Thorough QT Study to Evaluate the Effects of BI 1015550 as Single Doses Following Oral Administration on Cardiac Safety Parameters (Double-blind, Randomized, Placebo-controlled, Five-period Crossover, With Open-label Moxifloxacin as Positive Control) in Healthy Male and Female Subjects
Phase: PHASE1
Conditions: Healthy
Sponsor: Boehringer Ingelheim

BI-VQD-11906_40-106_AD-13 (8.0)
Clinical Trial Protocol
TITLE PAGE
Document Number:
c41839189-04
IRAS ID No.
Universal Trial No.
1008273
U1111-1295-4664
BI (QSC) Trial No.
1305-0026 (QSC301328)
BI Investigational
Medicinal Product
BI 1015550
Title
Thorough QT study to evaluate the effects of BI 1015550 as 
single doses following oral administration on cardiac safety 
parameters (double-blind, randomized, placebo-controlled, five-
period crossover, with open-label moxifloxacin as positive 
control) in healthy male and female subjects
Lay Title
A study in healthy people to test whether different doses of
BI 1015550 have potential to induce heart rhythm abnormalities
Clinical Phase
I
Clinical Trial Leader
Phone: 
Fax: 
Investigator
Phone:
Fax: 
Current Version, Date
Version 3.0, 21 MAR 2024
Original Protocol Date
01 SEP 2023
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CLINICAL TRIAL PROTOCOL SYNOPSIS
Company name
Boehringer Ingelheim
Original protocol date
01 SEP 2023
Revision date
21 MAR 2024
BI trial number
1305-0026
Title of trial
Thorough QT study to evaluate the effects of BI 1015550 as single doses following 
oral administration on cardiac safety parameters (double-blind, randomized, 
placebo-controlled, five-period crossover, with open-label moxifloxacin as positive 
control) in healthy male and female subjects
Investigator 
Trial site
Clinical phase
I
Trial rationale
This trial is intended to investigate the effects of BI 1015550 on cardiac safety 
parameters according to the guideline ICH E14 (CHMP/ICH/2/04 2005) ‘The 
clinical evaluation of QT/QTc interval prolongation and proarrhythmic potential for 
non-antiarrhythmic drugs’
Trial objective
To evaluate the effects of a single therapeutic and a single supra-therapeutic dose of 
BI 1015550 on the QT/QTc interval and other ECG parameters
Trial endpoints
Primary endpoints:
The maximum mean difference between each single dose of 
 
of BI 1015550 and placebo in QTcF changes from baseline between 20 min to 24 
hours after drug administration.
Secondary endpoint:
The maximum mean difference between moxifloxacin and placebo in QTcF 
changes from baseline between 20 min to 24 hours after drug administration. (The 
formal test for assay sensitivity will be based on the results for the pre-selected time 
points 2, 3 and 4 h post dosing.)
Trial design
Double-blind (moxifloxacin: open-label), randomized, placebo-controlled, 
crossover with five treatment periods: 
 BI 1015550, 
400 mg moxifloxacin (positive control) and 
Number of subjects 
total entered
45
on each treatment
45 (at least 10 of each sex)
Diagnosis
Not applicable

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Main inclusion criteria
Healthy male/female subjects, age of 18 to 50 years (inclusive), body mass index 
(BMI) of 18.5 to 32 kg/m2 (inclusive)
Test Product
BI 1015550,
mode of admin.
Oral with 240 mL of water after an overnight fast of at least 10 h
Reference product
Placebo tablets, 
mode of admin.
Oral with 240 mL of water after an overnight fast of at least 10 h
Auxiliary medicinal 
product
Moxifloxacin (Avelox®
 plc) film-coated tablets (400 mg)*
dose
400 mg in treatment period [M])
mode of admin.
Oral with 240 mL of water after an overnight fast of at least 10 h
* Moxifloxacin is an auxiliary medicinal product (AxMP) in this trial
Duration of treatment
One day (single dose) for each treatment period
Statistical methods
For the analysis of QTcF changes from baseline (ΔQTcF) at each time point 
between 20 min to 24 hours post drug administration, a linear mixed-effects model 
for repeated measurements will be used. The comparison between each dose of 
BI 1015550 and placebo will be performed pairwise, i.e., data not relevant for the 
comparison of interest will be excluded. The model includes the covariates ‘period 
baseline’ and ‘subject baseline’ (defined as the arithmetic mean of the respective 
period baselines), the fixed categorical effects ‘treatment’, ‘period’, and ‘time’, the 
interaction terms ‘period baseline-by-time’, ‘subject baseline-by-time’, ‘treatment-
by-time’, and ‘period-by-time’. For comparisons between BI 1015550 and placebo, 
two-sided 90% confidence intervals (CI) for the mean differences per time point 
and corresponding point estimators will be computed.
For assessment of assay sensitivity, the same model will be used to compare QTcF 
changes from baseline between moxifloxacin and placebo including all time points 
between 20 min to 24 hours post drug administration.
The relationship between the placebo-corrected QTcF changes from baseline 
(ΔΔQTcF) and corresponding plasma concentrations of R-BI 1015550 will be 
examined based on a random coefficient model. The mean placebo-corrected QTcF 
change from baseline and its 90% CI at the geometric mean of Cmax for each dose of 
BI 1015550 will be estimated.
Descriptive statistics for safety endpoints and PK parameters will be calculated.

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TABLE OF CONTENTS
TITLE PAGE ......................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS ................................................2
TABLE OF CONTENTS ...................................................................................6
ABBREVIATIONS AND DEFINITIONS..................................................... 10
1.
INTRODUCTION.................................................................................... 13
1.1
MEDICAL BACKGROUND............................................................................13
1.2
DRUG PROFILE...............................................................................................13
1.2.1
BI 1015550 .............................................................................................13
1.2.1.1
Non-clinical pharmacokinetics ................................................13
1.2.2
1.2.3
1.4
BENEFIT - RISK ASSESSMENT ...................................................................22
1.4.1
Benefits...................................................................................................22
1.4.2
Risks .......................................................................................................23
1.4.3
Discussion...............................................................................................31
2.
TRIAL OBJECTIVES AND ENDPOINTS........................................... 32
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS ......32
2.1.1
Main objectives......................................................................................32
2.1.2
Primary endpoints ................................................................................32
2.1.3
Secondary endpoint ..............................................................................32
2.2.2.3
Safety and tolerability..............................................................34
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.............. 35
3.1
OVERALL TRIAL DESIGN............................................................................35
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S).....................................................................................35
3.3
SELECTION OF TRIAL POPULATION ......................................................36
3.3.1
Main diagnosis for trial entry..............................................................37
3.3.2
Inclusion criteria...................................................................................37

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3.3.3
Exclusion criteria ..................................................................................38
3.3.4
Withdrawal of subjects from treatment or assessments ...................40
3.3.4.1
Withdrawal from trial treatment ..............................................40
3.3.4.2
Withdrawal of consent to trial participation ............................42
3.3.4.3
Discontinuation of the trial by the sponsor..............................42
3.3.5
Replacement of subjects .......................................................................42
4.
TREATMENTS........................................................................................ 44
4.1
INVESTIGATIONAL TREATMENTS ..........................................................44
4.1.1
Identity of the Investigational Medicinal Products ...........................44
4.1.2
Identity of the Auxiliary Medicinal Products.....................................44
4.1.3
Selection of doses in the trial and dose modifications........................45
4.1.4
Method of assigning subjects to treatment groups ............................45
4.1.5
Drug assignment and administration of doses for each subject .......46
4.1.6
Blinding and procedures for unblinding ............................................47
4.1.6.1
Blinding ...................................................................................47
4.1.6.2
Procedures for emergency unblinding .....................................48
4.1.7
Packaging, labelling, and re-supply ....................................................48
4.1.8
Storage conditions.................................................................................49
4.1.9
Drug accountability ..............................................................................49
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS ...............................................................................................50
4.2.1
Other treatments and emergency procedures....................................50
4.2.2
Restrictions............................................................................................50
4.2.2.1
Restrictions regarding concomitant treatment .........................50
4.2.2.2
Restrictions on diet and lifestyle..............................................50
4.2.2.3
Contraception requirements.....................................................51
4.3
TREATMENT COMPLIANCE.......................................................................51
5.
ASSESSMENTS....................................................................................... 52
5.1
ASSESSMENT OF EFFICACY.......................................................................52
5.2
ASSESSMENT OF SAFETY............................................................................52
5.2.1
Physical examination ............................................................................52
5.2.2
Vital signs...............................................................................................52
5.2.3
Safety laboratory parameters..............................................................52
5.2.4
Electrocardiogram................................................................................56
5.2.4.1
12-lead continuous (Holter) ECG recording............................56
5.2.4.2
Central 12-lead triplicate ECG extraction and evaluation.......56
5.2.4.3
Safety 12-lead single standard ECG ........................................57
5.2.5
Assessment of adverse events...............................................................58
5.2.5.1
Definitions of adverse events...................................................58

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5.2.5.1.1 Adverse event ............................................................58
5.2.5.1.2 Serious adverse event ................................................59
5.2.5.1.3 AEs considered ‘Always Serious’.............................59
5.2.5.1.4 Adverse events of special interest .............................59
5.2.5.1.5 Intensity (severity) of AEs.........................................61
5.2.5.1.6 Causal relationship of AEs ........................................61
5.2.5.2
Adverse event collection and reporting ...................................62
5.2.5.2.1 AE collection.............................................................62
5.2.5.2.2 AE reporting to the sponsor and timelines ................63
5.2.5.2.3 Pregnancy ..................................................................63
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS..................................................................................63
5.3.1
Assessment of pharmacokinetics .........................................................63
5.3.2
Methods of sample collection...............................................................64
5.3.4
Pharmacokinetic - pharmacodynamic relationship...........................65
5.4
ASSESSMENT OF BIOMARKERS................................................................65
5.5
BIOBANKING ...................................................................................................65
5.6
OTHER ASSESSMENTS .................................................................................65
5.7
APPROPRIATENESS OF MEASUREMENTS.............................................65
6.
INVESTIGATIONAL PLAN.................................................................. 66
6.1
VISIT SCHEDULE............................................................................................66
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS ................67
6.2.1
Screening period....................................................................................67
6.2.2
Treatment periods.................................................................................67
6.2.3
Follow-up period and trial completion ...............................................68
7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE......................................................................................... 69
7.1
NULL AND ALTERNATIVE HYPOTHESES ..............................................69
7.2
PLANNED ANALYSES....................................................................................69
7.2.1
General considerations.........................................................................69
7.2.1.1
Trial design ..............................................................................69
7.2.1.2
Derivation of ECG variables....................................................70
7.2.1.3
Analysis sets.............................................................................71
7.2.1.4
Pharmacokinetics.....................................................................72
7.2.2
Primary endpoint analyses...................................................................72
7.2.3
Secondary endpoint analyses ...............................................................74
7.2.5
Safety analyses.......................................................................................76

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7.2.6
Interim analyses ....................................................................................77
7.3
HANDLING OF MISSING DATA ..................................................................77
7.3.1
Safety......................................................................................................77
7.3.2
Pharmacokinetics..................................................................................77
7.4
RANDOMISATION ..........................................................................................78
7.5
DETERMINATION OF SAMPLE SIZE ........................................................78
8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY, AND 
ADMINISTRATIVE STRUCTURE...................................................... 81
8.1
TRIAL APPROVAL, SUBJECT INFORMATION, INFORMED 
CONSENT ..........................................................................................................81
8.2
DATA QUALITY ASSURANCE .....................................................................82
8.3
RECORDS..........................................................................................................82
8.3.1
Source documents .................................................................................82
8.3.2
Direct access to source data and documents.......................................83
8.3.3
Storage period of records.....................................................................83
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS .................................84
8.5
STATEMENT OF CONFIDENTIALITY AND SUBJECT PRIVACY.......84
8.5.1
Collection, storage and future use of biological samples and 
corresponding data ...............................................................................84
8.6
TRIAL MILESTONES .....................................................................................85
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL ..................................85
9.
REFERENCES......................................................................................... 87
9.1
PUBLISHED REFERENCES...........................................................................87
9.2
UNPUBLISHED REFERENCES.....................................................................89
10. APPENDICES .......................................................................................... 92
11. DESCRIPTION OF GLOBAL AMENDMENT(S).............................. 93
11.1
GLOBAL AMENDMENT 1 .............................................................................93
11.2
GLOBAL AMENDMENT 2 .............................................................................94

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ABBREVIATIONS AND DEFINITIONS
ADME
Absorption, distribution, metabolism, and excretion
AE
Adverse event
AESI
Adverse events of special interest
ALCOA
Attributable, Legible, Contemporaneous, Original, Accurate
AxMP
Auxiliary medicinal product
BI
Boehringer Ingelheim
BID
Bis in die, twice daily
BMI
Body mass index (weight divided by height squared)
BP
Blood pressure
CA
Competent authority
cAMP
Cyclic adenosine monophosphate
CDISC
Clinical Data Interchange Standards Consortium
CKD
Chronic Kidney Disease
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration
CNS
Central nervous system
COVID-19
Corona virus disease 2019
CRF
Case Report Form, paper or electronic (sometimes referred to as ‘eCRF’)
CT Leader
Clinical Trial Leader
CT Manager
Clinical Trial Manager
CTP
Clinical trial protocol
CTR
Clinical trial report
CYP
Cytochrome P450
DDI
Drug Drug Interaction

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DILI
Drug induced liver injury
ECG
Electrocardiogram
eCRF
Electronic case report form
eDC
Electronic data capture
EDTA
Ethylenediaminetetraacetic acid
EFD
Embryo-fetal development
EoS
End of Study (synonym for End of Trial)
FEED
Fertility and early embryonic development
FU
Follow-up
FVC
Forced vital capacity
GCP
Good Clinical Practice
GI
Gastro-intestinal
GLP
Good Laboratory Practice
gMean
Geometric mean
hERG
Human Ether-a-go-go Related Gene
HEK
Human embryonic kidney (cells)
HR
Heart rate
HV
Healthy Volunteer
IB
Investigator’s brochure
iCF
Intended commercial formulation
IEC
Independent Ethics Committee
ILD
Interstitial lung disease
IPD
Important protocol deviation
IPF
Idiopathic Pulmonary Fibrosis
IRB
Institutional Review Board
ISF
Investigator site file
LC-MS/MS
Liquid chromatography with tandem mass spectrometry
LOAEL
Lowest observed adverse effect Level
MDA
Methylenedioxyamphetamine
MDMA
Methylenedioxymethamphetamine
MedDRA
Medical Dictionary for Regulatory Activities
MMRM
Mixed-effects model for repeated measurements
MRD
Multiple-rising dose
MSEC
Millisecond
NOAEL
No adverse effect level
PD
Pharmacodynamic(s)
PDE4B
Phosphodiesterase 4B
PDEi
Phosphodiesterase inhibitor

