note, this criterion may not be applicable to events whose time course is prolonged 
despite removing the original trigger.

Additional arguments amongst those stated before, like alternative explanation (e.g. 
situations where other drugs or underlying diseases appear to provide a more likely 
explanation for the observed event than the drug concerned).

Disappearance of the event even though the trial drug treatment continues or remains 
unchanged. 
5.2.2.2
Adverse event collection and reporting
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: 
-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 AEs but should only 
reported related SAEs and related AESIs of which the investigator may become aware of 
by any means of communication, e.g. phone call. Those AEs should however, not be 
reported in the CRF.
Figure 5.2.2.2:1 AE reporting requirements 
The REP for BI 1015550, when measurable drug levels or PD effects are still likely to be
present, is defined as 7 days after the last administration of BI 1015550. Therefore, all AEs
which occurred through the treatment phase and throughout the REP will be considered as on
treatment; please see Section 7.3.3. Events which occurred after the REP but prior to the last
per protocol contact will be considered as follow up events.
AE reporting to sponsor and timelines
The investigator must report SAEs, AESIs and non-serious AEs which are relevant for the 
reported SAE or AESI on the BI SAE form via fax immediately (within 24 hours) to the 
sponsor’s unique entry point (country specific contact details will be provided in the ISF). 
The same timelines applies if follow-up information becomes available.  In specific occasions 
the investigator could inform the sponsor upfront via telephone. This does not replace the 
requirement to complete and fax the BI SAE form.
With receipt of any information to these events, a follow-up SAE form has to be provided. 
For follow-up information the same rules and timelines apply as for initial information.

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Information required
For each AE, the investigator should provide the information requested on the appropriate 
eCRF pages, and the BI SAE form, if applicable. The investigator should determine the 
causal relationship to the trial medication.
The following should also be recorded as an (S)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 pre-exist prior to trial inclusion they will be considered as 
baseline conditions and should be collected in the eCRF only.  
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. 
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 a written consent of 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 Trials (Part B). 
The ISF will contain the Pregnancy Monitoring Form for Clinical Trials (Part A and B).
As pregnancy itself is not to be reported as an AE, in the absence of an accompanying SAE 
and/or AESI, only the Pregnancy Monitoring Form for Clinical Trials and not the SAE Form 
is to be completed.  If there is an SAE and/or AESI associated with the pregnancy, an SAE 
form must be completed in addition. 
5.2.3
Assessment of safety laboratory parameters
For the assessment of laboratory parameters, blood and urine samples will be collected by the 
trial site at the time points indicated in the Flow Chart after the patients have fasted for at 
least 10 h. Overnight fasting is not required at the discretion of the investigator or designate 
for retests.
The parameters that will be determined are listed in Table 5.2.3: 1 and table 5.2.3: 2. 
Reference ranges will be provided in the ISF.

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Manual differential white blood cell count or urine sediment examinations will only be 
performed if there is an abnormality in the automatic blood cell count or in the urinalysis, 
respectively, i.e. if automatic count is not feasible or differential WBC is abnormal (i.e. 
pathological or atypical cells) and clinically relevant in the opinion of the investigator. In 
case the urinalysis is positive for erythrocytes, leukocytes, nitrite or protein, microscopic 
examination of the urine sediment will be performed. Positive findings of the urine sediment 
examination will be monitored and if needed based on the medical judgment of the 
investigator an urologist may be consulted.
Fecal occult blood testing and fecal calprotectin testing will be performed by the central 
laboratory. Both tests will be performed at the time points indicated in the Flow Chart.
As patients may not be able to defecate at the trial site in the morning of the visit, after 
screening (visit 1) they may collect the specimen at home and bring the test specimen to the 
trial site after the screening visit, within the screening period. In addition, samples collected 
within 3 days prior to first dosing (ie day -3 to day -1) may be collected as visit 2 (day -1) 
sample and samples collected within 3 days prior to subsequent visits may be used, with the 
exception of the sample taken at day 2.
In case of GI AEs (e.g. diarrhea, constipation), additional testing for fecal
occult blood and fecal calprotectin may be carried out at the discretion of the investigator.
If a patient tests positive for occult blood in feces, further tests will be performed and the
patient will be monitored closely.

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Table 5.2.3: 1
Routine laboratory tests
Functional lab group
Test name 
Haematology
Haematocrit
Haemoglobin
Red blood cell count (RBC)
Reticulocyte count
White blood cell count (WBC)
Platelet count
Erythrocyte sedimentation rate (ESR)
Automatic WBC differential 
(relative and absolute)
Neutrophils, eosinophils, basophils, monocytes, lymphocytes
Manual differential WBC (if automatic
differential WBC is abnormal)
Polymorphnuclear neutrophils (segs), band neutrophils (stabs), 
eosinophils, basophils, monocytes, lymphocytes 
Coagulation
Activated partial thromboplastin time (aPTT)
Prothrombin time (Quick’s test and INR)
Fibrinogen
Enzymes
Aspartate transaminase (AST/GOT)
Alanine transaminase (ALT/GPT)
Alkaline phosphatase (AP)
Gamma-glutamyl transferase (GGT)
Creatine kinase (CK)
CK-MB, only if CK is elevated 
Lactate dehydrogenase (LDH)
Lipase
Amylase
Hormones1
Thyroid stimulating hormone (TSH)
fT3, fT4
Substrates1
Plasma glucose
Creatinine 
Total bilirubin 
Direct and indirect bilirubin
Total protein
High sensitivity C-Reactive Protein (hs CRP)
Uric acid 
Total cholesterol 
Triglycerides
Albumin
Electrolytes
Sodium
Potassium
Chloride
Calcium
Inorganic phosphate

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Table 5.2.3: 2
Exclusionary laboratory tests
Functional lab group
Test name 
Drug screening (urine)
Amphetamine/MDA
Barbiturates
Benzodiazepine
Cannabis
Cocaine 
Methadone
Methamphetamines/MDMA/XTC
Opiates 
Phencyclidine
Tricyclic antidepressants
Infectious serology (blood)
Hepatitis B surface antigen (qualitative)
Hepatitis B core antibody (qualitative)
Hepatitis C antibodies (qualitative)
HIV-1 and HIV-2 antibody (qualitative)
The tests listed in Table 5.2.3: 2 are exclusionary laboratory tests which may be repeated as 
required. The results will not be entered in the CRF/database and will not be reported in the 
CTR. Infectious serology will be tested at screening (visit 1) only. Drug screening is to be 
performed at visit 2 (day -1).
To encourage compliance with alcoholic restrictions, a breath alcohol test will be performed 
at visit 2, and may be repeated at any time during the study at the discretion of an investigator 
or designate. The results will not be included in the CTR.
The laboratory tests listed in Table 5.2.3: 1 and 5.2.3: 2 will be performed at a central lab as 
selected by Boehringer Ingelheim, with the exception of the drug screening, which will be 
performed at the trial site. 
Laboratory data will be transmitted electronically from the laboratory to the trial site.
5.2.4
Electrocardiogram
5.2.4.1
12-lead resting ECG
Recording
Twelve-lead resting ECGs (I, II, III, aVR, aVL, aVF, V1 - V6) will be recorded using a 
computerised electrocardiograph which will be provided to the sites, at the time points given 
in the Flow Chart.
In order to achieve a stable heart rate (HR) at rest and to assure high quality recordings at 
comparable resting phases, all ECGs will be recorded for 10-sec duration after the patients 
have rested for at least 10 min in a supine position. The site personnel will be instructed to 
assure a relaxed and quiet environment so that all patients are at complete rest during the 
recordings. ECG assessment will always precede all other study procedures of the same time 
point (except blood drawing from an intravenous cannula which is already in place) to avoid 
compromising the ECG quality.