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P-gp
P-glycoprotein
PK
Pharmacokinetic(s)
PKS
Pharmacokinetic set
PPF 
Progressive Pulmonary Fibrosis
PR
Pulse rate
PXR
Pregnane X receptor
QRS duration
Combination of the Q, R, and S waves
QT interval
ECG interval from the start of the QRS complex to the end of the T wave
QTc interval
QT interval corrected for heart rate, e.g. using the method of Fridericia 
(QTcF) or Bazett (QTcB)
REP
Residual effect period
SAE
Serious adverse event
StaR
Statistical randomization
SARS-CoV-2
Severe acute respiratory syndrome coronavirus 2
SCR
Screening
SmPC
Summary of Product Characteristics
SOP
Standard operating procedure
SUSAR
Suspected unexpected serious adverse reaction
t1/2
Terminal half-life of the analyte in plasma
tmax
Time from (last) dosing to the maximum measured concentration of the 
analyte in plasma
TB
Tuberculosis
tQT
Thorough QT
TS
Treated set
TSAP
Trial statistical analysis plan
UGT
Uridine diphosphoglucuronosyl transferase
UIP
Usual interstitial pneumonia
ULN
Upper limit of normal
WBC
White blood cells
WOCBP
Women of childbearing potential
WONCBP
Women of non-childbearing potential

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1.
INTRODUCTION
BI 1015550, 
 
, is being 
developed by Boehringer Ingelheim (BI) for the treatment of idiopathic pulmonary fibrosis 
(IPF) and other forms of progressive pulmonary fibrosis.
1.1
MEDICAL BACKGROUND
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 
(UIP) [P11-07084]. While IPF is considered a prototypical form of progressive pulmonary 
fibrosis, there is a group of patients with different underlying clinical interstitial lung disease 
(ILD) diagnoses who develop a phenotype similar to patients with IPF during the course of 
their disease [P17-10582, P18-04729, P19-01738, R19-0854, P20-01299], which is 
characterised by increasing extent of pulmonary fibrosis on imaging, declining lung function, 
worsening respiratory symptoms and quality of life despite disease management considered 
appropriate in clinical practice, and, ultimately, early mortality [P17-10582, P18-04729, 
P19-01738, R19-0854, P20-01299].
Nintedanib and pirfenidone are the only drugs registered for the treatment of IPF and both 
treatments are recommended in the recent ATS/ERS/JRS/ALAT Clinical Practice Guideline 
for the Treatment of Idiopathic Pulmonary Fibrosis [P15-07539]. Nintedanib is also 
registered for the treatment of adults with other chronic fibrosing ILDs with a progressive 
phenotype and Systemic Sclerosis-associated ILD. However, despite existing treatment, there 
remains a high unmet need for new treatments for IPF and other fibrosing ILDs that have 
greater efficacy and fewer side effects than existing therapies [P18-06345].
BI 1015550 is an oral preferential inhibitor of the PDE4B with broad anti-inflammatory and 
antifibrotic activities. Based on its mode of action, as well as available pre-clinical and 
clinical data, BI 1015550 is hypothesised to have complementary activity to current therapies 
in IPF and other forms of progressive pulmonary fibrosis.
1.2
DRUG PROFILE
1.2.1
BI 1015550
For a more detailed description of BI 1015550 profile, please refer to the current
Investigator’s Brochure (IB) [c02094779].
1.2.1.1
Non-clinical pharmacokinetics
The disposition of BI 1015550 in non-clinical species is characterized
, 
. The half-life of BI 
1015550 is short in rats, moderate in mice, and long in monkeys and minipigs.
Potential DDIs may occur for concomitantly administered medications that are substantially 
metabolized by 
 

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 by BI 1015550 at the 
 
 In addition, 
 
of BI 1015550, concomitant therapies that are 
 may cause 
clinically significant changes in BI 1015550 exposure.
BI 1015550 
. As such, BI 1015550 exposure could be affected by co-
administered drugs 
. One 
, has been 
identified in human plasma.

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1.2.1.4
Clinical safety and efficacy
BI 1015550 has been investigated in a total of 11 clinical studies: 10 Phase I trials (nine trials 
in healthy subjects and one in patients with IPF), and 1 proof-of-clinical principle Phase II 
trial in patients with IPF. Overall, 185 healthy volunteers and 107 patients with IPF have 
been exposed to BI 1015550. Currently, 2 Phase III trials are ongoing in patients with IPF
and PPF with a planned number of approximately 2.000 patients treated.
BI 1015550 was well tolerated in healthy volunteers following single dose administration 
 
 (136 volunteers) and multiple dose administration 
 
(49 volunteers), and in patients following multiple administrations 
 
.
Clinical safety
In healthy subjects, nine clinical studies in healthy subjects have been completed with BI 
1015550. Overall, BI 1015550, 
 
appeared to show acceptable safety and tolerability. Headache, abdominal pain, nausea and 
diarrhoea, all of mild to moderate intensity, were the most commonly reported events. 
Overall, no clear dose-dependency in the frequency and intensity of these AEs was observed. 
A trend toward weight loss in subjects treated with BI 1015550 was observed in study 
1305-0011 [c22991937] in healthy volunteers.
In the MRD trial (1305-0002), 
 experienced 
postprandial pain, constipation, lower abdominal pain, lower left quadrant abdominal pain, 
and increased CRP in blood. These events were classified as drug-related. They were of mild 
intensity, with the exception of CRP increase which was of moderate intensity and led to 
discontinuation of the subject [c02191718].
In the bioavailability and food effect study (1305-0028 [c40013550]), one subject was 
reported with an AE of bradycardia 
 
and did 
not continue to receive further treatment because of this AE.

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No severe, serious, fatal AEs, nor SUSARS have been reported in the healthy volunteer 
studies. No cardiac safety signals were observed in healthy volunteer studies.
In patients with IPF, two clinical studies have been completed with BI 1015550: a Phase Ic
MRD study in patients without background antifibrotic treatment (1305-0012 [c25085412]) 
and a proof-of-clinical principle Phase II study in patients stratified by background 
antifibrotic treatment (1305-0013 [c37065416]).
Overall, in Phase Ic and II trials in patients with IPF, BI 1015550 
 showed acceptable safety and tolerability, both in patients without or with
background antifibrotic treatment (nintedanib or pirfenidone). The most common AEs were
GI events (more specifically diarrhoea), which were reported with a higher frequency under
BI 1015550 treatment (vs. placebo) and in patients with background antifibrotic treatment.
In the Phase II trial which investigated treatment with BI 1015550 
 in
patients with IPF, diarrhoea was the most common AE leading to discontinuation of
treatment. AEs leading to discontinuation of trial treatment were only observed in the BI 
1015550 group. The frequency of SAEs in patients was numerically higher in placebo-treated 
patients, which was driven by placebo-treated patients without antifibrotic background 
treatment. Two patients with IPF treated with BI 1015550 had fatal AEs: one case of 
COVID-19 pneumonia and one case of suspected condition aggravated/suspected vasculitis; 
in both cases, risk factors were present. One AESI was reported (the fatal AE of suspected
vasculitis), and evaluation by an external, independent Data Monitoring Committee could 
neither confirm the diagnosis of vasculitis, nor a causal relationship with BI 1015550. There 
were no AESIs of hepatic injury. No relevant patterns, clusters or imbalances were observed 
for any of the other safety topics of interest, including depression, anxiety, malignancies, 
insomnia, major adverse cardiac events, or tachyarrhythmia. No clinically relevant changes in 
vital signs (including body weight) or ECG parameters (including QTc) were observed. No 
changes in the C-SSRS and no AEs of suicidal ideation or behaviour were reported during 
trial treatment.
Clinical efficacy
In the proof-of-clinical principle Phase II trial, a relevant treatment effect in favour of 
BI 1015550 
 was observed on the primary efficacy endpoint, the change from 
baseline in forced vital capacity (FVC) at 12 weeks. Treatment with BI 1015550 prevented a 
decline in FVC in patients with IPF, irrespective of background antifibrotic treatment, in 
contrast to the placebo groups in which a marked decline in FVC was observed. Thus, 
treatment with BI 1015550 
 preserved lung function in patients with IPF 
over 12 weeks.
1.2.2
Moxifloxacin
Moxifloxacin is a fourth-generation fluoroquinolone antibacterial agent. It is marketed 
worldwide for treatment of a number of infections including respiratory tract infections, 
cellulitis, anthrax, intra-abdominal infections, endocarditis, meningitis, and tuberculosis.
Moxifloxacin has been used in several QT trials in healthy volunteers as a positive control 
due to its modest QT-prolonging properties at a dose of 400 mg. Moxifloxacin was shown 
to induce a mean increase in the QTc interval of between 7.5-12.5 msec with a median tmax

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of 2 h after a single oral dose of 400 mg [R10-0867]. Because the magnitude of the QT 
prolongation is small after 400 mg, there is minimal risk of moxifloxacin-induced Torsade de 
Pointes.
The pattern of side effects of moxifloxacin is well established, with the most common 
adverse effects being headache, dizziness, nausea, vomiting, diarrhea, 
gastrointestinal/abdominal pain and aspartate transaminase (AST)/alanine transaminase 
(ALT) increase [R22-1459]. Apart from nausea and diarrhea all adverse reactions were 
observed at frequencies below 3%.
Following oral administration, moxifloxacin is rapidly and almost completely absorbed. The 
absolute bioavailability amounts to approximately 91%. Following a 400 mg oral dose, peak 
concentrations of 3.1 mg/l are reached within 0.5-4 h post administration. Moxifloxacin 
undergoes Phase II biotransformation and is excreted via renal and biliary/fecal pathways as 
unchanged drug as well as in the form of a sulpho-compound and a glucuronide. 
Moxifloxacin is eliminated from plasma with a mean terminal half-life of approximately 
12 h.
For a more detailed description of the moxifloxacin profile including the list of adverse 
reactions, please refer to the SmPC [R23-2891]
1.2.3
The REP of moxifloxacin is 4 days.
1.4
BENEFIT - RISK ASSESSMENT
1.4.1
Benefits
Participation in this clinical trial is without any (therapeutic) benefit for healthy subjects. 
Their participation, however, is of major importance for the development of a drug 

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(BI1015550) that will support the patient population in the treatment of IPF and other forms 
of progressive pulmonary fibrosis.
1.4.2
Risks
Subjects are exposed to risks of trial procedures and risks related to the exposure to the trial 
medication. An overview of trial-related risks is given in Table 1.4.2: 1.
To date, no side effects have been identified for BI 1015550. Potential side effects of 
BI 1015550 will be under continuous evaluation during clinical development. Vasculitis and 
foetal loss are considered as important potential risk based only on non-clinical findings. The 
risks shown in the table below are hypothetical in nature; these are derived from general 
safety considerations of immunomodulatory drugs and from preclinical and clinical data of 
compounds with a comparable mode of action. For adverse events reported during clinical 
trials with BI 1015550 please refer to Section 1.2.1.

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Table 1.4.2: 1
Overview of trial-related risks for this trial
Possible or known risks 
of clinical relevance 
Summary of data, rationale for 
the risk
Mitigation strategy
Investigational Medicinal Product: BI 1015550
Vasculitis

Vasculopathy is an established 
preclinical toxicity of PDE4 
inhibitors

Vasculitis has been shown in 
rats and minipigs following oral 
administration of BI 1015550 
but not in monkeys treated for 
up to 13 weeks

Vasculitis is listed as an 
important potential risk for the 
marketed PDE4- inhibitor 
apremilast

In marketed PDE4 inhibitors, 
vasculitis has not been 
identified as an adverse drug 
reaction in humans.

Close clinical monitoring for 
AEs of vasculitis

Treatment interruption in 
case of any suspected 
vasculitis adverse event. 
Weight decrease in 
underweight patients 
(BMI < 18.5 kg/m2)

For the marketed PDE4i 
apremilast and roflumilast 
weight loss in underweight 
participants is an identified 
important risk

Presumably caused by 
increased energy expenditure 
and causing predominately loss 
of body fat.

Inclusion of subjects with 
BMI > 18.5 only is routine 
inclusion criterion in Phase I

Subjects who reach a BMI 
<18.5 kg/m2, and 
subsequently experience 
unexplained and clinically 
significant weight loss 
(>10%) will be discontinued 
from trial treatment

Weight will be monitored 
throughout the study. With 2 
single dose administrations 
of BI 1015550, the risk is 
considered to be very low.

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Table 1.4.2: 1
Overview of trial-related risks for this trial (cont.)
Possible or known risks 
of clinical relevance 
Summary of data, rationale for 
the risk
Mitigation strategy
Investigational Medicinal Product: BI 1015550
Reproductive toxicity: 
foetal loss, decreased 
fertility

No teratogenicity was seen in 
preclinical studies and 
exposure with BI 1015550 via 
the semen is expected to be 
very low

In rats, male and female 
fertility was potentially 
reduced. Long-term toxicity 
studies with BI 1015550 in rat 
and monkey showed no 
microscopic evidence of 
changes in female reproductive 
organs or male 
spermatogenesis

For another PDE4 inhibitor 
with comparable preclinical 
findings (class-effect), clinical 
data showed no effect on male 
fertility and sperm in humans

Foetal loss was increased in 
female rats treated with 
BI 1015550

Women of childbearing 
potential (WOCBP) need 
to use a highly effective 
method of contraception
from the time of informed 
consent until 37 days after 
the last trial drug 
administration (i.e., REP of 
BI 1015550 of 7 days plus 
30 days). WOCBP taking 
oral contraceptives (OCs) 
also have to ensure the use 
of one barrier method 
during sexual intercourse 
with their partner, 
e.g.,condom to account for 
the risk of potentially 
reduced efficacy of the 
OCs in the event of severe 
vomiting and diarrhea

Thorough counselling 
about appropriate 
contraceptive measures

Repeated pregnancy testing

Discontinuation of trial 
treatment in case of 
pregnancy
Major Adverse 
Cardiovascular Events 
(MACE) and 
tachyarrhythmia

Important potential risk for 
marketed PDE4 inhibitor 
apremilast.

In preclinical studies with 
BI 1015550 no adverse 
cardiovascular findings detected
(focal myocardial degeneration 
or necrosis in monkeys were 
with no apparent vascular 
changes).

In clinical trials with BI 
1015550 no relevant findings 
were observed.

These risks will be 
addressed by careful safety 
monitoring and safety 
measures such as close 
clinical monitoring for AEs;
regular monitoring of vital 
signs and ECG assessments

Subjects will stay in the 
Phase I unit under close 
medical surveillance until at 
least 24 h after the drug 
administration in each 
treatment period

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Table 1.4.2: 1
Overview of trial-related risks for this trial (cont.)
Possible or known risks 
of clinical relevance 
Summary of data, rationale for 
the risk
Mitigation strategy
Investigational Medicinal Product: BI 1015550
Psychiatric disorders:
Depression and anxiety
Suicidality

For the marketed PDE4i 
depression is listed as side 
effect and they are associated 
with increased risk of 
depression with some patients 
reporting suicidal ideation and 
attempts and also reported cases 
of completed suicide.

In IPF patients treated wit
 
 
 no on treatment events 
of suicidal ideation or behaviour 
and no events of depression or 
anxiety were reported.

Prospective assessment of 
suicidal ideation and behaviour 
and depression are not required
in single-dose trials in healthy 
volunteers

The risk after 2 single dose 
administrations in Phase I 
(done on site) is considered 
low and will be addressed 
by careful close clinical 
monitoring for AEs and 
increased awareness by the 
investigator for signs and 
symptoms of depression and 
anxiety as well as for signs 
and symptoms of suicidal 
ideation and behaviour

Only healthy subjects with 
no relevant medical history 
including psychiatric 
disorders will be enrolled
Severe infections 
including, serious, 
opportunistic and 
mycobacterium 
tuberculosis infections

Inhibition of the immune 
response due to the anti-
inflammatory mode of action of 
BI 1015550 potentially 
increases the risk of severe and 
serious infections.

Serious infections were 
balanced between placebo and 
BI 1015550 in Phase II trial.

Nasopharyngitis was more 
frequently reported under 
treatment with BI 1015550 in 
Phase Ic/II but not in Phase I 
trials and the numbers were 
very small.

Screening procedures for 
infections are defined for 
this trial. Subjects with any 
relevant chronic or acute 
infections are excluded from 
the trial

Treatment of infections 
should be initiated promptly 
according to standards of 
care

Treatment interruption in 
case of severe acute 
infection until the subject 
has recovered based on the 
investigator’s medical 
judgement.

Close monitoring to detect 
potential infections 
promptly will minimise the 
risk of serious infection.

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Table 1.4.2: 1
Overview of trial-related risks for this trial (cont.)
Possible or known risks 
of clinical relevance 
Summary of data, rationale for 
the risk
Mitigation strategy
Investigational Medicinal Product: BI 1015550
Malignancies

Inhibition of the immune 
response with an 
immunomodulatory drug may 
potentially impair immune 
defences and thus, theoretically 
decrease immune defence 
against malignancies.

Subjects with a recent 
history of malignancy within 
5 years will be excluded 
from participation in this 
trial

In case of occurrence of 
malignant neoplasm other 
than appropriately treated 
basal cell carcinoma or 
squamous cell carcinoma of 
the skin or in situ carcinoma 
of uterine cervix, the 
investigator should 
discontinue trial treatment

Diagnostics and treatment 
have to be initiated 
according to local standard 
of care.

The risk after 2 single dose 
administrations in Phase I is 
considered low
Gastrointestinal disorders 
(e.g., diarrhoea, nausea, 
vomiting, abdominal 
pain)

Vomiting and diarrhoea are 
important dose-limiting side 
effects of marketed oral PDE-4 
inhibitors

In Phase II study of 
BI 1015550, diarrhoea was the 
most frequently reported AE.

Increased awareness of 
symptoms

Careful monitoring of 
hydration in subjects with 
diarrhoea recommended

Symptomatic treatment if 
required.
Drug-induced liver 
injury (DILI)

Rare but severe event, thus 
under constant surveillance by 
sponsors and regulators.

Timely detection, 
evaluation, and follow-up of 
laboratory alterations in 
selected liver laboratory 
parameters to ensure 
subjects´ safety

Increased awareness and 
expedited reporting (AESI).

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Table 1.4.2: 1
Overview of trial-related risks for this trial (cont.)
Possible or known risks 
of clinical relevance 
Summary of data, rationale for 
the risk
Mitigation strategy
Investigational medicinal product: Moxifloxacin
Common (≥1/100 to 
<1/10) adverse drug 
reactions (ADR)
- Superinfections due to 
resistant bacteria or 
fungi 
- Headache, dizziness
- QT prolongation in 
patients with 
hypokalaemia
- Nausea, vomiting, 
gastrointestinal and 
abdominal pains, 
diarrhea
- Increase in 
transaminases
Uncommon (≥1/1,000 to 
<1/100), rare (≥1/10,000 
to <1/1,000) and very 
rare (<1/10,000) ADRs
(see the SmPC [R23-
2891])

For a more detailed description 
please refer to Section 1.2.2 and 
the SmPC for Moxifloxacin 
(Avelox®) 400 mg film-coated 
tablets [R23-2891].

A thorough screening 
examination: specifically 
subjects with high liver 
enzymes, a marked baseline 
prolongation of QT/QTc 
interval, a history of 
additional risk factors for 
Torsade de Pointes will be 
excluded (see Section 3.3.3)

Only single doses of 
moxifloxacin will be given

The subjects will be closely 
monitored through 
assessment of adverse 
events, safety lab, ECG and 
vital signs in each treatment 
period

The subjects will maintain 
under close medical 
surveillance for at least 24 
hours post dosing in each 
treatment period
Effects on ability to drive 
and use machines

No studies on the effects of 
moxifloxacin on the ability to 
drive and use machines have 
been performed. However, 
fluoroquinolones including 
moxifloxacin may result in an 
impairment of the patient's 
ability to drive or operate 
machinery due to CNS reactions 
(e.g. dizziness; acute, transient 
loss of vision) or acute and 
short lasting loss of 
consciousness (syncope).

The subjects will maintain 
under close medical 
surveillance for at least 24 
hours post dosing in each 
treatment period

The subjects should be 
advised to see how they 
react to moxifloxacin before 
driving or operating 
machinery

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Table 1.4.2: 1
Overview of trial-related risks for this trial (cont.)
Possible or known risks 
of clinical relevance 
Summary of data, rationale for 
the risk
Mitigation strategy
Investigational medicinal product: Moxifloxacin
Effects on pregnancy and 
lactation

The safety of moxifloxacin in 
human pregnancy has not been 
evaluated. Animal studies have 
shown reproductive toxicity 
The potential risk for humans is 
unknown.

There is no data available in 
lactating or nursing women. 
Preclinical data indicate that 
small amounts of moxifloxacin 
are secreted in milk.

Moxifloxacin must not be 
used in pregnant or lactating 
women, they will be 
excluded (see Section 3.3.3)

Women of childbearing 
potential need to use a 
highly effective method of 
contraception.

Thorough counselling of 
women of childbearing 
potential about appropriate 
contraceptive measures

Repeated pregnancy testing

Discontinuation of trial 
treatment in case of 
pregnancy
Trial procedures
Bruising and, in rare 
cases, phlebitis, or nerve 
injury, potentially 
resulting in paraesthesia, 
reduced sensibility, 
and/or pain 
General risk by venipuncture for 
blood sampling, acceptable in the 
framework of trial participation.
Medical expertise of the trial 
site 
Local skin irritation and 
discomfort
General risk from ECG stickers,
acceptable in the framework of 
trial participation.
Medical expertise of the trial 
site
The total volume of blood withdrawn per subject during the entire trial will not exceed the 
volume of a normal blood donation (approximately 500 mL). No health-related risk to 
healthy subjects is expected from withdrawal of this volume of blood.

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Considerations on COVID-19:
Generally, in healthy volunteers' population, the risk of severe COVID-19 infection is not 
higher, and study participation would not increase the risk of becoming infected with SARS-
CoV-2 beyond the potential risk associated with any need for the study participant to leave 
their home for study related activities. The appropriate risk minimisation measures will be 
taken in accordance with the public health precautions if needed due to the current status of 
the pandemic/endemic.
Based on the pharmacological mechanism and existing non-clinical and clinical data, there is
no indication that treatment with BI 1015550 may increase the risk of infection including
SARS-CoV-2 infection. Even though an increased risk of SARS-CoV-2 infection -or of a 
more severe COVID-19 disease in case of such an infection appears unlikely, subjects with 
active or recent (i.e. within the 4 weeks prior to screening) SARS CoV-2 infection should not 
be included in the trial which is also applicable for any other relevant acute infection 
(exclusion criterion No. 9).
In case of severe COVID-19 infection during the conduct of the trial, treatment with
BI 1015550 has to be interrupted which is also applicable for any other relevant acute 
infection (criterion of withdrawal from trial treatment No. 9). The appropriate diagnostic and 
treatment measures will be taken in accordance with the public health precautions.
Of note, depending on the current status of the COVID-19 pandemic/endemic, all subjects 
with confirmed SARS CoV-2 infection will be handled in accordance with local guidance 
and SOPs meaning that any confirmed SARS CoV-2 infection during the conduct of the trial
will lead to withdrawal of the subject from further trial treatment and/or trial procedures to 
avoid undue risks to other subjects at the trial site and the site personnel. The appropriate 
diagnostic and treatment measures will be taken in accordance with the public health 
precautions. If feasible, the EoS examination to be performed as early as possible after the 
SARS CoV-2 infection is resolved.
COVID-19 testing may be performed based on current infection rates, status of the 
pandemic/endemic and availability of tests. If required, testing will comprise an antigen test 
performed on screening and within 72 h prior to admission to the clinical unit. Testing time 
points may be changed and additional time points may be added throughout the study as 
required. The decision on COVID-19 testing and the definition of the testing time points are 
subject to change based on the current risk mitigation in place and will be agreed by the study 
team and documented in the Investigator Site File (ISF) via the Clinical Kick-Off Meeting 
minutes or in a file note if the study is ongoing.
The risk mitigation measures, where applicable, will be amended based on emerging 
government guidance.

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1.4.3
Discussion
The nature of the target and the mechanism of action of BI 1015550 is well understood. 
BI 1015550 
 
In summary, BI 1015550 has a favorable benefit-risk-assessment based on a thorough pre-
clinical data package as well as knowledge gained from previous clinical trials using 
BI 1015550, which justifies further investigation in humans. 

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2.
TRIAL OBJECTIVES AND ENDPOINTS
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS
2.1.1
Main objectives
The main objective of this trial is to investigate the effect of BI 1015550 on the QT/QTc 
interval as measured by the QTcF changes from baseline compared with placebo in healthy 
male and female volunteers following oral administration. The QT effect will be assessed 
that provides exposures exceeding the high clinical exposure scenario accounting 
for potential exposure increase due to intrinsic and extrinsic factors (see Section 4.1.3).
The secondary objective is to show the assay sensitivity of the trial, by reproducing the 
typical effect of the positive control moxifloxacin on the QT/QTc interval.
The assessment of safety and tolerability of BI 1015550 particularly with regard to cardiac 
safety are additional objectives of this trial.
2.1.2
Primary endpoints
The maximum mean difference between 
 
in QTcF changes from baseline between 20 min to 24 hours after 
drug administration.
2.1.3
Secondary endpoint
The maximum mean difference between moxifloxacin and placebo in QTcF changes from 
baseline between 20 min to 24 hours after drug administration. (The formal test for assay 
sensitivity will be based on the results for the pre-selected time points 2, 3, and 4 hours post 
dosing.)

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2.2.2.3
Safety and tolerability
Safety and tolerability of BI 1015550 will be assessed based on:  

Adverse events (including clinically relevant findings from the physical examination)

Safety laboratory tests (only abnormal findings will be reported as AEs)

12-lead single safety ECGs or triplicate ECGs derived from Holter ECG recordings

Vital signs (blood pressure (BP), pulse rate (PR)), body weight

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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN
The trial will be performed as a randomized, placebo controlled, double-blind, five-period, 
four treatment crossover trial with two placebo periods and moxifloxacin (open-label) as 
positive control in healthy male and female subjects. The replicate design with respect to 
placebo allows for estimating the treatment contrasts of each active drug to placebo more 
precisely than with only one single placebo period, thus enabling a reduced sample size 
(see [R12-0517] and Section 7.5).
The treatments will be:

Treatment 3 ([M] – moxifloxacin): 
400 mg moxifloxacin (1 tablet) in the fasting state, single dose
For details, refer to Section 4.1.
The subjects will be randomly allocated to one of the 15 treatment sequences (3 subjects per 
sequence) planned in this trial (see Section 7.2.1). There will be a 
between the treatments.
An overview of all relevant trial activities is provided in the Flow Chart. For visit schedule 
and details of trial procedures at selected visits, refer to Sections 6.1 and 6.2, respectively.
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)
According to the guideline ICH E14 (CHMP/ICH/2/04 2005) ‘The clinical evaluation of 
QT/QTc interval prolongation and proarrhythmic potential for non-antiarrhythmic drugs’ 
(2005) [R07-4722] and the respective ‘Questions and Answers Document’ (2017) 
[R17-2903] concerning the evaluation of QT/QTc-interval prolongation, a randomized trial 
with concurrent placebo control and a positive control will be conducted in order to 
investigate the effect of a drug (BI 1015550) on QT/QTc-interval in healthy volunteers.
As positive control, the subjects will receive a single dose of moxifloxacin 400 mg, which is 
known to induce moderate QT/QTc-prolongation (see Section 1.2.2) and will therefore verify 
the ability of the trial to detect relevant changes in the QT/QTc-interval. Moxifloxacin is an 
auxiliary medicinal product (AxMP) in this trial and marketed in the UK/EU. It is to be used 

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in the clinical trial within the terms of the marketing authorization, other than being 
administered to healthy volunteers.
For thorough QT trials, the crossover design is preferred due to its efficiency: since each 
subject serves as his/her own control, the comparison between treatments is based on a 
comparison within subjects rather than between subjects. This trial design therefore removes 
inter-subject variability from the comparison between treatments [R94-1529]. Moreover, with 
proper randomization of subjects to the different sequences of treatment administrations, it 
provides the best unbiased estimates for the differences between treatments. Additionally, the 
total number of subjects needed to participate in this trial is minimized compared to a parallel 
group design trial. Since all assessments in tQT trials are based on the comparisons between 
active treatment and placebo, these treatment contrasts should be estimated with the highest 
statistical efficiency. To account for this, the selected crossover design for this trial will 
include a second placebo period instead of only one. The sample size for the resulting 
4-treatment 5-period crossover design can be determined as 3/4 of the sample size of the 
corresponding 4-period crossover design (see also Section 7.5).
Blinding with regard to the study drug substances to be investigated versus their matching 
placebos is essential in such a trial. ECG profiles will be performed for BI 1015550 and 
placebo in a double-blind fashion. The positive control (moxifloxacin) will be administered 
open-label. This is not expected to bias results, since moxifloxacin is known to robustly 
induce a mean increase in the QTc interval of between 7.5 - 12.5 msec with a median tmax of 
2 hours after a single oral dose of 400 mg [R10-0867]. The technicians and cardiologists at 
the ECG laboratory performing the ECG interval measurements and assessments will remain 
blinded in this trial with regard to all treatments, including moxifloxacin and placebo (see 
Section 4.1.5).
BI 764333, major human metabolite of BI 1015550, have been evaluated in nonclinical 
studies, and pharmacological contribution of this metabolite is considered to be low. Also, 
BI 764333 was evaluated in a cardiovascular safety pharmacology study in minipigs under 
GLP 
 with no effects observed. Thus, 
is not 
considered for analyses of the current clinical trial.
3.3
SELECTION OF TRIAL POPULATION
It is planned that 45 healthy male and female subjects (at least 10 of each sex) will enter the 
trial. They will be recruited from the volunteers' pool of the trial site. 
A log of all subjects enrolled into the trial (i.e., who have signed informed consent) will be 
maintained in the investigator site file (ISF), irrespective of whether they have been treated 
with investigational drug or not.
must have a full medical history from each subject’s general practitioner 
(GP) within the last 24 months, prior to enrolment in the study. Before subjects are admitted 
to the clinical unit, The Over Volunteering Prevention System (TOPS) will be checked to 
ensure that each subject has not participated in a study at another site within at least 90 days 
of the dosing date.