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Electrode placement will be performed according to the method of Wilson, Goldberger and 
Einthoven or limb leads modified by Mason and Likar (hips and shoulders instead of ankles 
and wrists). 
ECGs will be recorded as single ECGs or as triple ECGs (three single ECGs recorded within
180 sec) as indicated in the Flow Chart.
ECGs may be repeated for quality reasons for instance due to alternating current artefacts, 
muscle movements, or electrode dislocation. For repetition within triplicate ECGs the time 
window of 180 sec applies as well. The repeat ECGs are assigned to the respective scheduled 
time point.
Additional (unscheduled) ECGs may be recorded for safety reasons. These ECGs are 
assigned to the prior scheduled time point in the sponsor’s database. 
Data transfer
All ECGs will be transferred electronically to the central ECG lab for storage and evaluation.
In case of repeat ECGs due to quality reasons, all ECGs will be transferred to the central 
ECG lab who will select the correct one for analysis. 
Unscheduled ECGs (for safety reasons) will be transferred to the central ECG lab but will not 
be included into the statistical analysis of interval lengths.
Data transfer from the central ECG lab to the sponsor is described in the ECG data transfer 
agreement (see TMF).
Evaluation
a) Central ECG lab
Central ECG lab evaluation will be performed for the first of three replicate ECGs per 
time point on Day 1, day 2 (planned time 23:30h only) and day 14. For baseline, where 3 
triplicate ECGs are recorded, only the first single ECG per triplicate ECG (i.e. 3 single 
ECGs) will be evaluated.
This will include the determination of cardiac QRS-axis as assessed by the ECG 
machine’s algorithm as well as the intervals RR, PR, QRS and QT measured semi-
automatically.
Heart rate (HR) and the QT interval corrected for HR (QTc e.g. QTcF and QTcB) will be 
determined by the sponsor (see TSAP for details).
All semi-automatic interval measurements in one subject will be performed on the same 
lead. The intervals will be measured from four cardiac cycles (beats) in lead II. If lead II 
shows a flat T wave or is not measurable for any reason, lead V5 will be used, or if that 
lead is not measurable, then lead I will be used. The lead actually used will be reported in 
the CTR.
For automatic interval measurements no lead will be provided.
For blinding arrangements see section 4.1.5.1. No more than two blinded readers will 
evaluate all ECGs of the study. ECGs from a particular subject should be evaluated by a 
single reader. For quality assurance and control of the measurements, all ECGs of a 

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subject will be subsequently reviewed by the ECG technician supervisor or his/her 
designee to assess the overall variance of the measured intervals and, to detect accidental 
switching of leads and/or false subject assignments of the ECGs. After quality control, the 
fiducial point markings will be reviewed by the cardiologist assigned to the study.
Evaluation of ECGs will comply with the ICH E14 guidance document and supplements 
[R07-4722, R16-0366] as well as the FDA requirements for annotated digital ECGs [R09-
4830].
b) Trial site
All local ECGs will be evaluated by the investigator or a designee.
For the inclusion or exclusion (see section 3.3) of a patient and for the assessment of 
cardiac safety during the study, the QT and QTc values generated by the ECG machines 
or their manual corrections by the investigators will be used. In doubtful cases, ECGs 
may be sent upfront for centralised evaluation (see below). In this case, these centrally 
measured results would overrule any other results obtained.
Abnormal findings, irrespective of whether they originate from central or local evaluation, 
will be reported as AEs (during the trial) or baseline conditions (at screening) if judged 
clinically relevant by the investigator. Any ECG abnormalities will be monitored carefully 
and, if necessary, the patient will be removed from the trial and will receive the appropriate 
medical treatment. 
5.2.5
Assessment of other safety parameters
5.2.5.1
Vital signs
Systolic and diastolic BP as well as HR (considered to be equal to PR) will be measured by a 
blood pressure monitor at the times indicated in the Flow Chart, after patients have rested for 
at least 10 min in a supine position. All recordings should be made using the same type of 
blood pressure recording instrument on the same arm if possible. Further, respiratory rate 
[RR] and oral body temperature will be monitored. Body temperature will be determined at 
the time points indicated in the Flow Chart using electronic thermometers. Respiratory rate 
will be counted by trained study personal by observing the chest movements over a period of 
one minute after the subject has rested in the supine position for 5 minutes. Recording of the 
values will be done at the time points indicated in the Flow Chart.
5.2.5.2
Medical examinations
At the screening visit, after informed consent is obtained, the medical examination will 
include documentation of patient information, demographics including height and body 
weight, smoking and alcohol history, relevant medical history and concomitant therapy, 
review of inclusion and exclusion criteria, review of vital signs (BP, PR, body temperature, 
respiratory rate), 12-lead ECG, laboratory tests including fecal occult blood and fecal 
calprotectin testing, suicidality assessment (C-SSRS) and, and a physical examination. At the 
end of treatment (EOT) examination, it will include review of vital signs, 12-lead ECG, 
laboratory tests, and a physical examination with determination of weight. Body weight 
should be measured with the patient wearing indoor clothing and no shoes. For each

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individual patient, weight should be measured consistently in the morning or afternoon at all 
visits. 
5.2.5.3
Suicidal risk assessed by the C-SSRS
For the marketed PDE4-inhibitors apremilast [R17-1427];[R17-1539];[R17-1540] and
roflumilast [R17-1542] an increased risk of suicidality has been described. Therefore
prospective suicidality monitoring, will be performed throughout this trial using the
Columbia Suicidal Severity Rating scale (C-SSRS).
C-SSRS results will be reported in terms of AEs as described in Section 5.2.2.1.
For additional details refer to appendix 10.1.
5.3
OTHER
5.4
APPROPRIATENESS OF MEASUREMENTS
All measurements performed during this trial are standard measurements and will be 
performed in order to monitor patients’ safety and to determine PK and pharmacodynamics 
(PD) parameters in an appropriate way. The scheduled measurements will allow monitoring
of changes in vital signs, standard laboratory values, and ECG parameters that might occur as 
a result of administration of trial medication. The safety assessments are standard, are 
accepted for evaluation of safety and tolerability of an orally administered drug, and are 
widely used in clinical trials. The PK parameters and measurements outlined in section 5.5

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are generally used assessments of drug exposure. 
 
5.5
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS
Date and clock time of drug administration and PK sampling will be recorded in the CRFs.
The actual sampling times will be used for determination of PK parameters.
PK sampling times and periods may be adapted during the trial based on information 
obtained during trial conduct (e.g. preliminary PK data) including addition of samples and 
visits as long as the total blood volume taken per patient does not exceed 400 mL. Such 
changes would be implemented via non-substantial CTP Amendments.
5.5.1
Pharmacokinetic endpoints
The following PK parameters will be determined, if feasible:
5.5.1.1
Secondary endpoints
BI 1015550 
After the first dose (Day 1):

AUCτ,1 (area under the concentration-time curve of the analyte in plasma over a 
uniform dosing interval τ after administration of the first dose)

Cmax (maximum measured concentration of the analyte in plasma)
After the last dose (Day 14):

AUCτ,ss (area under the concentration-time curve of the analyte in plasma at steady 
state over a uniform dosing interval τ)

Cmax,ss (maximum measured concentration of the analyte in plasma at steady state over 
a uniform dosing interval τ)

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5.5.2
Methods of sample collection
5.5.2.1
Plasma sampling for pharmacokinetic analysis
For quantification of drug plasma concentrations of BI 1015550, BI 764333
, venous blood will be collected using a pre-labeled EDTA 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.
After completion of the trial the plasma samples may be used for further methodological 
investigations, e.g. for stability testing, assessment of metabolites. However, only data related 
to the analyte and/or its metabolite(s) including anti-drug antibodies (if applicable) will be 
generated by these additional investigations. The study samples will be discarded after 
completion of the additional investigations but not later than 5 years after the final study 
report has been signed.

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5.5.3
Analytical determinations
5.5.3.1
Analytical determination of plasma concentrations
BI 1015550 and BI 764333 concentrations in plasma will be determined by a validated high 
performance liquid chromatography with tandem mass spectrometry (HPLC-MS/MS) assay.  
The analysis will be performed under the responsibility of Drug Metabolism and 
Pharmacokinetics, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany at a 
suitable contract research organization (CRO).
As described in section 4.1.5, the bioanalyst will be unblinded during sample analysis.

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6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
Exact times of measurements outside the permitted time windows will be documented. The 
acceptable time windows for visits are given in the Flow Chart.
Study measurements and assessments scheduled to occur ‘before’ trial medication 
administration on Day 1 are to be performed and completed within a 2 h-period prior to the 
trial drug administration (including blank values for PK 
The acceptable deviation on profile days (day 1, day 14) from the scheduled time is as 
follows: For the first 4h after trial drug administration: vital signs and ECG, -10min and for
laboratory tests ± 30 min. After the first four hours after drug administration, vitals, ECG and 
laboratory tests ± 30 min.
Effort should be made to ensure that drug administration occurs at same time every day +/-
30 min. On day 1 and 14 extra care should be made to maintain consistency with accurate 
documentation of actual time of administration.
If scheduled in the Flow Chart at the same time as a meal, blood sampling, vital signs and 12-
lead ECG recordings have to be done first. Furthermore, if several measurements including 
venepuncture are scheduled for the same time, venepuncture should be the last of the 
measurements due to its inconvenience to the patient and possible influence on physiological
parameters.
For planned individual plasma concentration sampling times refer to the Flow Chart. While 
these nominal times should be adhered to as closely as possible, the actual sampling times 
will be recorded and used for determination of PK parameter.
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 
Blinded Report Planning Meeting.
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
6.2.1
Screening and run-in period(s)
After having been informed about the trial, all patients will give their written informed 
consent in accordance with ICH-GCP and local legislation prior to enrolment in the study.
For information regarding laboratory tests (including drug and virus screening), ECG, vital 
signs, and physical examination, refer to sections 5.2.3 to section 5.2.5. 
An historical HRCT can be used to determine eligibility, providing the scan was performed 
within the past 12 months prior to screening. If historical scan is not available, or an available 
scan fails to meet the required image acquisition specification, an HRCT may be performed 
after consent to determine eligibility. All HRCT scans will be sent to a central vendor for 