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3.3.1
Main diagnosis for trial entry
The trial will be performed in healthy subjects.
Please refer to Section 8.3.1 (Source Documents) for the documentation requirements 
pertaining to the in- and exclusion criteria.
3.3.2
Inclusion criteria
Subjects will only be included in the trial if they meet the following criteria:
1.
Healthy male or female subjects according to the assessment of the investigator, as 
based on a complete medical history including a physical examination, vital signs 
(BP, PR), 12-lead ECG, and clinical laboratory tests without any clinically significant 
abnormalities
2.
Age of 18 to 50 years (inclusive)
3.
BMI of 18.5 to 32 kg/m2 (inclusive)
4.
Signed and dated written informed consent in accordance with ICH-GCP and local 
legislation prior to admission to the trial
5.
Either male subjects, or female subjects meet the following criteria requiring highly 
effective contraception from at least 30 days before the first administration of trial 
medication until 37 days after the last administration of the study drug:
- Male participants must use condom plus their partner, if identified as a WOCBP, 
must use an oral contraceptive or highly effective contraception as defined below
- Female participants must be using highly effective contraception and in addition 
their male partner must use a condom if they are using an oral contraceptive (as per 
Table 1.4.2: 1)
Highly effective methods of contraception include:
- Use of combined (estrogen and progestogen containing) hormonal contraception that 
prevents ovulation (intravaginal or transdermal)
- Use of progestogen-only hormonal contraception that inhibits ovulation (only 
injectables or implants)
- Use of intrauterine device (IUD) or intrauterine hormone-releasing system (IUS)
- Sexually abstinent is considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk associated
with the study treatments. The reliability of sexual abstinence needs to be evaluated
in relation to the duration of the clinical trial and the preferred and usual lifestyle of 
the subject.
- Vasectomy in males, or a vasectomised sexual partner of females who received 
medical assessment of the surgical success (documented absence of sperm) and 
provided that partner is the sole sexual partner of the trial participant
- Bilateral tubal occlusion

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Women of non-childbearing potential (WONCBP) include:
- Permanently surgically sterilised (including hysterectomy, bilateral oophorectomy
and bilateral salpingectomy)
- Postmenopausal, defined as no menses for 1 year without an alternative medical 
cause (in questionable cases a blood sample with levels of FSH above 40 U/L is
confirmatory)
WONCBP are not required to use any methods of contraception.
Female subjects should not participate in egg donation and male subjects should not 
participate in sperm donation from the first study drug administration, for the duration 
of the study and for at least 37 days after the last study drug administration.
3.3.3
Exclusion criteria
Subjects will not be allowed to participate, if any of the following general criteria apply:
1.
Any finding in the medical examination (including BP, HR or ECG) deviating from 
normal and assessed as clinically relevant by the investigator
2.
Repeated measurement of systolic blood pressure outside the range of 90 to 140 
mmHg, diastolic blood pressure outside the range of 50 to 90 mmHg, or heart rate 
outside the range of 50 to 90 bpm
3.
Any laboratory value outside the reference range that the investigator considers to be 
of clinical relevance, in particular, hepatic parameters (ALT, AST, total bilirubin) or 
renal parameters (creatinine) exceeding the ULN
4.
Any evidence of a concomitant disease assessed as clinically relevant by the 
investigator
5.
Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological 
or hormonal disorders assessed as clinically relevant by the investigator
6.
Cholecystectomy or other surgery of the gastrointestinal tract that could interfere with 
the pharmacokinetics of the trial medication (except appendectomy or simple hernia 
repair)
7.
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 depression and suicidal behaviour
8.
History of clinically relevant orthostatic hypotension, fainting spells, or blackouts
9.
Relevant chronic or acute infections within the 4 weeks prior to screening
10. Any documented active or suspected malignancy or history of malignancy within 5 
years prior to screening, except appropriately treated basal cell carcinoma of the skin
or squamous cell carcinoma in situ of the skin or in situ carcinoma of uterine cervix
11. History of relevant allergy or hypersensitivity (including allergy to the trial 
medications or its excipients and quinolones, except non-active hay fever) 

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12. Use of drugs within 30 days (or 5 half-lives, whichever is longer) of planned
administration of trial medication that might reasonably influence the results of the 
trial (including drugs that cause QT/QTc interval prolongation)
13. Intake of an investigational drug in another clinical trial within 90 days of planned 
administration of investigational drug in the current trial or less than 5 elimination 
half-lives (whichever is longer), or concurrent participation in another clinical trial in 
which investigational drug is administered
14. Smoker including electronic cigarettes and shisha, as well as user of nicotine 
replacing products (e.g. nicotine chewing gum and patches)
15. A confirmed breath carbon monoxide test of greater than 10 ppm at screening or 
admission at Period 1
16. Alcohol abuse (consumption of more than 14 units per week for females and 21 units 
per week for males [1 unit = ½ pint beer, or a 25 mL shot of 40% spirit, 1.5 to 2 units 
= 125 mL glass of wine, depending on type]) or a positive alcohol breath test at 
screening or admission at Period 1
17. Drug abuse within the past 2 years or positive drug screening
18. Donation of blood or plasma or loss of greater than 400 mL of blood within the 
previous 3 months or intended blood or plasma donation during the trial
19. Intention to perform excessive physical activities within one week prior to the 
administration of trial medication or during the trial
20. Inability to comply with the dietary regimen of the trial site
21. A marked prolongation of QT/QTc interval (such as QTcF intervals that are 
repeatedly greater than 450 msec) or any other relevant ECG finding (such as QRS 
greater than 120 msec, PR interval less than 120 msec or greater than 210 msec) at 
screening
22. A history of additional risk factors for Torsade de Pointes (such as heart failure, 
hypokalaemia, or family history of Long QT Syndrome)
23. Presence of electrolyte disturbances, particularly in uncorrected hypokalaemia (i.e. 
potassium below the LLN)
24. Previous history of symptomatic arrhythmias
25. Subject is assessed as unsuitable for inclusion by the investigator, for instance,
because the subject is not considered able to understand and comply with study 
requirements, or has a condition that would not allow safe participation in the study 
26. For female subjects: Lactation, pregnancy, or plans to become pregnant during the 
trial or within 37 days after trial completion
27. For female subjects: Positive pregnancy test
28. Subjects with any condition that would preclude administration of moxifloxacin (i.e., 
contraindicated as per SmPC), such as but not limited to history of tendon 
disease/damage as a result of quinolone therapy, clinically relevant bradycardia, 

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clinically relevant heart failure with reduced left ventricular ejection fraction or a 
history of serious adverse reactions in the past when using quinolone or 
fluoroquinolone containing products
29. Concomitant intake
 
30. History or signs of vasculitis
31. Relevant immunodeficiency
32. History of residential exposure to tuberculosis, or a positive QuantiFERON® test 
within 4 weeks prior to or at the time of screening
33. Positive hepatitis B surface antigen (HBsAg), hepatitis C virus antibody (HCV Ab) or 
human immunodeficiency virus (HIV) 1 and 2 antibody results at screening
34. Subjects with 
at screening
35. Subjects who do not have suitable veins for multiple venepunctures/cannulation as 
assessed by the investigator or delegate at screening
36. Subjects who are, or are immediate family members of, a study site or sponsor 
employee
The following exclusion criteria will be re-assessed on admission for Period 1: 1, 2, 3, 8, 9, 
12, 15, 16, 18, 19, 20, 21, 23, 27, 28 and 29.
For restrictions of the trial, refer to Section 4.2.2.
3.3.4
Withdrawal of subjects from treatment or assessments
Subjects may withdraw or may be removed from trial treatment or may withdraw consent to 
trial participation as a whole (‘withdrawal of consent’) with very different implications; 
please see Sections 3.3.4.1 and 3.3.4.2 below.
If a subject is removed from or withdraws from the trial prior to the first administration of 
trial medication, the data of this subject will not be entered in the case report form (CRF) and 
will not be reported in the clinical trial report (CTR).
If a subject is removed from or withdraws from the trial after the first administration of trial 
medication, this will be documented and the reason for discontinuation must be recorded in 
the CRF; in addition, trial data will be included in the CRF and will be reported in the CTR. 
Following removal or withdrawal, a complete end-of-trial examination should be performed.
If the discontinuation or withdrawal occurs before the end of the REP (see Section 1.2.3, the 
discontinued subject should, if possible, be questioned for AEs and concomitant therapies at 
or after the end of the REP, in order to ensure collection of AEs and concomitant therapies 
throughout the REP, if not contrary to any consent withdrawal of the subject.
3.3.4.1
Withdrawal from trial treatment
An individual subject will be withdrawn from trial treatment if:

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1. The subject wants to withdraw from trial treatment. The subject will be asked to explain 
the reasons but has the right to refuse to answer
2. The subject has repeatedly shown to be non-compliant with important trial procedures 
and, in the opinion of both, the investigator and sponsor representative, the safety of the 
subject cannot be guaranteed as he / she is not willing or able to adhere to the trial 
requirements in the future
3. The subject needs to take concomitant medication that interferes with the investigational 
medicinal product or other trial treatment
4. The subject can no longer receive trial treatment for medical reasons (such as pregnancy, 
surgery, adverse events (AEs), or diseases), in particular, if an AE of severe intensity or a 
serious adverse event (SAE) occurs
5. The subject has an elevation of AST and/or ALT ≥3-fold ULN or an elevation of total 
bilirubin ≥2-fold ULN (measured in the same blood sample) and/or needs to be followed 
up according to the DILI checklist provided in the ISF
6. The subject has relevant individual QT prolongations, i.e. a QTcF increase of greater than 
60 ms from baseline and/or with absolute QT or QTcF greater than 500 ms, as confirmed 
by a repeat ECG recording
7. Subjects that experience an unexplained and clinically significant (>10%) weight loss 
during trial treatment
8. If any of the following AEs is reported, the treatment has to be discontinued: 
-
Severe or serious infections, opportunistic or mycobacterium tuberculosis infections
-
Malignancies 
-
Vasculitis
Of note, depending on the current status of the COVID-19 pandemic/endemic, all subjects 
with confirmed SARS CoV-2 infection will be handled in accordance with local guidance 
and SOPs meaning that any confirmed SARS CoV-2 infection during the conduct of the trial
will lead to discontinuation of the subject (refer to Section 1.4.2).
In addition to these criteria, the investigator may discontinue subjects at any time based on 
his or her clinical judgment.
If it is known that a subject becomes pregnant during the trial, administration of the trial 
medication is to be stopped immediately, and the subject is to be removed from the trial. The 
subject is to be followed until she has given birth or until the end of the pregnancy. The 
subject’s data are to be collected until the end of the trial (last visit of last subject) and 
reported in the CTR. For reporting of pregnancy and associated events, refer to Section 
5.2.5.2.3.
If new efficacy or safety information becomes available, Boehringer Ingelheim will review 
the benefit-risk-assessment and, if needed, pause or discontinue the trial treatment for all 
subjects or take any other appropriate action to guarantee the safety of the trial subjects.

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3.3.4.2
Withdrawal of consent to trial participation
Subjects may withdraw their consent to trial participation at any time without the need to 
justify the decision. If a subject wants to withdraw consent, the investigator should be 
involved in the discussion with the subject and explain the difference between trial treatment 
discontinuation and withdrawal of consent to trial participation, as well as explain the options 
for continued follow-up after trial treatment discontinuation, please see Section 3.3.4.1 above.
3.3.4.3
Discontinuation of the trial by the sponsor
Boehringer Ingelheim reserves the right to discontinue the trial at any time for any of the 
following reasons (if reasons 4 and/or 5 are met, the trial should be discontinued 
immediately):
1. Failure to meet expected enrolment goals overall or at the trial site
2. The sponsor decides to discontinue the further development of the investigational product
3. Deviation from GCP, or the CTP, or the contract with BI impairing the appropriate 
conduct of the trial
4. New toxicological findings, serious adverse events, or any safety information invalidating
the earlier positive benefit-risk-assessment (see Section 3.3.4.1). More specifically, the 
trial will be halted, and the risk to other subjects evaluated if:
- a serious adverse reaction (i.e. a SAE considered at least possibly related to the IMP 
administration) occurs in one subject;
or 
- severe non-serious adverse reactions (i.e. severe non-serious AE considered as, at 
least possibly related to the IMP administration) occur in two subjects, independent of 
within or not within the same system organ class. 
Relatedness will be determined by the investigator.
5. More than 50% of the subjects show drug-related and clinically relevant adverse events of 
moderate or severe intensity 
If the trial is halted, a temporary halt will be submitted to the Medicines and Healthcare 
products Regulatory Agency (MHRA) and ethics committee (EC) in the form of a substantial 
amendment. The trial may be resumed or terminated; however, it will not be resumed until a 
further substantial amendment to resume the study is submitted and approved by MHRA and 
EC.
The investigator / trial site will be reimbursed for reasonable expenses incurred in case of 
trial termination (except if item 3 applies).
3.3.5
Replacement of subjects
In case some subjects do not complete the trial (including subjects non-evaluable for PK, see 
section 7.2.1.4), additional subjects may be enrolled and treated, i.e. “replaced” if considered 

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necessary to reach the objective of the trial (see Section 7.5). The Clinical Trial Leader
together with the Trial Pharmacokineticist and the Trial Statistician are to decide, if and how 
many subjects will be replaced. A maximum of 7 subjects will be replaced. Thus, the total 
number of subjects entered and dosed in this trial will not exceed 52. A replacement subject 
will be assigned a unique trial subject number and will be assigned to the same treatment
sequence as the subject he or she replaces.
In case of replacement of subjects, the trial site should ensure that the requirements for 
distribution of sex (‘at least 10 of each sex) are still met within the overall group of further on 
treated and additionally entered subjects.

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4.
TREATMENTS
4.1
INVESTIGATIONAL TREATMENTS
4.1.1
Identity of the Investigational Medicinal Products
The characteristics of the test product are given below:
The characteristics of the reference product are given below:
Substance:
Placebo
4.1.2
Identity of the Auxiliary Medicinal Products
Name:
Avelox®
Substance:
Moxifloxacin
Pharmaceutical formulation: Film-coated tablet
Source:
Unit strength:
400 mg

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Posology:
Treatment 3 [M]: 1 x 400 mg tablet
Mode of administration:
Oral
Duration of use:
Single dose in Treatment 3 [M]
4.1.3
Selection of doses in the trial and dose modifications
Currently,
 doses are being evaluated in the Phase III trials. The dose of 
) was selected in order to achieve the anticipated clinical 
therapeutic exposure at steady state following oral administration of 
  
(the highest therapeutic dose being evaluated in the Phase III trials). Following 
 
 
 (1305.2, 1305-0011, 1305-0012, see Section 1.2.1.3). Therefore 
.
The dose of 
 was selected in order to measure the effect of a tolerable supra-therapeutic 
dose of BI 1015550 on cardiac safety (see Section 1.2.1.4). The selected supra-therapeutic 
dose of 
 is based on the highest dose of BI 1015550 being tested in clinical trials to 
date, the therapeutic doses being evaluated in the phase 3 trials (
) and the
potential increase in BI 1015550 concentration due to intrinsic and extrinsic factors. This 
dose of 
 is estimated to provide 
 compared with the clinical steady 
state exposure at 
 of 
BI 1015550), while the worst case intrinsic/extrinsic factors, namely DDI interaction with a 
(see 
Section 1.2.1.4).
The dose of 400 mg of moxifloxacin (single oral dose) was selected as it demonstrated to 
induce a mean increase in the QTc interval of between 7.5-12.5 msec (median tmax of 2 h) and 
was already used in several QT trials in healthy volunteers as a positive control due to its 
modest QT-prolonging properties [R10-0867]. Because the magnitude of the QT prolongation
is small after a single dose of 400 mg, the risk of moxifloxacin-induced Torsade de Pointes is 
considered minimal.
4.1.4
Method of assigning subjects to treatment groups
According to the planned sample size, at least 5 cohorts are planned. Prior to the start of the 
trial, subjects willing to participate will be recruited to cohorts according to their temporal 
availability. In the morning of Day 1 (Visit 2), each subject will be allocated to 1 of the 
15 treatment sequences prior to the first administration of trial medication. For this purpose, 
numbers of the randomization scheme will be allocated to the subjects by drawing lots. 
Subjects are then assigned to a treatment sequence according to the randomization scheme.
Once a subject number has been assigned, it cannot be reassigned to any other subject.
All subjects in one cohort may be treated on the same calendar day as close as 3 min apart
(minimum). Actual dosing stagger will be dependent on logistics as required by the site. For 
discussion of trial-associated risks and safety measures, see Section 1.4.