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review and confirmation of IPF diagnosis, prior to randomization. HRCT should not be 
repeated for eligibility if previous scan was taken within the past 3 months. 
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. HRCT scans will be sent 
to a central reviewer for confirmation of IPF diagnosis. Confirmation of diagnosis must be 
available prior to visit 2. 
Screening period may be extended for administrative reasons. Approval should be obtained 
from the sponsor who will also determine if any tests specified in the protocol must be 
repeated before the randomization visit. 
6.2.2
Treatment period
During the treatment period, patients will take trial medication twice daily. 
At least one visit (visit 3), will be conducted inpatient; during which time patients will be
kept under close medical surveillance. The patients will be allowed to leave the trial site only 
after formal assessment and confirmation of their fitness by the investigator or 
 designee. 
On all other study days, the study will be performed in an ambulatory fashion.
In addition to clinic visits, daily phone calls are required between study visits to assess and 
collect AE information and confirm compliance until day 14, with weekly phone calls 
between study visits thereafter until end of treatment.
Inpatient Visit 3: Day 1 and 2
Visit 3 will span at minimum, a two day period, day 1 and 2. 
All patients must be admitted (inpatient) at the morning of day 1, and kept under close 
medical surveillance for at least 2 hours following evening drug administration on day 2. The 
patients will then be allowed to leave the trial site after formal assessment and confirmation 
of their fitness by the investigator or 
 designee.
Each patient will receive the first dose of BI 1015550 or placebo the morning of Day 1 and 
the second dose the evening of day 1. Patients will take BI 1015550 (or placebo) twice daily 
(b.i.d) from Day 1 onwards. Trial medication will be taken orally. At clinic visits, trial 
medication will be taken under direct supervision of the investigator or 
 designee. Details 
on treatments and procedures of administration are described in section 4.1.4.
Patients will be given a diary to record intake of study medication taken at home since the 
last clinic visit, during the treatment period. At each visit, the diary will be collected and 
reviewed for compliance and a new diary will be dispensed. 
Visit 8:  Day 14

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Study participants are required to be on site under medical surveillance for approximately 16 
hours at day 14 to allow for required sampling and safety assessments as outlined in the Flow 
Chart.  The patients are permitted to leave the trial site after formal assessment and
confirmation of their fitness by the investigator or 
 designee. As an alternative, the patient 
may be admitted or relocated to a nearby facility overnight. No additional testing is required 
during this period. 
General:
For details on time points and procedures for collection of plasma samples for PK analysis, 
refer to Flow Chart and section 5.5.2.
The safety measurements performed during the treatment period are specified in section 5.2.
of this protocol and in the Flow Chart. For details on time points for all other trial procedures, 
refer to the Flow Chart. AEs and concomitant therapy will be assessed continuously from 
screening until the end of trial examination.
End of Treatment Visit:
The EOT visit is required for all patients. The EOT visit is conducted when patients have 
concluded treatment with BI 1015550. 
For patients who complete the full treatment period, this will be after 4 weeks of treatment, at 
visit 9. 
For patients who prematurely discontinue trial medication, for any reason prior to 4 weeks, 
the abbreviated EOT visit should be completed as indicated in the Flow Chart, as soon as 
possible after stopping treatment. 
6.2.3
Follow-up period and end of trial
A follow up period of a minimum of 7 days (+3 days) will be required. All patients will 
complete an end of trial visit, including patients who discontinue treatment early. For AE 
assessment, laboratory tests, recording of ECG and vital signs, and physical examination 
during the end of trial period, see sections 5.2.2 to 5.2.5.
All abnormal values (including laboratory parameters) that are judged clinically relevant by 
the investigator will be monitored using the appropriate tests until a return to a medically 
acceptable level is achieved. Adverse events persisting after trial completion must be 
monitored until they have normalised or have been sufficiently characterised. 
The end of the trial as a whole is defined by the ‘last regular visit completed by last patient’ 
or ‘end date of the last open AE’ or ‘date of the last follow-up test’ or ‘date of an AE has 
been decided as sufficiently followed-up’, whichever is latest.

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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
7.1
STATISTICAL DESIGN – MODEL
7.1.1
Objectives
Trial objectives are given in Section 2.2. 
The primary safety endpoint is defined in section 5.2.1. Inferential statistics are not planned 
(as explained in section 7.2).
PK endpoints as specified in section 5.5.1 will be analysed by descriptive statistics. Trough 
concentration values of BI 1015550 will be analysed regarding attainment of steady state as a 
pre-requisite for calculation of steady state parameters.
7.2
NULL AND ALTERNATIVE HYPOTHESES
Safety and tolerability of different dose strengths of BI 1015550 are to be determined on the 
basis of the investigated parameters in comparison to placebo. It is not planned to test any 
statistical hypotheses with regard to these variables in a confirmatory sense. Instead, they will 
be described in their entirety and evaluated by descriptive statistical methods.
Confidence intervals will be computed and will have to be interpreted in the perspective of 
the exploratory character of the study, i.e. confidence intervals are considered as interval 
estimates for effects.
7.3
PLANNED ANALYSES
All individual data will be listed.
Adherence to the protocol (such as inclusion/exclusion criteria, times of measurement, 
compliance with intake of trial medication, treatment dispensing errors, prohibited 
concomitant medication, completeness and consistency of data) will be checked. Important 
protocol deviations will be identified no later than in the Blinded Report Planning Meeting 
and provided in the TSAP.
7.3.1
Primary analyses
Analysis of safety and tolerability is described in section 7.3.3.
 

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7.3.2
Secondary analyses
The secondary 
 PK parameters (refer to section 5.5.1) will be calculated according 
to the BI SOP ‘Standards and processes for analyses performed within Clinical 
Pharmacokinetics/Pharmacodynamics’ (01-MCS-36-472).
Plasma concentration data and parameters of a subject will be included in the statistical PK
analyses if they are not flagged for exclusion due to a protocol violation relevant to the 
evaluation of PK (to be decided no later than in the Blinded Report Planning Meeting) or due 
to PK non-evaluability (as revealed during data analysis, based on the criteria specified 
below). Exclusion of a subject’s data will be documented in the CTR.
Relevant protocol violations may be

Incorrect trial medication taken, i.e. the subject received at least one dose of trial 
medication the subject was not assigned to

Incorrect dose of trial medication taken

Use of restricted medications.
Plasma concentrations and/or parameters of a subject will be considered as non-evaluable, if 
for example

the subject experienced emesis that occurred at or before two times median tmax of the 
respective treatment (Median tmax is to be determined excluding the subjects 
experiencing emesis),

missing samples/concentration data at important phases of PK disposition curve.
The PK parameter analysis set (PKS) includes all subjects in the Treated Set (TS) who 
provide at least one PK parameter that was not excluded according to the description above.
Attainment of steady state
Attainment of steady state will be explored by using the trough concentrations of BI 1015550
and BI 764333 between days 2 and 14 and the concentrations taken directly at the end of the 
dosing interval after the first drug administration and after the morning administration on Day 
14 (Cτ,1, Cτ,27) for each dose level.
A nonlinear mixed effects model will be used to estimate the time to reach steady-state
according to Hoffman et al. [R05-0788]. Accordingly, the observed trough plasma 
concentration Cij for subject i after the jth administration can be fitted by the following model:
 =  ∙exp() ∙(1 −exp(−( ∙exp() ⋅))) ∙exp()
where

is the average steady-state trough concentration in the population,

is the random deviation from Css with respect to subject i,

is the average first-order elimination rate in the population,

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
is the random deviation from with respect to subject i,

is the i.i.d. normally distributed random within-subject error (~(0, 
)).
The random effects  and  are multivariate normal distributed and independent of :
 
! " ~ #$%
%&, '

!
!
!
 ().
The time-point of sufficient approximation to the steady-state asymptote concentration is then 
determined from the fitted function. In other words, the time tf to reach * = 85, 90 and 95% 
of steady-state can be calculated as follows:
t , = log(1 −*) / (−),
where is again the average first-order elimination rate in the population.
Graphical displays
To support the analyses of attainment of steady state, graphical representations of the data 
might be created. These might include (but are not limited to) individual time-courses of 
trough plasma concentrations and the (geometric) mean plasma concentration time profiles.
7.3.3
Safety analyses
Safety will be assessed for the endpoints and parameters of interest listed in section 5.2.1. All 
treated patients (that is, all patients who received at least one dose of study drug), will be 
included in the safety evaluation. Safety analyses will be descriptive in nature and will be 
based on BI standards.
Treatments will be compared in a descriptive way. The placebo control group in the safety 
evaluation will consist of all placebo treated patients, regardless of the dose group in which 
they were treated. The active treatment groups will be compared to the placebo group in a 
descriptive way. Tabulations of frequencies/proportions will be used for the evaluation of 
categorical (qualitative) data, and tabulations of descriptive statistics will be used to analyse 
continuous (quantitative) data.
The analyses will be done by ‘treatment at onset’.
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 residual effect period (REP), a period 
of 7 days after the last dose of trial medication, will be assigned to the on-treatment period for 
evaluation.
Statistical analysis and reporting of adverse events will concentrate on treatment-emergent 
adverse events, i.e. all adverse events occurring between start of treatment and end of the
REP. Adverse events that start before first drug intake and deteriorate under treatment will 
also be considered as ‘treatment-emergent’.