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The randomization procedure is described in Section 7.4.
4.1.5
Drug assignment and administration of doses for each subject
This is a 5-way crossover trial. All subjects will receive the 4 treatments (including 2 placebo 
periods in the placebo treatment) in randomised order. The treatments to be evaluated are 
summarised in Table 4.1.5: 1 below. 
Table 4.1.5: 1
Dosage and treatment schedule
Treatment
Substance
Formulation
Unit 
strength
Dosage
Total dose
Treatment 3 [M] Moxifloxacin Tablet
400 mg
1 x 400 mg tablet, single dose
400 mg
N/A
In Treatment 1 
 
 of BI 1015550 will be administered as 
 
. In addition, placebo tablets (
 will be administered 
concomitantly to BI 1015550 in order to mask the treatment to other trial treatments and 
maintain double-blind conditions in the trial.
In Treatment 3 [M], administration of moxifloxacin will be handled open label. 
Administration of trial medication will be performed after subjects have fasted overnight; 
fasting is to start no later than 10 h before the scheduled dosing. In each treatment period, 
subjects will be provided with a light snack and then fast from all food and drink (except 
water) for a minimum of 10 h on the day prior to dosing until approximately 6 h post-dose at 
which time lunch will be provided. A voluntary snack will be suggested at 8 h post-dose. An 
evening meal will be provided at approximately 12 h post-dose. On subsequent days, meals 
will be provided at appropriate times.
The investigator (or authorised designee) will administer the trial medication as an oral dose 
together with about 240 mL of water to subjects who are in a sitting or standing position. For 
drug administration, the so-called four-eye principle (two-person rule) should be applied. For 
this, one authorised employee of the trial site should witness the administration of trial 
medication, and – if applicable – its preparation (e.g. dispensing), if correct dosage cannot be 
ensured otherwise.
Subjects will be kept under close medical surveillance until at least 24 h after drug 
administration (exact requirements for medical supervision to be outlined in the study 

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specific Risk Management Plan authored by the study PI). During the first 2 h after drug 
administration, subjects 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 examinations, single ECG 
recordings, and triplicate ECG extraction time points and preceding resting time. For 
restrictions with regard to diet see Section 4.2.2.2.
The treatments will be separated by a wash-out phase 
.
4.1.6
Blinding and procedures for unblinding
4.1.6.1
Blinding
The table below summarizes the masking/ blinding level of individual functions, roles and 
responsibilities involved in the trial. In addition, further details on blinding, roles and 
responsibilities in relation to blinding and how the blind will be maintained will be detailed 
within the study specific site Blinding Plan.
Table 4.1.6.1: 1
Blinding level of individual functions
Role/function
Timing of unblinding/ receiving access to the treatment information 
(including rationale)
Subject/Participant
This trial is blinded to the subject/ participant. The subject/ participant’s 
treatment information will be provided to the site after the trial has been
completed.
Investigator/Site Staff
The subject/ participant’s treatment information will be provided to the 
site after the trial has been completed except for the moxifloxacin 
treatment which will be known to the trial site. This will be 
implemented as follows: Prior to trial initiation, a member of StaR 
(Statistical randomization) will generate a list indicating the 
moxifloxacin treatment period for each subject in the form of e.g. X-X-
M-X-X or M-X-X-X-X based on the randomization scheme. This list 
will be provided to the clinical site to enable trial set up.
Sponsor trial team 
and database
Once the data has been declared ready for unblinding.
Bioanalytical Staff
As requested for analysis of bioanalytical samples. Prior to unblinding 
of the treatment information, the randomization codes will be provided 
to bioanalytical staff to allow them to exclude from the bioanalytical 
analyses PK samples taken from placebo-treated subjects. Bioanalytical 
staff will not disclose the randomization code or the results of their 
measurements until the trial is officially unblinded.
Pharmacokineticist/
Pharmacometrician
Once the data has been declared ready for unblinding.

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Table 4.1.6.1: 1
Blinding level of individual functions (cont)
Role/function (cont)
Timing of unblinding / receiving access to the treatment information 
(including rationale)
ECG laboratory
Within the central ECG laboratory, the staff involved with interval 
measurements will be blinded with respect to subject, treatment, 
recording date and time as well as planned time points of ECGs. The 
staff involved with the morphological analyses will be blinded with 
respect to treatment. For the quality control of the measurements, certain 
members of the ECG evaluation team will review the entire portfolio of 
ECG measurements for each subject blinded to recording date and time 
as well as the planned time point.
During the time a role/ function is blinded according to the table above, the randomisation 
schemes and medication kit lists (i.e., the treatment information) are kept restricted by the 
global Randomization Team within StaR per Sponsor SOP.
The evaluation of the effect of BI 1015550 on the QT/QTc interval and other ECG 
parameters as compared to placebo (Treatments 1, 2, and 4) will be handled in a double-blind 
fashion.
The evaluation of the effect of moxifloxacin (Treatment 3) on the QT/QTc interval and other 
ECG parameters will be handled in an open fashion throughout the trial.
PK samples will be labelled in such a way that treatment allocation cannot be derived by the 
analytical site.
4.1.6.2
Procedures for emergency unblinding
For this blinded trial, the investigator will be supplied with a set of sealed envelopes 
containing the medication codes for each subject according to the randomization scheme. The 
envelopes will be kept unopened at the trial site until the end of data collection. An envelope 
may only be opened in emergency situations when the identity of the trial drug must be 
known to the investigator in order to provide appropriate medical treatment or to assure 
safety of trial participants. If the envelope for a subject is opened, the sponsor must be 
informed immediately. The reason for opening the code break must be documented on the 
envelope or appropriate CRF page along with the date and the initials of the person who 
broke the code. At the close-out visit all envelopes are collected.
4.1.7
Packaging, labelling, and re-supply
Investigational Medicinal Products - BI 1015550 and placebo:
The investigational medicinal products BI 1015550 and placebo will be provided by BI. They
will be packaged and labelled in accordance with the principles of Good Manufacturing 
Practice (GMP).
For details of packing and the description of the label, refer to the ISF.
The telephone number of the sponsor and the name, address and telephone number of the trial 
site are provided in the subject information form. The IRAS ID and UTN numbers are

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indicated on the title page of this protocol as well as on the subject information and informed 
consent forms.
No re-supply is planned.
Auxiliary medicinal product - Moxifloxacin:
The auxiliary medicinal product moxifloxacin (Avelox®
 plc) will be sourced from a 
local pharmacy (or suitable approved supplier). A simple study specific product label will be 
applied by
 Moxifloxacin is marketed in the UK/EU and is to be used in 
the clinical trial within the terms of the marketing authorisation, other than being 
administered to healthy volunteers.
4.1.8
Storage conditions
Drug supplies will be kept in their original packaging and in a secure limited access storage 
area in accordance with the recommended (labelled) storage conditions. If 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 
Clinical Research Associate (as provided in the list of contacts) is to be contacted
immediately.
4.1.9
Drug accountability
The investigator or designee will receive the investigational drugs delivered from the sponsor
when the following requirements are fulfilled:

Approval of the clinical trial protocol by the IRB/ ethics committee

Availability of a signed and dated clinical trial contract between the sponsor or 
delegate and the investigational site

Approval/ notification of the regulatory authority, e.g., competent authority

Availability of the curriculum vitae of the Principal Investigator

Availability of a signed and dated clinical trial protocol
Only authorised personnel documented in the form 'Delegation Log' may dispense 
investigational drugs to trial subjects. Investigational drugs are not allowed to be used outside 
of this protocol.
The investigator or designee must maintain records of the product’s delivery to the trial site, 
the inventory at the site, the use by each subject, and the disposal of unused products. These 
records will include dates, quantities, batch / serial numbers, expiry ('use-by') dates, and the 
unique code numbers assigned to the investigational medicinal product and trial subjects. The 
investigator or designee will maintain records that document adequately that the subjects 
were provided the doses specified by the CTP and reconcile all investigational medicinal 
products received from the sponsor. At the time of disposal of remaining trial medication, the 
investigator or designee must verify that no remaining supplies are in the investigator’s 
possession.

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All unused medication will be disposed of locally by the trial site upon written authorisation 
of the Clinical Trial Leader. Receipt, usage and disposal of trial medication must be 
documented on the appropriate forms. Account must be given for any discrepancies.
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS
4.2.1
Other treatments and emergency procedures
There are no special emergency procedures to be followed. No additional treatment is 
planned. However, if adverse events require treatment, the investigator can authorise 
symptomatic therapy. In those cases, subjects will be treated as necessary and, if required, 
kept under supervision at the trial site or transferred to a hospital until all results of medical 
evaluations are acceptable.
Vasculitis
In case of events suspicious for vasculitis, trial treatment will be discontinued. A thorough 
work-up has to be initiated including at least but not limited to

appropriate imaging, including angiography

biopsy if possible

appropriate laboratory screening, including measurements of vasculitis markers at the 
local lab, see Section 5.2.3. In addition, an analysis of the previously collected and 
stored samples will need to be requested and considered.

thorough documentation of all reported symptoms
Referral to a vasculitis expert is recommended. If required, vasculitis treatment should be 
initiated according to standard of care.
4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
In principle, no concomitant therapy is allowed. 
No prescribed, over-the-counter medication or herbal remedies will be permitted from 
14 days before study drug administration until the EoT examination except short-term use of 
ibuprofen or paracetamol for treatment of headache, if necessary, hormone replacing therapy 
and hormonal contraception and those deemed necessary by the investigator to treat AEs. 
All concomitant or rescue therapies will be recorded (including time of intake on trial days) 
on the appropriate pages of the CRF.
4.2.2.2
Restrictions on diet and lifestyle
While admitted to the trial site, the subjects will be instructed not to consume any foods or 
drinks other than those provided by the staff. Standardised meals will be served at the times
indicated in the Flow Chart. No food is allowed for at least 6 h after drug intake.

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On Day 1 of each treatment period, from 1 h before drug intake until lunch, fluid intake is 
restricted to the water administered with the drug, and an additional 240 mL of water at 2 h 
and 4 h post-dose (mandatory for all subjects). From lunch until 24 h post-dose, total fluid 
intake is restricted to 3000 mL.
Subjects should refrain from eating food containing poppy seeds for 48 h prior to screening 
and for 48 h prior to admission until the end of in-house confinement in each treatment 
period.
.
Alcoholic beverages are not allowed from 48 h before administration of trial medication until 
the end of in-house confinement in each treatment period.
Must not donate blood or plasma (outside of this study) from screening until for at least 90 
days following last dose of study medication.
There is no evidence 
Excessive physical activity (such as competitive sport) should be avoided from 7 days before 
the first administration of trial medication until the end of trial examination.
4.2.2.3
Contraception requirements
If female subjects of child-bearing potential are included in the trial, adequate contraception 
is to be maintained throughout the course of the trial (see Section 3.3.2 for the definition of 
adequate measures).
Female subjects should not participate in egg donation and male subjects should not 
participate in sperm donation from dosing, for the duration of the study and for at least 37
days after last IMP administration.
4.3
TREATMENT COMPLIANCE
Compliance will be assured by administration of all trial medication in the trial centre under 
supervision of the investigating physician or a designee. The measured plasma concentrations 
of trial medication will provide additional confirmation of compliance.
Subjects 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.
ASSESSMENTS
5.1
ASSESSMENT OF EFFICACY
Not applicable.
5.2
ASSESSMENT OF SAFETY
5.2.1
Physical examination
At screening, the medical examination will include demographics, height and body weight, 
smoking and alcohol history (alcohol history not mandatory to be entered into CRF or to be 
reported), relevant medical history and concomitant therapy, review of inclusion and 
exclusion criteria, review of vital signs (BP, PR), 12-lead ECG, laboratory tests, and a 
physical examination. At the end of trial examination, it will include review of vital signs, 12-
lead ECG, laboratory tests, and a physical examination including determination of body 
weight.
5.2.2
Vital signs
Systolic and diastolic blood pressures (BP) as well as pulse rate (PR) or heart rate (heart rate 
is considered to be equal to pulse rate) will be measured by a blood pressure monitor (e.g. 
) at the times indicated in the Flow Chart, after subjects have rested 
for at least 5 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, body temperature 
will be monitored as part of vital signs assessment if still needed due to the current status of 
the pandemic/endemic.
5.2.3
Safety laboratory parameters
For the assessment of laboratory parameters, blood and urine samples will be collected by the 
trial site at the times indicated in the Flow Chart after the subjects have fasted for at least 
10 h. For retests, at the discretion of the investigator or designee, overnight fasting is not 
required. Blood and urine samples will be collected and processed as detailed in the Clinical 
Sample Processing Manual.
The parameters to be assessed are listed in Tables 5.2.3: 1 and 5.2.3: 2. Reference ranges will 
be provided in the ISF. 
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.

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Table 5.2.3: 1
Routine laboratory tests
Functional lab 
group
BI test name [comment/abbreviation]
A
B
C
Haematology
Haematocrit
Haemoglobin
Red Blood Cell Count/Erythrocytes 
White Blood Cells/Leucocytes 
Platelet Count/Thrombocytes (quant)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Automatic WBC 
differential, relative 
Neutrophils/Leukocytes; Eosinophils/Leukocytes; Basophils/ 
Leukocytes; Monocytes/Leukocytes; 
Lymphocytes/Leukocytes 
X
X
X
Automatic WBC 
differential, absolute 
Neutrophil, absol.; Eosinophils, absol.; Basophils, absol.; 
Monocytes, absol.; Lymphocytes, absol.
X
X
X
Manual differential 
WBC (if automatic
differential WBC is 
abnormal)
Neut. Poly (segs)/Leukocytes; Neut. Poly (segs), absol.; 
Neutrophils Bands/Leukocytes; Neutrophils Bands, absol.; 
Eosinophils/Leukocytes; Eosinophils, absol.; 
Basophils/ Leukocytes; Basophils, absol.; 
Monocytes/Leukocytes; Monocytes, absol.; 
Lymphocytes/Leukocytes; Lymphocytes, absol.
Coagulation
Activated Partial Thromboplastin Time 
Prothrombin time - Quick
Prothrombin time - INR (International Normalization Ratio)
X
X
X 
--
--
--
X
X
X
Enzymes
AST [Aspartate aminotransferase] /GOT, SGOT 
ALT [Alanine aminotransferase] /GPT, SGPT
Alkaline Phosphatase
Gamma-Glutamyl Transferase 
Creatine kinase [CK]
Creatine kinase isoenzyme MB [only if CK is elevated]
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hormones
Thyroid Stimulating Hormone 
X
--
--
Substrates
Glucose (Plasma)
Creatinine 
Bilirubin, Total 
Bilirubin, Direct
Protein, Total
C-Reactive Protein (Quant)  
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Electrolytes
Sodium
Potassium
Calcium
X
X
X
X
X
X
X
X
X
quant = quantitative; 
qual = qualitative; 
A: Parameters to be determined at Visit 1 (screening examination)
B: Parameters to be determined: in Period 1 (Visit 2) from Day -3 to -1, in Periods 2-5 (Visits 3-6) on Day 1 
prior to drug intake. In Period 1, safety laboratory test can be omitted if the screening examination is performed 
on Days -3 or -2.