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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 MedDRA
at the database lock.
Measurements (such as ECG, vital signs, or laboratory parameters) or AEs will be assigned to 
treatments (see section 4.1) based on the actual treatment at the planned time of the 
measurement or on the recorded time of AE onset (concept of treatment emergent AEs). 
Therefore, measurements planned or AEs recorded prior to first intake of trial medication will 
be assigned to 'screening', those between first trial medication intake and end of REP will be 
assigned to the treatment period, and all AEs occurring between the end of REP and trial 
termination date will be assigned to ’follow-up’. These assignments including the 
corresponding time intervals will be defined in detail in the TSAP. Please note that AEs 
occurring after the last per protocol contact but entered before database lock will be reported 
to drug safety only and will not be captured in the trial database.
Additionally, further treatment intervals (analysing treatments) may be defined in order to 
provide summary statistics for time intervals, such as combined treatments, on-treatment 
totals or periods without treatment effects (such as screening and post-study intervals).
Laboratory data will be analysed both quantitatively as well as qualitatively. The latter will 
be done via comparison of laboratory data to their reference ranges. Values outside the 
reference range as well as values defined as clinically relevant will be summarised. 
Additionally, differences from baseline will be evaluated.
For vital signs, the differences from baseline will be evaluated.
The ECG variables QT, PR, QRS, and RR are obtained from the centralised evaluation of 12-
lead ECG recordings.
The ECG variables HR, QTcF, QTcB will be derived from QT and RR interval obtained from 
central ECG evaluation.
These variables will be the basis for the derivation of quantitative and categorical ECG 
endpoints. The endpoints and their analyses will be described in the TSAP. 
7.3.4
Interim analyses
A preliminary analysis of PK parameters (AUC0-24 and Cmax of BI 1015550), provided as 
individual values and gMean of the first cohort per dose level, will be performed before 
proceeding to the next dose.
(Note: Data from the first cohorts of the above mentioned dose levels will be sufficient as 
long as the data from at least 4 patients on active drug were available)
In contrast to the final PK calculations, the preliminary analysis may be based on planned 
sampling times rather than on actual times, regardless of whether actual times were within the 
time windows or not. Therefore, minor deviations of preliminary and final results may occur. 
The preliminary analysis will provide individual and mean concentration/effect-time profiles 
and summary statistics of individual values without patient identification. The preliminary 
results will be distributed to the Investigator and the trial team. 

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Depending on the results of available preliminary PK analyses, the tolerability and safety of 
the compound, and changes of dosing schedule (e.g. additional intermediate doses) additional 
PK preliminary analysis may be performed based on the request of the clinical trial leader, 
the investigator, or Trial Clinical Pharmacokineticist. No formal preliminary PK/PD report 
will be written.
No formal inferential statistical interim analysis is planned. However, after each dose group,
summaries and listings may be created to support the safety reviews. The investigator (or 
 
deputy) is allowed to postpone further dose progression until a preliminary analysis of the 
data already obtained has been performed
7.3.5
Pharmacokinetic analyses
The PK parameters listed in section 5.5.1 for drug BI 1015550 will be calculated according to 
the BI SOP ‘Standards and processes for analyses performed within Clinical 
Pharmacokinetics/Pharmacodynamics’ (01-MCS-36-472).
Patients who are not included in the PKS (refer to section 7.3.1.) will be reported with their 
individual plasma concentrations and individual PK parameters; however, they will not be 
included in descriptive statistics for plasma concentrations, PK parameters or other statistical 
assessment.
Only concentration values within the validated concentration range and actual sampling times 
will be used for the calculation of PK parameters. Concentrations used in the PK calculations 
will be in the same format provided in the bioanalytical report, (that is, to the same number of 
decimal places provided in the bioanalytical report).

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7.4
HANDLING OF MISSING DATA
7.4.1
Safety
With respect to safety evaluations, it is not planned to impute missing values.
7.4.2
Plasma drug concentration - time profiles
Handling of missing PK data will be performed according to the relevant SOP of the Sponsor 
(01-MCS-36-472).
Drug concentration data identified with no sample available (NOS), no valid result (NOR), 
not analysed (NOA), or below the lower limit of quantification (BLQ) will be displayed as 
such and not replaced by zero at any time point (this rule also applies to the lag phase,
including the pre-dose values). 
7.4.3
Pharmacokinetic parameters
Handling of missing PK data will be performed according to the relevant SOP of the Sponsor 
(01-MCS-36-472).
For the non-compartmental analysis, concentration data identified with NOS, NOR or NOA 
will generally not be considered. Concentration values in the lag phase identified as BLQ will 
be set to zero. All other BLQ values of the profile will be ignored. The lag phase is defined as 
the period between time zero and the first time point with a concentration above the 
quantification limit.
7.5
RANDOMISATION
Patients will be randomised within each dose/treatment group in a 2:1 ratio, which reflects 
the ratio of patients receiving active drug to placebo.
The sponsor will arrange for the randomisation as well as packaging and labelling of trial 
medication. The randomisation list will be generated using a validated system, which 
involves a pseudo-random number generator and a supplied seed number so that the resulting 
allocation is both reproducible and non-predictable.
The randomisation list will contain additional blocks to allow for patient replacement (refer 
to section 3.3.5).
7.6
DETERMINATION OF SAMPLE SIZE
It is planned to include a total of 18 patients in this trial.
Additional patients may be entered to allow testing of additional intermediate doses within 
the planned dose range on the basis of experience gained during trial conduct (e.g. 
preliminary PK data), i.e. the actual number of patients entered may exceed 18.

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The planned sample size is not based on a power calculation. The size of 9 patients per dose 
group (6 on active treatment, and 3 on placebo) is commonly used in multiple-rising dose 
studies of the present type and is in general considered as sufficient for the exploratory 
evaluation of multiple dose safety and PK.
An additional 6 patients (4 on active, 2 on placebo) will be entered in dose group 1A (18mg 
bid), therefore the total number of patients planned to be included in the trial is up to 24.

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8.
INFORMED CONSENT, DATA PROTECTION, TRIAL 
RECORDS
The trial will be carried out in compliance with the protocol, the principles laid down in the 
Declaration of Helsinki, in accordance with the ICH-GCP and relevant BI SOPs.
The investigator should inform the sponsor immediately of any urgent safety measures taken 
to protect the study patients against any immediate hazard, and also of any serious breaches 
of the protocol or of ICH-GCP.
The rights of the investigator and of the sponsor with regard to publication of the results of 
this trial are described in a separate agreement between the investigator or the trial site and 
the sponsor. As a general rule, no trial results should be published prior to finalisation of the 
CTR.
8.1
STUDY APPROVAL, PATIENT INFORMATION, AND 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 a patient’s 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 subject 
information form are to be retained by the investigator as part of the trial records. A copy of 
the signed and dated written informed consent and any additional subject information must be 
given to each patient or the patient’s legally accepted representative.
The patient must be informed that his/her personal trial-related data will be used by 
Boehringer Ingelheim in accordance with the local data protection law. The level of 
disclosure must also be explained to the patient.
The patient must be informed that his or her medical records may be examined by authorised 
monitors CML/CRA or Clinical Quality Assurance auditors appointed by Boehringer 
Ingelheim, by appropriate IRB/IEC members, and by inspectors from regulatory authorities.
8.2
DATA QUALITY ASSURANCE
A quality assurance audit/inspection of this trial may be conducted by the sponsor or 
sponsor’s designees, by IRBs/IECs, 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.
The data management procedures to ensure the quality of the data are described in detail in 
the trial data management and analysis plan (TDMAP) available in the clinical TMF.

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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
Source documents provide evidence for the existence of the patient and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site.
All data reported in the CRFs must be consistent with the source data or the discrepancies 
must be explained.
The investigator may need to request previous medical records or transfer records, depending 
on the trial.
8.3.2
Direct access to source data and documents
The investigator/institution will permit trial-related monitoring, audits, IRB/IEC review and 
regulatory inspection, providing direct access to all related source data/documents. CRFs and 
all source documents, including progress notes (if applicable) and copies of laboratory and 
medical test results must be available at all times for review by the sponsor’s clinical trial 
monitor, auditor and inspection by health authorities (e.g. FDA). The CRA /on site monitor 
and auditor may review all CRFs, and written informed consents. The accuracy of the data 
will be verified by reviewing the documents described in section 8.3.1.
8.4
LISTEDNESS AND EXPEDITED REPORTING OF ADVERSE EVENTS
8.4.1
Listedness
To fulfil the regulatory requirements for expedited safety reporting, the sponsor evaluates 
whether a particular AE is ‘listed’, i.e. is a known side effect of the drug. Therefore a unique
reference document for the evaluation of listedness needs to be provided. For BI 1015550
this is the current version of the Investigator’s Brochure (c02094779-03). The current version 
of this reference document is to be provided in the ISF. 
8.4.2
Expedited reporting to health authorities and IECs/IRBs
Expedited reporting of SAEs, e.g. SUSARs to health authorities and IECs/IRBs, will be done 
according to local regulatory requirements. Further details regarding this reporting procedure 
are provided in the ISF.
8.5
STATEMENT OF CONFIDENTIALITY
Individual patient medical information obtained as a result of this trial is considered 
confidential and disclosure to third parties is prohibited with the exceptions noted below. 
Patient confidentiality will be ensured by using patient identification code numbers.
Treatment data may be provided to the patient’s personal physician or to other appropriate 
medical personnel responsible for the patient’s welfare. Data generated as a result of the trial 

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need to be available for inspection on request by the participating physicians, the sponsor’s 
representatives, by the IRB/IEC and the regulatory authorities, i.e. the CA.
8.6
COMPLETION OF TRIAL
The EC/competent authority in each participating EU member state needs to be notified about 
the end of the trial (last patient/patient out, unless specified differently in section 6.2.3 of the 
CTP) or early termination of the trial.

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9.
REFERENCES 
9.1
PUBLISHED REFERENCES
P05-12782
Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, 
Crapo R, Enright P, Grinten CPM van der, Gustafsson P, Jensen R, Johnson 
DC, MacIntyre N, McKay R, Navajas D, Pedersen OF, Pellegrino R, Viegi 
G, Wanger J. Standardisation of spirometry. Eur Respir J 26 (2), 319 - 338 
(2005).
P06-08316
Giembycz MA. An update and appraisal of the cilomilast phase III clinical 
development programme for chronic obstructive pulmonary disease. Br J 
Clin Pharmacol 2006;62(2):138-152.
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.
P15-07539
Raghu G, et al, American Thoracic Society (ATS), European Respiratory 
Society (ERS), Japanese Respiratory Society (JRS), Latin American 
Thoracic Association (ALAT). An official ATS/ERS/JRS/ALAT clinical 
practice guideline: treatment of idiopathic pulmonary fibrosis: an update of 
the 2011 clinical practice guideline. Am J Respir Crit Care Med 
2015;192(2):e3-e19.
R05-0788
Hoffman D, Kringle R, Lockwood G, Turpault S, Yow E, Mathieu G.  
Nonlinear mixed effects modelling for estimation of steady state attainment.  
Pharm Stat 4, 15 - 24 (2005).
R06-2002
Macintyre N, Crapo RO, Viegi G, Johnson DC, Grinten CPM van der, 
Brusasco V, Burgos F, Casaburi R, Coates A, Enright P, Gustafsson P, 
Hankinson J, Jensen R, McKay R, Miller MR, Navajas D, Pedersen OF, 
Pellegrino R, Wanger J . Standardisation of the single-breath determination 
of carbon monoxide uptake in the lung. Eur Respir J 2005; 26:720-35.
R07-4722
Guidance for industry: E14 clinical evaluation of QT/QTc interval 
prolongation and proarrhythmic potential for non-antiarrhythmic drugs.  
Rockville: U.S. Department of Health and Human Services, Food and Drug 
Administration, Center for Drug Evaluation and Research (CDER), Center 
for Biologics Evaluation and Research (CBER) (2005)
R09-4830
Brown BD, Badilini F.  HL7 aECG implementation guide (March 21, 
2005).

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R10-1555
Daxas (roflumilast) in chronic obstructive pulmonary disease, NDA 22-522, 
FDA Advisory Committee briefing document presented to: Pulmonary-
Allergy Drugs Advisory Committee (briefing book, April 7, 2010). 
website.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/
Pulmonary-AllergyDrugsAdvisoryCommittee/ucm207376.htm (access 
date: 23 November 2010); Jersey City: Forest Research Institute; 2010.
R10-1559
Giembycz MA. Life after PDE4: overcoming adverse events with dual-
specificity phosphodiesterase inhibitors. Curr Opin Pharmacol 2005;5:238-
244.
R11-2587
Ley B, Collard HR, King TE. Clinical course and prediction of survival in 
idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2011;183:431-
440.
R12-5527
Nalysnyk L, Cid-Ruzafa J, Rotella P, Esser D. Incidence and prevalence of 
idiopathic pulmonary fibrosis: review of the literature. Eur Respir Rev 
2012; 21(126):355-361.
R14-1795
Otezla (apremilast) tablets, for oral use (Celgene) (U.S. prescribing 
information, revised: 3/2014).
R16-0366
E14 Implementation Working Group ICH E14 guideline: the clinical 
evaluation of QT/QTc interval prolongation and proarrhythmic potential for 
non-antiarrhythmic drugs: questions & answers (R3) (current version dated 
10 December 2015).
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/E
fficacy/E1 4/E14_Q_As_R3__Step4.pdf (access date: 29 January 2015) ; 
Geneva: International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use (2015)
R16-1924
Gisbert JP, Bermejo F, Perez-Calle JL, Taxonera C, Vera I, McNicholl AG, 
Algaba A, Lopez P, Lopez-Palacinos N, Calvo M, Gonzalez-Lama Y, 
Cameros JA, Velasco M, Mate J.  Fecal calprotectin and lactoferrin for the 
prediction of inflammatory bowel disease relapse. Inflamm Bowel Dis. 15 
(8), 1190-1198 (2009).
R17-0158
Korkmaz S, Maupoil V, Sobry C, et al. An increased regional blood flow 
precedes mesenteric inflammation in rats treated by a phosphodiesterase 4 
inhibitor. Tox Sci 2009; 107(1):298-305.
R17-0915
Roflumilast 500 mcg tablets (Forest Research Institute): 
pharmacology/toxicology NDA/BLA review and evaluation, application 
number: 022522Orig1s000. 
website.accessdata.fda.gov/drugsatfda_docs/nda/2011/022522Orig1s000Ph
armR.pdf (access date: 13 March 2017) ; Department of Health and Human 
Services, Public Health Service, Food and Drug Administration, Center for 
Drug Evaluation and Research (2011)

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R17-0916
Losco PE, Evans EE, Barat SA, et al. The toxicity of SCH 351591, a novel 
phosphodiesterase-4 inhibitor, in cynomolgus monkeys. Toxicol Pathol 
2004; 32:295-308.
R17-0919
Otezla (apremilast) (Celgene): pharmacology/toxicology NDA/BLA review 
and evaluation, application number: 205437Orig1s000.
website.accessdata.fda.gov/drugsatfda_docs/nda/2014/205437Orig1s000Ph
armR.pdf (access date: 13 March 2017) ; Department of Health and Human 
Services, Public Health Service, Food and Drug Administration, Center for 
Drug Evaluation and Research (2014)
R17-1427
Otezla 10 mg, 20 mg, 30 mg film-coated tablets, Otezla 30 mg film-coated 
tablets (Celgene) (summary for product characteristics, manufacturer 
responsible for batch release, conditions or restrictions regarding supply 
and use, other conditions and requirements of the marketing authorisation, 
conditions or restrictions with regard to the safe and effective use of the 
medicinal product, labelling and package leaflet (first published 
16/02/2015). website.ec.europa.eu/health/documents/community-
register/2015/20 150115130395/anx_130395_en.pdf (access date: 19 April 
2017); 2015.
R17-1539
Otezla 30mg tablets (Celgene) (summary of product characteristics updated 
05-Jan-2017). website.medicines.org.uk/emc/print-
document?documentId=29792 (access date: 2 May 2017); 2017.
R17-1540
Otezla 10mg, 20mg, 30mg treatment initiation pack (Celgene) (summary of 
product characteristics updated 05-Jan-2017). 
website.medicines.org.uk/emc/print-document?documentId=29793 (access 
date: 2 May 2017); 2017.
R17-1542
Daxas 500 micrograms film-coated tablets (AstraZeneca) (summary of 
product characteristics updated 06-Dec-2016). 
website.medicines.org.uk/emc/print-document?documentId=23416 (access 
date: 2 May 2017); 2016.
R17-3686
Graham BL, Brusasco V, Burgos F, et al. 2017 ERS/ATS standards for 
single-breath carbon monoxide uptake in the lung. Eur Respir J 2017; 49: 
1600016 [https://doi.org/10.1183/ 13993003.00016-2016].
9.2
UNPUBLISHED REFERENCES
01-MCS-36-472 Standards and processes for analyses performed within Clinical 
Pharmacokinetics/Pharmacodynamics. Current version
001-MCG-312
Biomarker Assessments on Trial Level. Current version
U10-3777-01
 Investigator Brochure BI 137882 BS. 11 Feb 2011