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C: Parameters to be determined at Visit 7 (end of trial examination)
Table 5.2.3: 1
Routine laboratory tests (cont.)
Functional lab 
group (cont)
BI test name [comment/abbreviation]
A
B
C
Urinalysis (Stix)
Urine Nitrite (qual)
Urine Protein (qual)
Urine Glucose (qual)
Urine Ketone (qual)
Urobilinogen (qual)
Urine Bilirubin (qual)
Urine HGB (qual)
Urine leukocyte esterase (qual)
Urine pH
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urine sediment 
(microscopic 
examination if 
erythrocytes, 
leukocytes nitrite or 
protein are 
abnormal in urine)
Only positive findings will be reported (for instance, the 
presence of sediment bacteria, casts in sediment, squamous 
epithelial cells, erythrocytes, leukocytes)
quant = quantitative; 
qual = qualitative; 
A: Parameters to be determined at Visit 1 (screening examination)
B: Parameters to be determined: in Period 1 (Visit 2) from Day -3 to -1, in Periods 2-5 (Visits 3-6) on Day 1 
prior to drug intake. In Period 1, safety laboratory test can be omitted if the screening examination is performed 
on Days -3 or -2. 
C: Parameters to be determined at Visit 7 (end of trial examination)
The tests listed in Table 5.2.3: 2 are exclusionary laboratory tests that may be repeated as 
required. Except for pregnancy tests and drug screening, it is planned to perform these tests 
during screening only. Pregnancy testing in women will be performed at screening, prior to 
admission at each treatment period, and as part of the end of trial examination. Drug 
screening will be performed at screening and prior to admission at each treatment period.

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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/Ecstasy
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)
Hepatitis B DNA PCR (quantitative)1
QuantiFERON®-TB Gold Test (IGRA)2
Pregnancy test (urine)3
Beta human chorionic gonadotropin (beta-HCG)
COVID-19 (nasopharyngeal 
swab)4
SARS CoV-2 PCR test or antigen test at screening and prior to 
admission in each treatment period
1 to be conducted if Hepatitis B core antibody is positive and Hepatitis B surface antigen is negative.
2 if the first QuantiFERON®-TB Gold Test result is undetermined, a retest should be performed. If the retest is
undetermined as well, a tuberculin skin test (PPD or Mantoux) should be performed.
3 pregnancy tests in serum only at screening and EOT and in urine at each other time point as per Flow Chart
4 if needed due to the current status of the pandemic/endemic, evaluation will be performed at screening and 
shortly (within 72 h) before admission to trial site as per Flow Chart.
To encourage compliance with alcoholic and smoking restrictions, a breath alcohol test (e.g. 
or equivalent) and carbon monoxide breath test will be performed at 
screening and prior to admission at each treatment period, and may be repeated at any time 
during the trial at the discretion of an investigator or designee. The results will not be 
included in the CTR.
The laboratory tests listed in Tables 5.2.3: 1 and 5.2.3: 2 will be performed at ‘
with the 
exception of drug screening and pregnancy tests. These tests will be performed at the trial site 
using Alere Drug Screen Test Cup and SureScreen Diagnostics HCG Pregnancy Rapid Test, 
respectively, or comparable test systems. Urinalysis assessments also will be performed at the 
trial site using, e.g., 
 Urine Test Strips. If urine microscopy is required, a 
sample will be shipped to “
 for analysis.
Laboratory data will be transmitted electronically from the laboratory to the trial site.
The safety laboratory tests’ results will not be entered in the CRF. It is the responsibility of 
the Investigator to evaluate the laboratory reports. Clinically relevant abnormal findings as 
judged by the Investigator are to be reported as adverse events (please refer to Section 5.2.5). 

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In case the criteria for hepatic injury are fulfilled, a number of additional measures will be 
performed (please see Section 5.2.5.1.4). 
5.2.4
Electrocardiogram
5.2.4.1
12-lead continuous (Holter) ECG recording
To determine potential effects of BI 1015550 on cardiac safety parameters, 12-lead 
continuous 24-hour Holter ECG recordings will be used to extract 10-second triplicate ECGs 
for analysis (see Section 5.2.4.2).
The continuous ECGs will be recorded using digital Holter devices (e.g.
 
) provided by the central ECG laboratory. Specific site 
training and procedures for ECG Holter recording and data transfer will be provided by the
core lab to the Clinical Unit. Separate operational documents will be generated to detail the 
procedures and processes used for the Holter ECG data recording.
Recordings will be started within 2 h prior to drug administration and will last at least until 
24 h post drug administration in each treatment period. A lead system with modified 
Einthoven/Goldberger leads (the so-called Mason/Likar lead system) and precordial leads 
according to Wilson will be applied. Electrode placement will be performed by trained 
personnel according to established anatomical landmarks to ensure individual placement of 
electrodes will be identical throughout all 5 treatment periods.
Recordings will be started at the time points specified in the Flow Chart and will be stopped 
after the last time point in the respective period. The exact starting and end times of the 
Holter recordings as well as the medication intake will be documented and also provided to 
the core lab.
Before and at the planned time points at which resting ECGs are to be extracted from 24-hour 
Holter ECG recordings, the subjects should be kept in a relaxed and quiet environment. Thus, 
at least 10 minutes prior to the triplicate ECG extraction time points (see Flow Chart), 
subjects will take a supine position to ensure a stable heart rate at rest and high ECG quality 
during the recordings. These resting periods and ECG recordings will always precede all 
other trial procedures planned for the same time point to avoid compromising ECG quality.
To guide the extraction of the ECGs by the core lab, the trial staff will record the start and 
end times of rest periods and provide this to the core lab as well.
The Holter ECG recordings will be transmitted to a central ECG laboratory using a provided 
secure transfer program. The data will be checked by the core laboratory for any 
demographic and timing inconsistencies prior to the evaluation of the ECGs. In case of 
issues, queries will be sent to the site.
5.2.4.2
Central 12-lead triplicate ECG extraction and evaluation
At the central ECG laboratory, triplicate 10-second ECGs will be extracted in a defined time 
window during the resting periods. The evaluation of the extracted ECGs comprises the 
determination of cardiac axis (measured automatically) as well as the intervals RR, PR, QRS,
and QT, measured semi-automatically. All semi-automatic interval measurements in an 

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individual subject will be performed on the same lead. The intervals will be measured from 4 
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. Heart rate and the QT interval corrected for 
HR (QTc, e.g. QTcF) will be determined by BI (see TSAP for details).
Morphological analyses of the extracted triplicate ECGs will be performed by a board 
certified cardiologist or equivalent for one randomly selected ECG per extraction time point. 
The cardiologists’ assessments will include an overall assessment (classifications are: 
‘normal’, ‘abnormal, clinically relevant’, ‘abnormal, clinically not relevant’, ‘not evaluable’) 
as well as qualitative ECG findings with respect to e.g., rhythm, conduction and 
morphological abnormalities, presence of myocardial infarction, ST segment deviations, 
T wave morphology and presence of U-wave. Basis of the terminology used for the 
evaluation is the most current published version of CDISC controlled terms at the time of the 
final ECG transfer. Abnormalities detected during central ECG evaluation will be entered as 
AEs if assessed as clinically relevant based on the investigator’s judgement (the investigator 
takes the final decision on AE documentation after having reviewed the cardiologist 
assessment provided by the core laboratory).
For blinding arrangements see Section 4.1.5. Within the ECG laboratory, the staff involved 
with ECG interval measurements will be blinded with regard to subject, treatment, date and 
time as well as time points of the ECG measurements. The staff involved with the 
morphological analyses will be blinded with respect to treatment. No more than two blinded 
readers will evaluate all ECGs of the trial. The interval measurements for a given subject will 
be performed in random and blinded sequence by a single reader. For quality assurance and 
control of the measurements, all ECGs of an individual 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 trial.
Evaluation of extracted triplicate ECGs will comply with the ICH E14 guidance document 
and supplements [R07-4722, R17-2903] as well as the FDA requirements for annotated 
digital ECGs [R09-4830].
Where any scheduled rest times are missed or where there is less than a 10 min rest period a 
protocol deviation will be recorded and the Holter provider informed. Where there is an 
interruption(s) to the rest period, a comment will be recorded in the source (e.g. subject 
movement or loss of leads) and where possible, the time of interruption will be captured. The 
Holter provider will be informed of any interruptions during the rest period. Loss of leads or 
interruption of the recording outside of the scheduled rest times will not be considered a 
protocol deviation but should be recorded in the source.
5.2.4.3
Safety 12-lead single standard ECG
For immediate cardiac safety assessment, a single standard 12-lead ECG will be recorded at 
the times provided the Flow Chart.

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These 12-lead single ECGs (I, II, III, aVR, aVL, aVF, V1 - V6) will be recorded using a 
computerized electrocardiograph (e.g., 
or equivalent) provided by the site. 
Electrode placement for the chest leads will be performed according to the method of Wilson 
adjacent to the Holter ECG electrodes either using so- called "dual snap" or separate 
electrodes. The limb leads will be placed according to Goldberger and Einthoven.
All ECGs will be stored at the trial site. For each time point, a printout should be obtained 
and filed at the investigational site.
All locally printed ECGs will be evaluated by the investigator or a designee. These ECGs will 
not be sent to the central ECG laboratory. Abnormal findings will be reported as AEs (during 
the trial) if assessed to be clinically relevant by the investigator. Any ECG abnormalities will 
be carefully monitored and, if necessary, the subject will be removed from the trial and will 
receive the appropriate medical treatment.
Safety ECGs may be repeated for quality reasons (for instance, due to alternating current 
artifacts, muscle movements, or electrode dislocation) and the repeated ECG will be used for 
evaluation. Additional (unscheduled) ECGs may be collected by the investigator for safety 
reasons. 
5.2.5
Assessment of adverse events
5.2.5.1
Definitions of adverse events
5.2.5.1.1
Adverse event
An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a medicinal product and which does not necessarily have 
to have a causal relationship with this treatment.
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether considered related or not.
The following should also be recorded as an AE in the CRF and BI SAE form (if applicable):

Worsening of the underlying disease or of other pre-existing conditions 

Changes in vital signs, ECG, physical examination, and laboratory test results, if they 
are judged clinically relevant by the investigator

If such abnormalities already pre-exist prior to trial inclusion, they will be considered 
as baseline conditions and should be collected in the eCRF only.
Adverse event report for diarrhea events:

In case of events of diarrhoea the following definitions should be followed:

Diarrhoea is defined ≥3 loose/liquid stools per day (WHO definition) 

If <3 stools please report as “frequent bowel movements”

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5.2.5.1.2
Serious adverse event
A serious adverse event (SAE) is defined as any AE which fulfils at least one of the 
following criteria:

Results in death 

Is life-threatening, which refers to an event in which the patient was at risk of death 
at the time of the event; it does not refer to an event that hypothetically might have 
caused death if more severe 

Requires inpatient hospitalisation, or prolongation of existing hospitalisation

Results in persistent or significant disability or incapacity 

Is a congenital anomaly/birth defect 

Is deemed serious for any other reason if it is an important medical event when based 
upon appropriate medical judgment which may jeopardise the patient and may 
require medical or surgical intervention to prevent one of the other outcomes listed in 
the above definitions. Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalisation or development of dependency or 
abuse
5.2.5.1.3
AEs considered ‘Always Serious’
In accordance with the European Medicines Agency initiative on Important Medical Events, 
Boehringer Ingelheim has set up a list of AEs, which, by their nature, can always be 
considered to be ‘serious’ even though they may not have met the criteria of an SAE as 
defined above.
The latest list of ‘Always Serious AEs’ can be found in the eDC system, an electronic data 
capture system which allows the entry of trial data at the trial site. A copy of the latest list of 
‘Always Serious AEs’ will be provided upon request. These events should always be reported 
as SAEs as described in Section 5.2.5.2.
Cancers of new histology must be classified as a serious event regardless of the time since 
discontinuation of the trial medication and must be reported as described in 5.2.5.2, 
subsections ‘AE Collection’ and ‘AE reporting to sponsor and timelines’.
5.2.5.1.4
Adverse events of special interest
The term adverse events of special interest (AESI) relates to any specific AE that has been 
identified at the project level as being of particular concern for prospective safety monitoring 
and safety assessment within this trial, e.g. the potential for AEs based on knowledge from 
other compounds in the same class. AESIs need to be reported to the sponsor’s 
Pharmacovigilance Department within the same timeframe that applies to SAEs, please see 
Section 5.2.5.2.2.
The following are considered as AESIs:

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
Potential severe DILI
A potential severe Drug Induced Liver Injury (DILI) that requires follow-up is 
defined by the following alterations of hepatic laboratory parameters: 
o
An elevation of AST (aspartate aminotransferase) and/or ALT (alanine 
aminotransferase) ≥3-fold ULN combined with an elevation of total bilirubin 
≥2-fold ULN measured in the same blood sample, or in samples drawn within 
30 days of each other, or
o
Aminotransferase (ALT, and/or AST) elevations ≥10-fold ULN
These lab findings constitute a hepatic injury alert and the subjects showing these lab 
abnormalities need to be followed up according to the ‘DILI checklist’ provided in the 
ISF. In case of clinical symptoms of hepatic injury (icterus, unexplained 
encephalopathy, unexplained coagulopathy, right upper quadrant abdominal pain, 
etc.) without lab results (ALT, AST, total bilirubin) available, the Investigator should 
make sure that these parameters are analysed, if necessary in an unscheduled blood 
test. Should the results meet the criteria of hepatic injury alert, the procedures 
described in the DILI checklist should be followed.

Vasculitis events
In this CTP, vasculitis is defined as any event term included in the MedDRA SMQ 
Vasculitis (broad). This includes clinical and pathological features related to primary 
or secondary vasculitis syndromes and involving any type, size, and location of blood 
vessels. 
The investigator should monitor for any signs and symptoms of vasculitis at all times 
and specifically as part of the AE questioning. 
In case of (suspected) events of vasculitis, further work-up and management as 
outlined in Section 4.2.1 has to be followed, including biopsy, appropriate 
imaging/angiography, laboratory measures (e.g. ESR, additional lab sample for 
immunological and further inflammation markers).