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U13-1792-01
 Safety, tolerability and 
pharmacokinetics of single rising oral doses of BI 1015550 in healthy male 
volunteers (a partially randomised, single-blinded, placebo-controlled Phase 
I study). 1305.1. 21 Jun 2013
c02094779-03
Investigator's Brochure BI 1015550 for Idiopathic Pulmonary Fibrosis. 
22Feb2018
c02191718-02
 Safety, tolerability and 
pharmacokinetics of multiple rising oral doses of BI 1015550 powder for 
oral solution in healthy male volunteers q.d. or b.i.d. for 14 days (a 
randomised, double-blind, placebo-controlled within dose groups Phase I 
trial). 1305.2. 15 Apr 2014
c20307414-01
Final Clinical Trial Report (1305-0020).  Relative bioavailability of BI 
1015550 following oral administration under fed and fasted conditions in 
healthy male subjects.  16 July 2018
c22991937-01
Final Clinical Trial Report (1305-0011).  Safety, tolerability, and 
pharmacokinetics of single (Part 1) and multiple rising oral doses (Part 2) of 
BI 1015550 in healthy male subjects.  15 November 2018

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10.
APPENDICES
10.1
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.
At screening, C-SSRS (screening version) will be assessed with the aim to exclude patients
with suicidal ideation type 2-5 within the preceding 12 months and patients with any lifetime
history of suicidal behavior. Subsequently, the C-SSRS “since last visit” assessment will be
performed at the time points given in the Flow Chart. For assessment, paper forms will be
used and results will be transcribed into the CRF.
All positive reports during trial treatment are treatment-emergent adverse events (AEs).
The results of further medical, including psychiatric examinations should be documented as
adverse events where appropriate.
The original Columbia Suicidal Severity Rating scales used in this trial are shown as follows:
Visit 1 –Screening version
Subsequent visits- Since last visit version. 

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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
Number of global amendment
1.0
Date of CTP revision
21 Jun 2018
EudraCT number
2017-002736-16
BI Trial number
1305-0012
BI Investigational Product(s)
BI 1015550
Title of protocol
Safety, tolerability, and pharmacokinetics of 
multiple rising oral doses of BI 1015550 in 
patients with idiopathic pulmonary fibrosis (IPF) 
on no background anti-fibrotic (Part 1) and safety 
and tolerability of BI 1015550 on top of 
Nintedanib and Pirfenidone (Part 2)
To be implemented only after 
approval of the IRB / IEC /
Competent Authorities
To be implemented 
immediately in order to 
eliminate hazard –
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval
Can be implemented without 
IRB / IEC / Competent 
Authority approval as changes 
involve logistical or 
administrative aspects only
Section to be changed
Flow chart 1A- MRD Overview
Flow chart 1B- part 1: Visit 3 
Flow chart 1C- part 1: Visit 8
 
Description of change
 
Rationale for change
The risk of human disproportionate metabolite is 
turned out to be low based on the recently 
available metabolite identification data from 
Study 1305-0011. Therefore, samplings for 

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metabolite identification were eliminated to 
reduce the burden of patients.
Section to be changed
Flow chart 2A: SOC Overview
Description of change
Phone visit:
Compliance check removed from part 2 flow 
chart 
Concomitant therapy added to part 2 flow chart
Rationale for change
Phone visits updated for consistency between 
part1 and 2 
Section to be changed
Flow chart 1A: MRD Overview
Flow chart 2A: SOC Overview
Description of change
Footnote 13 regarding pre dose PK samples, 
updated for clarification that day 84 (part 1) and 
day 28 (part 2) pk samples are taken the morning 
of the visit, similar to other samples listed. These 
samples are not considered pre dose as there is no 
dosing at day 84 (part 1) or day 28 (part 2) and 
are therefore considered post (previous day) dose.
Rationale for change
Clarification
Section to be changed
Abbreviations
Description of change
Columbia-suicide severity ranking score corrected 
to Columbia-suicide severity rating scale
Rationale for change
Correction
Section to be changed
1.2.4
Description of change
Missing information about CYP3A induction and 
no clinically relevant PK-DDI potential of BI 
1015550 with nintedanib and pirfenidone was 
added.
Rationale for change
Updated as applicable to DDI potential with SOC. 
Section to be changed
1.2.5.1.3
1.2.5.2.2
Description of change
Preliminary results pertaining to clinical safety 
and clinical pharmacokinetics for trial 1305-0011 
added to introduction section.  
Rationale for change
Preliminary results have become available since 
finalization of protocol. 
Section to be changed
1.2.5.1.4
1.2.5.2.3 (new section added)

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Number of global amendment
1.0
Description of change
Preliminary results pertaining to clinical safety 
and clinical pharmacokinetics for trial 1305-0020 
added to introduction section.
Rationale for change
Preliminary results have become available since 
finalization of protocol
Section to be changed
1.2.5.2.3 updated to section 1.2.5.2.4
Description of change
Statement “Exposure estimate will be updated to 
include PK data from ongoing trials (1305.11, 
1305.20) as they become available” has been
removed and the respective expected exposures in 
Section 1.2.5.2.4 were updated.
Rationale for change
PK information has been updated and therefore 
statement is no longer applicable. 
Section to be changed
3.1.1 
Description of change
Additional description added regarding meeting 
with investigators 
Rationale for change
This will ensure key findings of safety review 
committee are outlined with investigators and 
investigators have intimate knowledge of the data. 
Section to be changed
3.3
Description of change
Description of re-screening added. 
Rationale for change
Re-screening may be permitted in specific 
circumstances. Clarification in protocol added to 
ensure sites are aware of requirements. 
Section to be changed
3.3.3
Description of change
Exclusion 3, cholecystectomy removed. 
Rationale for change
Cholecystectomy was eliminated from the 
exclusion criteria because food effect trial show 
negligible effect of food on AUC and the risk that 
cholecystectomy could interfere with PK of BI 
1015550 is low considering the contribution of 
major drug transporters in BI 1015550 disposition 
is minimal based on in vitro data.
Section to be changed
3.3.3
Description of change
Exclusion 17 updated with respect to abstinence 
requirements.
Rationale for change
Clarification that only true abstinence is
Permitted. Periodic abstinence (e.g calendar, 
ovulation), declaration of abstinence for the
duration of exposure to IMP, and withdrawal are 

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not acceptable methods of contraception
Section to be changed
3.3.3 and table 4.2.2.1:1
Description of change
Exclusion 20 updated-  prior use of SOC is 
acceptable, but restricted if taken within 30 days 
prior to screening (V1).
Rationale for change
More in line with clinical practice. Patients are 
often tried on antifibrotic therapy for longer than 
3 months before discontinuation due to the 
severity of the disease. Time window of 30 days
is considered adequate to minimize any potential 
carried over effects of these treatments on the PK 
and safety of BI 1015550.
Section to be changed
4.1.3.1
Description of change
Table 4.1.3.1 was updated based on the most 
recent data.
Rationale for change
Expected exposure in the present trial in Table 
4.1.3.1 was updated based on the most recent data 
(1305-0011 and 1305-0020).
Section to be changed
4.2.2.1
Description of change
Clarification to medication restrictions part 2 
Table 4.2.2.1:2, footnote 7 added, additional text 
in note
Rationale for change
Clarifications of potential drug-drug interactions 
as applicable to pirfenidone SOC. 
Section to be changed
5.2.3
Description of change
Clarification that stool sample collection 3 days 
prior to first dose is collected as v2 (day (-1) 
sample. No sample is required at randomization 
(day 1). 
Rationale for change
Correction
Section to be changed
5.2.3 Table 5.2.3:1
Description of change
Glutamate dehydrogenase (GLDH) removed as a 
required parameter to be measured. 
Rationale for change
Based on current liver safety profile collected, 
additional collection of this parameter was 
removed as it is not considered necessary for 
monitoring of potential liver injury.
Section to be changed
5.5.1.2, 5.5.2.1, 5.5.3.1 and 7.3.2

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Description of change
Update to include name of metabolite. 
Rationale for change
The name of metabolite to be measured was 
added based on the recent data.
Section to be changed
5.2.4.1
Description of change
Clarification on timing and evaluation of triple 
ECGs. 
Rationale for change
Clarification 
Section to be changed
9.2 References
Description of change
Updated reference c02094779-02 to    
c02094779-03. 
Added missing references R05-0788 and R09-
4830. 
Rationale for change
Reference (Investigator brochure) has been 
updated since final protocol. 
Section to be changed
-2.2
-2.3.2
-2.3.3
-4.1.3
-5.2.5.1
-5.5.3.1
-6.2.2
-Appendix 10.1
Description of change
-BI1015550 typo corrected
-typo- know corrected to  known
- ‘one’ corrected to ‘on’ and duplicate word 
‘patient’ removed
-typo in half-life corrected (16-29 hours) was 
incorrectly listed as (2016 -29)
-reference to ear removed as oral temperature is 
required
 
-removed duplicate wording ‘or relocate to a 
nearby facility overnight’
-deleted typo ‘o’
Rationale for change
Correction of typos

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Number of global amendment
2.0
Date of CTP revision
06 Dec 2018
EudraCT number
2017-002736-16
BI Trial number
1305-0012
BI Investigational Product(s)
BI 1015550
Title of protocol
Safety, tolerability, and pharmacokinetics of 
multiple rising oral doses of BI 1015550 in 
patients with idiopathic pulmonary fibrosis (IPF) 
on no background anti-fibrotic (Part 1) and safety 
and tolerability of BI 1015550 on top of 
Nintedanib and Pirfenidone (Part 2)
To be implemented only after 
approval of the IRB / IEC / 
Competent Authorities
To be implemented 
immediately in order to 
eliminate hazard –
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval
Can be implemented without 
IRB / IEC / Competent 
Authority approval as changes 
involve logistical or 
administrative aspects only
Section to be changed
Synopsis
Description of change
Main criteria for inclusion. Part 1 SOC 
requirements updated for consistency with 
changes to exclusion 20 made in global 
amendment 1. 
Rationale for change
Correction
Section to be changed
Flow chart 1A and 2A
Description of change
Weight measurement updated for consistency 
between part1 and part 2. Baseline weight 
measurement added. 
Rationale for change
Correction. 
Section to be changed
Flow chart 1A
Description of change
 

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evening dose.
Rationale for change
Clarification of meaning of “post dose” sample at 
part 1 EOT visit. As there is no dose taken on day 
84 the last dose is taken the evening of day 83.
Section to be changed
Flow chart 2A
Description of change
Footnote 16 updated to clarify, at day 28 
 
 sample to be taken ~12h post day 27 
evening dose.
Rationale for change
Clarification of meaning of “post dose” sample at 
part 2  EOT visit. As there is no dose taken on 
day 28, the last dose is taken the evening of day 
27.
Section to be changed
3.3 Exclusion Criteria
Description of change
Exclusion 22 “positive testing for fecal 
calprotectin’ has been removed. 
Rationale for change
Calprotectin is a stable protein released by white 
blood cells during inflammation. Fecal 
Calprotectin (FC) constitutes an unspecific 
biomarker of gastrointestinal inflammation.
A considerable variability among measurements 
in the same fecal sample or different samples 
from stools of consecutive days of the same 
patient is possible [R16-1924].  FC is established 
in general practice to only help clinicians 
differentiate between Irritable Bowel Syndrome 
(IBS) and Inflammatory Bowel Disease (IBD) in 
the presence of suspicious symptoms, or in the 
ongoing monitoring of established IBD. It is not 
established for any other purpose.
Experience in the first IPF cohort of this study 
shows unexpectedly high baseline values (average 
above 50 mcg/g) together with a very high intra-
patient variability also without drug treatment 
(with changes of up to 10 fold), independent of 
any GI symptoms or changes in other laboratory 
parameters.
FC is increased with increase age, concomitant 
diseases such as GERD, colonic polyps, diabetes, 
and concomitant medications such as NSAIDs 
and PPIs. The high frequency of such 

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concomitant diseases and medications in IPF and 
in the elderly population highly contribute to FC 
fluctuations. As FC has not been systematically 
evaluated in IPF, an influence of the underlying 
disease cannot be excluded.  
Overall, given the high variability in the measure 
in this population within and between patients,
also independent of study medication and 
multiple underlying reasons for increase, the 
utility of FC cut off values for inclusion in the 
current study is not appropriate.  
Consequently, FC will no longer be considered an 
exclusion criterion in this trial.  FC will continue 
to be measured at the specified time points in the 
trial, to allow an exploratory analysis.
Investigator judgment on the overall clinical 
picture will continue to apply during the study.
Section to be changed
5.2.5.3
Description of change
Information added to standardize weight 
measurements
Rationale for change
To ensure consistency and minimize variability in 
weight due to time of day or clothing. 
Section to be changed
9.2 References
Description of change
Gisbert 2009 reference added [R16-1924]
Rationale for change
New reference. 

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Number of global amendment
3.0
Date of CTP revision
12 Feb 2019
EudraCT number
2017-002736-16
BI Trial number
1305-0012
BI Investigational Product(s)
BI 1015550
Title of protocol
Safety, tolerability, and pharmacokinetics of 
multiple rising oral doses of BI 1015550 in 
patients with idiopathic pulmonary fibrosis (IPF) 
on no background anti-fibrotic therapy.
To be implemented only after 
approval of the IRB / IEC / 
Competent Authorities
To be implemented 
immediately in order to 
eliminate hazard –
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval
Can be implemented without 
IRB / IEC / Competent 
Authority approval as changes 
involve logistical or 
administrative aspects only
Section to be changed
Cover page, Synopsis
Description of change
Title, lay title
Rationale for change 
Updated to reflect removal of part 2 (on top of 
standard of care)
Section to be changed
Cover page, Section 3.1.1, 3.3.5, 
Description of change
Trial clinical monitor updated to Clinical trial 
leader
Rationale for change 
For consistency with updated Boehringer 
Ingelheim trial team titles.  
Section to be changed
Synopsis, Flow chart (2a, b, c), Section 2, Section 
3 (including figure 3.1:1 and 3.1:2), Section 4, 
Section 5, Section 6, Section 7
Description of change
All references to part 2 – BI 1015550 on top of 
SOC have been removed. Terminology stating 
Part 1 has removed as no longer required. 
Rationale for change 
Part 2 ‘BI 1015550 on top of standard of care’ is 
no longer planned to be conducted within this 
phase 1C trial. A short treatment duration of 4 

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weeks is not adequate to support efficacy or 
biomarker endpoints given recent data from the 
INMARK trial (1199.227), and therefore removal 
of part 2 helps to focus the study from a logistic 
and practical point of view on safety and 
tolerability and pharmacodynamics of BI 
1015550 in a treatment naïve population.
Section to be changed
Synopsis, Section 3.3, section 7.6
Description of change
Number of patients has been updated from 36 to 
18
Rationale for change
Result of removal of part 2, only 18 treatment 
naïve patients will be recruited. 
Section to be changed
Section 1.2.4, 2.3.2, 3.1.1, 4.1.4.3, 4.2.1, section 
5, section 6.2.2
Description of change
References to nintedanib and pirfenidone or 
standard of care (SOC) (within the context of the 
removal of study part 2) have been removed. 
Rationale for change
See rationale for removal of part 2, above. 
Section to be changed
Synopsis: Duration of treatment
Description of change
Changed from 12 weeks to 4 weeks for treatment 
naïve patients.
Rationale for change
Consistency with change in treatment period. 
See rationale for change section 3.2 Discussion of 
trial design, including choice of control group
Section to be changed
Synopsis: Criteria for safety
Description of change
Primary endpoint changed from 12 weeks to on 
treatment AEs, for treatment naïve patients. 
Rationale for change
To allow primary endpoint analysis for all 
patients whether at 4 weeks for new patients or 12 
weeks for completed (treatment naïve) patients. 
Section to be changed
Synopsis: Criteria for safety
Description of change
Rationale for change
Section to be changed
Flow chart 1A: overview
Description of change
Visits 10, 11, 12 removed 
Visit 9 updated to include EOT (end of treatment) 

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procedures
“Visit 13/End of Trial” renamed to “End of Trial” 
Rationale for change
With change in treatment duration, visits after day 
28 visit 9 are no longer required. 
Section to be changed
Flow chart 1A: Footnote 13 and 15
Description of change
Requirements updated in consideration of new 
treatment duration. 
Rationale for change
Requirement for sampling for PK 
 
updated to remove samples past day 28.
Section to be changed
1.2.5.1 Clinical Safety
Description of change
Information on completed and ongoing trials has 
been updated. New references have been added. 
Rationale for change
Trial results have become available since initial 
protocol and have been updated accordingly. 
Information on additional trials in program (1305-
0015 and 1305-0017) have been added. 
Section to be changed
1.2.5.1.3 SRD and MRD Study
Description of change
Addition of weight data from study 1305.11
Rationale for change
For completion with final study report of 1305.11
Section to be changed
Tables 1.2.5.2.1:1 and 1.2.5.2.2:1
Description of change
Updated results 
Rationale for change
Consistent with final study report for 1305.11
Section to be changed
1.2.5.2.1 Single rising dose trial 
Description of change
Statement ‘data from 1305-0011 are preliminary’ 
has been removed 
Data updated based on final report. 
Rationale for change
Data are no longer preliminary as trial is 
complete. Updated values based on final report. 
Section to be changed
1.2.5.2.2 Multiple rising dose trial
Description of change
Final report pending removed and reference 
added. 
Rationale for change
Final report is now available
Section to be changed
1.2.5.2.3 Food effect trial
Description of change
Reference added. 
Rationale for change
Based on final report. 
Section to be changed
2.3 Benefit risk assessment