Serious infections, opportunistic or mycobacterium tuberculosis infections. 
These include Pneumocystis jirovecii, BK virus disease including polyomavirus-
associated nephropathy (PVAN), Cytomegalovirus (CMV), post-transplant 
lymphoproliferative disorder (Epstein–Barr virus [EBV]), progressive multifocal 
leucoencephalopathy, bartonellosis (disseminated only), blastomycosis, 
toxoplasmosis, coccidioidomycosis, histoplasmosis, aspergillosis (invasive only), 
candidiasis (invasive or pharyngeal), cryptococcosis, other invasive fungi 
(mucormycosis (zygomycosis, rhizopus, mucor, lichtheimia), 
Scedosporium/Pseudallescheria boydii, fusarium), legionellosis, Listeria 
monocytogenes (invasive only), tuberculosis, nocardiosis, non-tuberculous 
mycobacterium, salmonellosis (invasive only), HBV reactivation, herpes simplex 
(invasive only), herpes zoster, strongyloides (hyperinfection syndrome and 
disseminated forms only), paracoccidioides, Penicillium marneffei, Sporothrix 

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schenckii, cryptosporidium species (chronic only), microsporidiosis, leishmaniasis 
(visceral only), Trypanosoma cruzi infection (Chagas’ disease) (disseminated only), 
campylobacteriosis (invasive only), shigellosis (invasive only), vibriosis (invasive due 
to vibrio vulnificus), HCV progression [R17-2617]
5.2.5.1.5
Intensity (severity) of AEs
The intensity (severity) of the AE should be judged based on the following:
Mild:
Awareness of sign(s) or symptom(s) that is/are easily tolerated
Moderate:
Sufficient discomfort to cause interference with usual activity
Severe:
Incapacitating or causing inability to work or to perform usual activities
5.2.5.1.6
Causal relationship of AEs
Medical judgment should be used to determine whether there is a reasonable possibility of a 
causal relationship between the AE and the given trial treatment, considering all relevant 
factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge, 
confounding factors such as concomitant medication, concomitant diseases and relevant 
history. An AE for which a causal relationship to the trial treatment is at least reasonably 
possible (i.e. the relationship cannot be ruled out) is to be classified as drug-related.
Arguments that may suggest that there is a reasonable possibility of a causal relationship 
could be:

The event is consistent with the known pharmacology of the drug 

The event is known to be caused by or attributed to the drug class

A plausible time to onset of the event relative to the time of drug exposure

Evidence that the event is reproducible when the drug is re-introduced

No medically sound alternative aetiologies that could explain the event (e.g. pre-
existing or concomitant diseases, or co-medications)

The event is typically drug-related and infrequent in the general population not 
exposed to drugs (e.g. Stevens-Johnson syndrome)

An indication of dose-response (i.e. greater effect size if the dose is increased, smaller 
effect size if dose is reduced)
Arguments that may suggest that there is no reasonable possibility of a causal relationship 
could be:

No plausible time to onset of the event relative to the time of drug exposure is evident 
(e.g. pre-treatment cases, diagnosis of cancer or chronic disease within days / weeks 
of drug administration; an allergic reaction weeks after discontinuation of the drug 
concerned)

Continuation of the event despite the withdrawal of the medication, taking into 
account the pharmacological properties of the compound (e.g. after 5 half-lives). Of 
note, this criterion may not be applicable to events whose time course is prolonged 
despite removing the original trigger

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
There is an alternative explanation (e.g. situations where other drugs or underlying 
diseases appear to provide a more likely explanation for the observed event than the 
drug concerned

Disappearance of the event even though the trial drug treatment continues or remains 
unchanged
5.2.5.2
Adverse event collection and reporting
5.2.5.2.1
AE collection
Upon enrolment into a trial, the subject’s baseline condition is assessed (for instance, by 
documentation of medical history/concomitant diagnoses), and relevant changes from 
baseline are noted subsequently. 
Subjects will be required to report spontaneously any AEs. In addition, each subject will be 
regularly assessed by the medical staff throughout the clinical trial and whenever the 
investigator deems necessary. As a minimum, subjects will be questioned for AEs (and 
concomitant therapies) at the time points indicated in the Flow Chart. Assessment will be 
made using non-specific questions such as ‘How do you feel?’. Specific questions will be 
asked wherever necessary in order to more precisely describe an AE.
A carefully written record of all AEs shall be kept by the investigator in charge of the trial. 
Records of AEs shall include data on the time of onset, end time, intensity of the event, and 
any treatment or action required for the event and its outcome.
The following must be collected and documented on the appropriate CRF(s) by the 
investigator:

From signing the informed consent onwards until an individual subject’s end of trial
(the End of Study (EoS) visit): 
o
All AEs (serious and non-serious) and all AESIs 
o
The only exception to this rule are AEs (serious and non-serious) and AESIs 
in Phase I trials in healthy volunteers, when subjects discontinue from the trial 
due to screening failures prior to administration of any trial medication. In 
these cases, the subjects’ data must be collected at trial site but will not be 
entered in the CRF and will not be reported in the CTR.

After the individual subject’s end of trial: 
o
The investigator does not need to actively monitor the subject for new AEs but 
should only report any occurrence of cancer and trial treatment related SAEs
and trial treatment related AESIs of which the investigator may become aware 
of by any means of communication, e.g. phone call. Those AEs should be 
reported on the BI SAE form (see Section 5.2.5.2.2), but not on the CRF.

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5.2.5.2.2
AE reporting to the sponsor and timelines
The Investigator must report SAEs, AESIs, and non-serious AEs which are relevant for the 
reported SAE or AESI, on the BI SAE form to the sponsor’s unique entry point within 
24 hours of becoming aware of the event, the country specific reporting process will be 
provided in the ISF. The same timeline applies if follow-up information becomes available. 
On specific occasions, the Investigator could inform the sponsor upfront via telephone. This 
does not replace the requirement to complete and send the BI SAE form. 
With receipt of any further information to these events, a follow-up SAE form has to be 
provided. For follow-up information, the same rules and timeline apply as for initial 
information. All (S)AEs, including those persisting after the individual subject’s end of trial, 
must be followed up until they have resolved, have been sufficiently characterized (e.g. as 
‘chronic’ or ‘stable’), or no further information can be obtained.
5.2.5.2.3
Pregnancy
In rare cases, pregnancy might occur in a clinical trial. Once a subject 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. Reporting and consenting must be in line with local 
regulations. The ISF will contain the trial specific information and consent for the pregnant 
partner.
The outcome of the pregnancy associated with the drug exposure during pregnancy must be 
followed up and reported to the sponsor’s unique entry point on the Pregnancy Monitoring 
Form for Clinical Studies (Part B). The ISF will contain the Pregnancy Monitoring Form for 
Clinical Studies (Part A and Part B).
As pregnancy itself is not to be reported as an AE, in the absence of an accompanying SAE 
and/or AESI, only the Pregnancy Monitoring Form for Clinical Studies and not the SAE form 
is to be completed. If there is an SAE and/or AESI associated with the pregnancy, an SAE 
form must be completed in addition.
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS
5.3.1
Assessment of pharmacokinetics
For the assessment of pharmacokinetics of 
, blood samples will be collected at 
the time points indicated in the Flow Chart. The actual sampling times will be recorded and 
used for determination of pharmacokinetic parameters. 
In Treatment 3 [M], no assessment of moxifloxacin pharmacokinetics will be done, thus, 
there will be no PK blood sampling after open-label moxifloxacin administration.

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5.3.2
Methods of sample collection
 
 
. Blood will be withdrawn by means of either an indwelling venous catheter or 
by venipuncture with a metal needle. The first 0.5 mL withdrawn by an indwelling cannula
will be discarded.
 
 
 
 
 
 
 
 
 
 
At a minimum, the sample tube labels should list BI trial number, subject number, visit, and 
planned sampling time and aliquot (‘A1’ or ‘A2’).
After analysis, the plasma samples may be used for further methodological investigations 
(e.g. for stability testing or assessment of metabolites) or to address Health Authority 
questions regarding the results/methodology. 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 trial samples will be discarded after completion of the 
additional investigations but not later than 5 years after the CTR is archived.
There will no blood samples taken in the open-label Moxifloxacin treatment arm.

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5.3.4
Pharmacokinetic - pharmacodynamic relationship
The relationship between the placebo-corrected QTcF changes from baseline (ΔΔQTcF) and 
corresponding plasma concentrations of 
 will be evaluated (see Section 
7.2.4.3).
5.4
ASSESSMENT OF BIOMARKERS 
Not applicable.
5.5
BIOBANKING
Not applicable.
5.6
OTHER ASSESSMENTS
Not applicable.
5.7
APPROPRIATENESS OF MEASUREMENTS
All measurements performed during this trial are standard measurements and will be 
performed in order to monitor subjects’ safety and to determine pharmacokinetic 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 pharmacokinetic parameters and measurements outlined in Section 5.3 are 
generally used assessments of drug exposure

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6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
Exact times of measurements outside the permitted time windows will be documented. 
Time windows are permitted as follows:

The acceptable time windows for screening and the end of trial examination are provided 
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

The acceptable deviation from the scheduled time for vital signs and single safety 12-lead 
ECGs will be ±30 min on Day 1 and 2 of each treatment period except for procedures 
which are to be completed within 2 h prior to drug administration as outlined in the Flow 
Chart

The timing of ECG extractions from 24-hour Holter recordings (see Flow Chart) is of 
particular importance in this clinical trial. Thus, triplicate ECG extraction from Holter 
ECG recordings will always precede PK sampling and measurements of vital signs if 
scheduled for the same time point. The acceptable time windows for ECG extractions in 
Holter ECG recordings (see Section 5.2.4) are ±5 min up to 2 h after dosing and ±10 min 
from more than 2 h to 24 h after dosing

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 pharmacokinetic 
parameter. The acceptable deviations from the nominal blood sampling times are as 
follows:
- The pre-dose samples will be taken ≤2 h before dosing
- 0 to 1 h post-dose samples will be taken within ± 2 min of the planned post-dose 
sampling time 
- 1.5 to 12 h post-dose samples will be taken within ± 10 min of the planned post-dose 
sampling time
- 24 h post-dose samples will be taken within ± 30 min of the planned post-dose 
sampling time  

Regarding the intended exposure-response analysis, ECG extractions and actual times of 
PK sampling at a planned time point need to be time-matched and should be as close as 
technically feasible

If scheduled in the Flow Chart at the same time as a meal, blood sampling or vital signs 
assessment, the end of the ECGs extraction from Holter ECG recordings have to be 
performed first with the exception of single safety ECGs which should be printed before 
the actual ECG extractions. Furthermore, if several measurements including venipuncture 
are scheduled for the same time, venipuncture should be the last of the measurements due 

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to its inconvenience to the subject and possible influence on physiological parameters, 
including ECG time intervals

For a particular subject, the clock time of dosing should be similar in all 5 treatment
periods (90 min). In case the time switch from normal time to daylight saving time (or 
vice versa) occurs throughout the trial conduct, the actual clock times will be followed 
(and not the clock times of first dosing). 
If a subject misses an appointment, it will be rescheduled if possible. The relevance of 
measurements outside the permitted time windows will be assessed no later than at the Report 
Planning Meeting.
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
6.2.1
Screening period
After having been informed about the trial, all subjects will provide written informed consent 
in accordance with GCP and local legislation prior to enrolment in the trial.
For information regarding laboratory tests (including drug and virus screening, and 
pregnancy test in females), ECG, vital signs, and physical examination, refer to 
Sections 5.2.1 to 5.2.5.
Screening safety procedures such as safety bloods, ECGs, vital signs, smoking (carbon 
monoxide) breath tests, alcohol breath tests and urinalysis can be repeated as clinically 
indicated under the discretion of the investigator or sub-investigator if there is a concern 
regarding a subject’s safety or eligibility to participate in the trial.
This study permits the re-screening of a subject who has discontinued the study as a pre-
treatment failure (i.e. subject has not been randomized); the reason for failure must be 
temporary and expected to resolve. If re-screened, the subject must be re-consented.
6.2.2
Treatment periods
Each subject is expected to participate in 5 treatment periods (Days -1, 1, and 2 in each 
period). At least 7 days will separate drug administrations between treatment periods.
On Day -1 of each treatment period, trial participants will be admitted to the trial site and 
kept under close medical surveillance for at least 24 h following drug administration in all 
treatment periods. The subjects will then be allowed to leave the trial site after formal 
assessment and confirmation of their fitness.
For details on time points and procedures for collection of plasma samples for PK analysis, 
refer to Flow Chart and Section 5.3.2. After administration of moxifloxacin, no blood 
samples for pharmacokinetic analysis will be taken.
The safety measurements performed during the treatment period are specified in Section 5.2
of this protocol and in the Flow Chart. AEs and concomitant therapy will be assessed 
continuously from obtaining subject’s written informed consent until the end of trial 
examination.
For details on times of all other trial procedures, refer to the Flow Chart.

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Admission/pre-dose safety procedures such as safety bloods, ECGs, vital signs, urinalysis and 
drugs abuse tests can be repeated as clinically indicated under the discretion of investigator or 
sub-investigator if there is a concern regarding a subject’s safety or eligibility to participate in 
the clinical trial.
Reserve subjects for the first dose occasion, in any group, will not require admission 
procedures to be repeated, if dosing is within 2 days. If dosing is subjects who have 
completed admission procedures do not need admission procedures to be repeated if dosing is 
within 2 days and the subjects have remained resident in the clinical unit.
6.2.3
Follow-up period and trial completion
For AEs and concomitant therapies assessment, laboratory tests (including pregnancy test in 
females), recording of ECG and vital signs, as well as physical examination during the 
follow-up period, see Section 5.2.
Subjects who discontinue treatment before the end of the planned treatment period should 
undergo the end of trial (EoS) visit.
If needed in the opinion of the investigator, additional visits may be scheduled after the EoS 
visit for continued safety monitoring.
All abnormal values (including laboratory parameters) that are assessed as clinically relevant 
by the investigator will be monitored using the appropriate tests until a return to a medically 
acceptable level is achieved. (S)AEs persisting after a subject’s EoS visit must be followed 
until they have resolved, have been sufficiently characterized, or no further information can 
be obtained.