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Description of change
Rewording regarding target engagement in 
completed study 1305.11
Rationale for change
Consistency with final report
Section to be changed 
2.3 Benefit risk assessment 
Description of change
References to 1305-0011 are updated from 
preliminary and statement regarding TE 
biomarkers added. 
Rationale for change
Information now based on final report. 
Section to be changed 
2.3 Benefit risk assessment
Description of change
Update of treatment period from 12 to 4 weeks. 
Rationale for change
Consistency with change in treatment period. 
See rationale for change section3.2 Discussion of 
trial design, including choice of control group
Section to be changed 
3.1 Overall trial design and plan &
Figure 3.1:1 1305-0012 study design overview
Figure 3.1:2 Design and decision point
Description of change
Updated references to treatment period from 12 to 
4 weeks. 
Rationale for change
Consistency with change in treatment period. 
See rationale for change section 3.2 Discussion of 
trial design, including choice of control group
Section to be changed 
3.1.1 Administrative structure
Description of change
Updated number of trial sites to approximately 20
Rationale for change
Trial site participation has been expanded to 
include additional sites as needed to support 
recruitment. 
Section to be changed 
3.2 Discussion of trial design, including choice of 
control group
Description of change
Rationale included supporting reduction of 
treatment duration from twelve to four weeks. 
Rationale for change
Non clinical toxicology data currently supports 
studies up to 12 weeks of durations. A treatment 
duration of 4 weeks however, is sufficient to 
capture safety and tolerability of a PDE4 inhibitor 
in support of longer term studies, evaluate PK and 
explore induction potential, 
 
 in a patient population.
Disease specific biomarkers and pulmonary
function outcomes would require longer than 4 

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weeks. Recent disease specific biomarker data 
from the INMARK study (1199-0227) suggest 
that effects on disease specific exploratory 
biomarkers would require much larger sample 
size and with longer duration, to gain a robust 
evaluation of disease specific biomarkers. Four 
weeks data allows first generation of normative 
data on BI 1015550. 
Section to be changed
3.3.2 Inclusion criteria
Description of change
Inclusion 6 removed 
Rationale for change
No longer relevant with removal of study part 2 
(SOC)
Section to be changed 
4.1.1 Identity of BI investigational product and 
comparator product 
Description of change
Duration of use updated from 84 days to 28 days 
for both BI 1015550 and Placebo matching.  
Rationale for change
Consistency with change in treatment period. 
See rationale for change section 3.2 Discussion of 
trial design, including choice of control group
Section to be changed
4.1.3 Selection of doses in the trial
Description of change
Information regarding 1305-0011 trial was 
updated to final. Rewording of starting dose 
justification.
Rationale for change
Information now based on final report.
Section to be changed
4.1.4.2 Dispensing of medication 
Description of change
Table 4.1.4.2:1 Quantity of medication kits 
dispensed per visit
Rationale for change
Updated based on revised treatment duration and 
visit schedule. 
Section to be changed
4.1.4.3 Administration of dose
Description of change
Added “taken at home since last clinic visit”
Rationale for change
For clarification on when the diary should be 
filled in 
Section to be changed
5.1.1 Endpoints of Efficacy 
Description of change
12 week time point removed from all endpoints as 
per revised treatment duration. Rewording to 
“over time” rather than 4 and 12 weeks
Rationale for change
To allow PE analysis for all patients whether at 4 

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weeks for new patients or 12 weeks for completed 
patients
Section to be changed
5.2.1 Endpoints of safety
Description of change
Primary endpoint (for treatment naïve patients)
changed to “AEs on treatment” rather than 4 
weeks or 12 weeks.  
To allow PE analysis for all patients whether at 4 
weeks for new patients or 12 weeks for completed 
patients. 
Rationale for change
Consistency with change in treatment period. 
See rationale for change section 3.2 Discussion of 
trial design, including choice of control group
Section to be changed
Description of change
Rationale for change
Section to be changed
6.2.1 Screening and run in period(s)
Description of change
Addition of “Screening period may be extended 
for administrative reasons. Approval should be 
obtained from the sponsor who will also 
determine if any tests specified in the protocol 
must be repeated before the randomization visit.”
Rationale for change
To allow flexibility between screening and pre-
randomisation visit especially when escalating to 
the next dose level, hence potential time gap for 
safety review of previous cohort
Section to be changed
6.2.2 Treatment period
Description of change
Addition of “will be given a diary to record intake 
of study medication taken at home since the last 
visit”
Rationale for change
To clarify the timing of the recording of the study 
medication intake since the last visit. 
Section to be changed
6.2.2 Treatment period
Description of change
End of treatment visit:
End of treatment visit timing changed from visit 
12 (day 84)to visit 9 (day 28) for treatment naïve 

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Number of global amendment
3.0
patients. 
Explanation of requirements for EOT visit for 
prematurely discontinued patients if patients 
discontinue, changed from ‘prior to 12 weeks’ to 
‘prior to 4 weeks’. 
Rationale for change
Consistency with change in treatment period. 
See rationale for change section3.2 Discussion of 
trial design, including choice of control group
Section to be changed
9.0 References
Description of change
New references added
Rationale for change
New reference. 

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Number of global amendment
4.0
Date of CTP revision
27 MAR 2019
EudraCT number
2017-002736-16
BI Trial number
1305-0012
BI Investigational Product(s)
BI 1015550
Title of protocol
Safety, tolerability, and pharmacokinetics of 
multiple rising oral doses of BI 1015550 in 
patients with idiopathic pulmonary fibrosis (IPF) 
on no background anti-fibrotic therapy. 
To be implemented only after
approval of the IRB / IEC / 
Competent Authorities
To be implemented 
immediately in order to 
eliminate hazard –
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval
Can be implemented without 
IRB / IEC / Competent 
Authority approval as changes 
involve logistical or 
administrative aspects only
Section to be changed
Synopsis
Section 3.1
Table 3.1:1
Section 3.2
Section 7.6
Description of change
Information regarding the addition of 6 patients 
(4 active, 2 placebo) to the 18mg bid dose group, 
has been added. 
Rationale for change 
Further to the safety review, for the purpose of 
escalation, of the completed 2 weeks treatment of 
the 9 patients in the 18 mg bid cohort, whilst 
safety and tolerability were considered 
acceptable, the prediction for the 24 mg bid 
cohort regarding the AUC gMean (2290 nM*h) 
exceeded the threshold (2284 nM*h) as set in the 
protocol on the basis of the 13 weeks rat 
toxicology data. The observed PK data of the 18 
mg bid cohort showed a higher variability, 
including outliers, in IPF patients as compared to 
the HV data. It is therefore deemed appropriate to 

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BI Trial No.: 1305-0012
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extend the current 18 mg bid cohort (4 on verum 
and 2 on placebo) to further characterize, 
understand and refine PK variability at 2 weeks 
in the target IPF population. Increasing the 
number of patients may confirm the magnitude of 
the PK variability. 
After 6 additional patients, the safety review 
committee will review all 18mg bid patient data, 
in order to determine if escalation can proceed to 
the 24 mg bid cohort. This will only occur if 
the safety and tolerability are maintained as 
acceptable and if PK projections for the next dose 
are within defined limits. 
Section to be changed
Section 7.3.4 
Description of change
Third paragraph, change in wording “In contrast 
to final PK calculations, the preliminary analysis 
will be based on planned sampling times rather 
than actual times” was changed to “In contrast to 
final PK calculations, the preliminary analysis 
may be based on planned sampling times rather 
than actual times”
Rationale for change 
This modification is made to allow a decision to 
proceed with analysis using planned times or 
directly with actual times. As there may be a 
relevant discrepancy in actual sampling times and 
planned sampling times, actual times can be 
preferable in the PK analysis.

 
 
 
 
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c17703547
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clinical-trial-protocol-version-05
Safety, tolerability, and pharmacokinetics of multiple rising oral doses of BI 1015550
in patients with idiopathic pulmonary fibrosis (IPF) on no background anti-fibrotic
therapy.
Author-Clinical Trial Leader
27 Mar 2019 15:55 CET
Author-Trial Statistician
27 Mar 2019 15:58 CET
Author-Trial Clinical
Pharmacokineticist
27 Mar 2019 16:02 CET
Approval-Team Member Medicine
27 Mar 2019 16:31 CET
Approval-Therapeutic Area 
28 Mar 2019 10:16 CET
Verification-Paper Signature
Completion
28 Mar 2019 14:11 CET

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