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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
7.1
NULL AND ALTERNATIVE HYPOTHESES
The primary objective of this clinical trial will be assessed by testing the null hypothesis for 
each single dose of 
of BI 1015550 that the maximum mean difference 
between BI 1015550 and placebo in QTcF changes from baseline between 20 min to 24 hours 
is greater than or equal to 10 msec, against the alternative hypothesis that the maximum mean 
difference is below the threshold of 10 msec.
The conclusion that this tQT trial is negative as per ICH E14 will be based on the rejection of 
this null hypothesis for each of the two doses of BI 1015550. The one-sided tests will be 
performed at the 5% level, which is equivalent to the estimation of two-sided 90% confidence 
intervals because of the symmetry of the normal distribution. The trial will then be deemed as 
negative if the upper limit of the two-sided 90% confidence bound for the maximum mean 
difference between BI 1015550 and placebo in QTcF changes from baseline is less than 
10 msec, for both doses of BI 1015550.
For the assessment of assay sensitivity of the trial, the null hypothesis that the mean 
difference in the QTcF changes from baseline between moxifloxacin and placebo is less than 
or equal to 5 msec for all of the time points 2, 3, and 4 hours after dosing will be tested at the 
5 % level, against the alternative hypothesis that the mean difference is above the threshold of 
5 msec for at least one of the three time points. The Hochberg correction will be used for 
adjusting for multiplicity (see Section 7.2.3). 
7.2
PLANNED ANALYSES
7.2.1
General considerations
7.2.1.1
Trial design
The trial will be performed as a randomized, double-blind, 5-period crossover of single dose 
treatments including BI 1015550
, as well as open-label moxifloxacin. The 
placebo will be given twice in two separate periods. This choice of BI 1015550 doses allow 
subjects to reach BI 1015550 exposure levels at and above the anticipated daily exposure of 
BI 1015550 in the target population. The replicate design with respect to placebo allows for 
estimating the treatment contrasts of each active drug to placebo more precisely than with 
only a single placebo period, thus enabling a reduced sample size (see [R12-0517] and 
Section 7.5).
There will be 15 treatment sequences based on a Prescott triple Latin square design for 
5 treatments and 5 periods, which is a balanced, efficient design [R14-5088]. Fifteen 
sequences will be formed according to the following scheme:

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Table 7.2.1.1: 1
Prescott triple Latin square crossover design for 5 treatments and 5 
periods
Sequence
Treatment Period
1
2
3
4
5
1
2
3
4
5
A
B
C
D
E
B
C
D
E
A
D
E
A
B
C
E
A
B
C
D
C
D
E
A
B
6
7
8
9
10
A
B
C
D
E
C
D
E
A
B
E
A
B
C
D
D
E
A
B
C
B
C
D
E
A
11
12
13
14
15
A
B
C
D
E
E
A
B
C
D
D
E
A
B
C
B
C
D
E
A
C
D
E
A
B
The allocation of the codes (A, B, C, D, E) to the 4 treatments 
 
(see Section 3.1) will be done prior to the randomization in a way that the knowledge of the 
open-label treatment M does not unblind the other 3 treatments.
7.2.1.2
Derivation of ECG variables

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In the second step, for obtaining one ECG variable value per subject per time point, the 
calculated values of the three 10-second ECGs (triplicate ECGs extracted from the Holter 
recordings) will be averaged. 
Since it is not expected that the mean of the placebo-corrected HR change from baseline will 
be larger than 10 beats/min (bpm) for both doses of BI 1015550, QTcF will be selected as the 
heart rate correction method for the present trial.  
Throughout the trial protocol, the term ‘baseline’ (if not specified further) refers to the 3 pre-
dose triplicate ECG measurements at Visits 2-6 (i.e., a separate baseline for each period will 
be derived from the 9 ECG recordings that comprise 4 cardiac cycles each). 
7.2.1.3
Analysis sets
Statistical analyses will be based on the following analysis sets:

Treated set (TS): The treated set includes all subjects who were treated with at least 
one dose of trial drug. 

ECG set (ECGS): This subject set includes all subjects in the TS who have at least one 
on-treatment value for at least one ECG endpoint, which is not excluded due to ECG 
relevant iPDs. Such iPDs may be e.g., the use of pro-arrhythmic medications. 
Exclusion of single ECG values due to relevant iPDs is to be decided no later than in 
the Report Planning Meeting before data base lock and will be documented in the CTR

Pharmacokinetic parameter analysis set (PKS): This set includes all subjects in the 
treated set (TS) who provide at least one PK endpoint that was defined as a further 
endpoint and was not excluded due to a protocol deviation relevant to the evaluation of 
PK or due to PK non-evaluability (as specified in the following subsection 
‘Pharmacokinetics’). Thus, a subject will be included in the PKS, even if he/she 
contributes only one PK parameter value for one period to the statistical assessment. 

ECG pharmacokinetic concentration set (ECGPCS): This subject set includes all 
subjects from the ECGS who provide at least one pair of a valid 
plasma 
concentration and a corresponding (i.e., time-matched) ECG endpoint to be used in the 
exposure-response analysis. The decision whether the time differences at each PTM 
between the respective ECG recording and PK blood sampling are acceptable (and 
thus whether the pairs of values will be used) is to be made no later than at the Report 
Planning Meeting before data base lock. For subjects treated with BI 1015550, the 
decision about concentration value validity needs to be made within the Clinical 
Pharmacology Group
The ECGS will be used for all analyses of the centrally assessed ECG data, except for the 
exposure-response analyses, which will be performed on the ECGPCS. The TS will be used 
for all other safety summaries and all safety listings. Descriptive analyses and model-based 
analyses of PK parameters will be based on the PKS. 
Descriptions of additional analysis sets may be provided in the TSAP.

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Adherence to the protocol will be assessed by the trial team. Important protocol deviation 
(IPD) categories will be suggested in the IPD specification file. IPDs will be identified no 
later than in the Report Planning Meeting, and the IPD categories will be updated as needed.
7.2.1.4
Pharmacokinetics
The pharmacokinetic parameters listed in Section 2.1 and 2.2.2 for drug BI 1015550 will be 
calculated according to the relevant BI internal procedures. 
Plasma concentration data and parameters of a subject will be included in the statistical 
pharmacokinetic (PK) analyses if they are not flagged for exclusion due to a protocol 
deviation relevant to the evaluation of PK (to be decided no later than in the 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.
Important protocol deviations 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). A predose concentration is >5% Cmax value of that subject

Missing samples/concentration data at important phases of PK disposition curve
Plasma concentration data and parameters of a subject which are flagged for exclusion will be 
reported with its individual values but will not be included in the statistical analyses. 
Descriptive and inferential statistics of PK parameters will be based on the PKS.
Only concentration values within the validated concentration range and actual sampling times 
will be used for the calculation of pharmacokinetic parameters. Concentrations used in the 
pharmacokinetic 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). 
7.2.2
Primary endpoint analyses
Primary analyses
For the analysis of the QTcF changes from baseline at each time point between 20 min to 
24 hours after dosing, a linear mixed-effects model for repeated measurements (MMRM) will 
be used. 
The comparison between each dose of BI 1015550 and placebo will be performed pairwise, 
i.e., data not relevant for the comparison of interest will be excluded. Data from both placebo 
periods per subject will be included simultaneously in the analysis, using the same treatment 

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code ‘placebo’ but differentiated by the respective period numbers. This means that the 
model defined below can directly be used for estimating the treatment contrast between the 
active drug under consideration and placebo, using the observations from both placebo 
periods. In the following, the ‘subject baseline’ is defined as the arithmetic mean of the 
period baselines per subject (only from the periods involved in the comparison, i.e., the 
period baseline of the active treatment period and those of the 2 placebo periods).
The MMRM is based on Schall and Ring [R10-5353] and includes the fixed categorical 
effects of ‘treatment’, ‘period’ and ‘time’, the ‘treatment-by-time’ interaction and ‘period-by-
time’ interactions, as well as the continuous fixed covariates ‘period baseline’ and ‘subject 
baseline’, and the ‘period baseline-by-time’ interaction and ‘subject baseline-by-time’ 
interaction. Subject is included as a random effect on the intercept. For the repeated effect 
‘time’, an unstructured covariance pattern is chosen, using the blocking factor ‘subject-by-
period’. Note that the ‘subject baseline’ is included in the model to avoid cross-level bias 
affecting treatment comparisons; see Kenward and Roger [R10-4391].
More precisely, the model is given by
() =  + !" + !#"$ + % + & + ' + !" + !
#"$ + (%')
+ (&') + ( + ),
(~,(0, -.
/), (), … , )1) ~,1 (2, 3),
where i=1,...,I indicates the subject, k=1,…,4 the time point within period, m=1,…,M the 
period and j=1,2 the treatment,
()
the QTcF change from period baseline for subject i receiving treatment j in 
period m at repeated measures time point k,

the overall intercept, 
"
the baseline value for subject i in period m (period baseline),
!
the associated covariate effect of period baseline,
"$
the subject baseline value (mean of 3 period baselines) for subject i,
!#
the associated covariate effect of subject baseline,
%
the effect of period m,
&
the effect of treatment j,
'
the effect of time k,
!
the interaction effect of period baseline and time,
!
#
the interaction effect of subject baseline and time,
(%')
the interaction effect of period and time,
(&')
the interaction effect of treatment and time,

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(
the random effect of subject i on intercept, assumed mutually independent 
across subject,
)
the random error associated with subject i for time k and period m, assumed 
independent across period and subject (indices m, i), and
Ψ
an unstructured K-by-K covariance matrix.
The random subject effects ( and the random errors ) are assumed to be independent of 
one another.
The primary analyses use the MMRM described above for the QTcF data from BI 1015550
and placebo treatments, based on the ECG set. 
For the pairwise comparisons between each dose of BI 1015550 and placebo, mean treatment 
differences in the QTcF changes from baseline at each time point will be estimated by the 
differences in the corresponding least-squares means. Two-sided 90% confidence intervals 
based on the t-distribution will also be computed for each time point. 
Further exploratory analyses
For assessing the robustness of the MMRM defined above, a reduced model without the 
‘period-by-time’ and the ‘subject baseline-by-time’ interactions will be fitted.
Subgroup analyses with respect to sex will be performed as supportive, non-confirmatory 
analyses.
In addition to the model based approach the QTcF changes from baseline will be analyzed 
descriptively.
Further analyses will be described in the TSAP, if applicable.
7.2.3
Secondary endpoint analyses
Assessment of assay sensitivity 
The effect of moxifloxacin on the QTcF changes from baseline in comparison with placebo 
will be assessed using the same MMRM as applied in the primary analysis. 
For this analysis, only the data from the moxifloxacin and placebo periods will be used.
For describing the time course of the effect of moxifloxacin on QTcF, 90% confidence 
intervals for the mean differences of the QTcF changes from baseline between moxifloxacin 
and placebo will be provided. 
For the formal test of assay sensitivity at level α=5%, the method by Hochberg [R97-1003] 
will be applied. To this end, the three single hypotheses that the mean difference in the QTcF 
change from baseline between moxifloxacin and placebo is less than or equal to 5 msec at a 
given time point (out of the three time points 2, 3, and 4 hours after drug administration) will 
be tested based on the results of the MMRM (fitted to the data for all time points). If the 
largest of the three p-values is less than 5% (=α), then all single hypotheses can be rejected. If 

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the second largest p-value is less than 2.5% (=α/2), then the corresponding null hypothesis 
and the one regarding the test with the lowest p-value can be rejected. If the lowest p-value is 
less than 1.667% (=α/3), then only the null hypothesis corresponding to this p-value can be 
rejected. Note that it is sufficient to reject only one of the three single null hypotheses in 
order to reject the overall null hypothesis stated in Section 7.1 (i.e., the intersection of the 
three single hypotheses), and hence to show assay sensitivity.
Further exploratory analyses
For assessing the robustness of the MMRM defined above, a reduced model without the 
‘period-by-time’ and the ‘subject baseline-by-time’ interactions will be fitted.

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7.2.5
Safety analyses 
Safety will be analyzed based on the assessments described in Section 2.2.2.3. 2.2.2.3. All 
treated subjects (TS, refer to Section 7.2) will be included in the safety analysis. Safety 
analyses will be descriptive in nature and based on BI standards. No hypothesis testing is 
planned.
For all analyses, the treatment actually administered (= treatment at onset) to the subject will 
be used (any deviations from the randomized treatment will be discussed in the minutes of 
the Report Planning Meeting).
Treatments will be compared in a descriptive way. Tabulations of frequencies/ proportions 
will be used to evaluate categorical (qualitative) data, and tabulations of descriptive statistics 
will be used to analyses continuous (quantitative) data.

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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 time of the measurement or 
on the recorded time of AE onset (concept of treatment emergent AEs). Therefore, 
measurements performed or AEs recorded prior to first intake of trial medication will be 
assigned to the screening period, those between first trial medication intake and end of REP 
(see Section 1.2.3) will be assigned to the treatment period, i.e., all adverse events with an 
onset between start of treatment and end of the REP, 
days after the last dose of 
trial medication (in treatment periods with BI drug or placebo) or a period of 4 days after the 
last dose of trial medication (in moxifloxacin treatment period), will be assigned to the on-
treatment period for evaluation. Events occurring after the REP but prior to next intake or end 
of trial termination date will be assigned to ’follow-up’. In case of two or more treatments, 
the follow-up will be summarized according to the previous treatment. These assignments 
including the corresponding time intervals will be defined in detail in the TSAP. Note that 
AEs occurring after the last per protocol contact but entered before unblinding the trial will 
be reported to Pharmacovigilance only and will not be captured in the trial database.
Additionally, further treatment intervals (analyzing treatments) may be defined in the TSAP 
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 follow-up 
intervals).
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). Frequency, severity, and causal relationship of AEs will be tabulated by 
treatment, system organ class, and preferred term. SAEs, AESIs (see Section 5.2.5.1), and 
other significant AEs (according to ICH E3) will be listed separately. 
Previous and concomitant therapies will be presented per treatment group without 
consideration of time intervals and treatment periods.
Vital signs or other safety-relevant data will be assessed with regard to possible on-treatment 
changes from baseline.
Relevant ECG findings or findings in safety laboratory data will be reported as AEs.
7.2.6
Interim analyses
No interim analysis is planned.
7.3
HANDLING OF MISSING DATA
7.3.1
Safety
It is not planned to impute missing values for safety parameters.
7.3.2
Pharmacokinetics
Handling of missing PK data will be performed according to the relevant BI internal 
procedures. 
PK parameters that cannot be reasonably calculated based on the available drug 
concentration-time data will not be imputed.

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7.4
RANDOMISATION
Subjects will be randomized to the 15 treatment sequences in a balanced ratio. The block size 
will be documented in the CTR.
The sponsor will arrange for the randomization as well as packaging and labelling of trial 
medication. The randomization scheme will be generated using a validated system that uses a 
pseudo-random number generator and a supplied seed number so that the resulting allocation 
is both reproducible and non-predictable. 
The randomization scheme will contain additional blocks to allow for subject replacement 
(refer to Section 3.3.5).
Access to the codes will be controlled and documented according to the standard procedures 
in place at BI.
7.5
DETERMINATION OF SAMPLE SIZE
The following sample size considerations are performed for the MMRM based analysis of the 
primary endpoint.
Thorough QT trials conducted at BI under similar conditions to the present trial, e.g. single-
center, crossover, including male and female subjects, with agents not showing QTc 
prolongation, revealed within-subject standard deviations for the mean difference between 
BI drug and placebo in QTc change from baseline of about 8.5 to 11.5 msec (reference trials 
1289-0038 [c30409140-01], 1245.16 [U11-1908-01], 1220.16 [U09-1853-01], 1218.32 
[U09-1067-01], 1222.8 [U08-1543-02].
Based on results of trial 1305-0011, the maximum effect of BI 1015550 on the QTc interval 
is expected within the first 4-6 hours after drug administration. This closely related to the PK 
results from previous trials in healthy volunteers, where the tmax is expected within the first 4
hours after a single administration of BI 1015550 (Section 1.2.1.3). 
In case of a QT prolonging drug effect of BI 1015550, the highest effect would be expected 
for the higher dose. Since the effects of the two doses on QTc are considered to be highly 
correlated (especially since all comparisons are done with the same comparator), the sample 
size determination will be based on the assumptions for the higher dose. Hence, in the 
following, we focus only on one single testing problem (i.e., for only one dose).
Further, since the above worst case scenarios (maximum effect over time, maximum standard 
deviation of the difference over time) will be used, the following power calculations are 
performed only for the univariate testing problem of non-inferiority at a single time point.
Since all assessments in tQT trials are based on the comparisons between active treatment 
and placebo, these treatment contrasts should be estimated with the highest statistical 
efficiency. To account for this, the selected crossover design for this trial will include a 
second placebo period instead of only one, following the arguments in [R12-0517]. The 
sample size for the resulting 4-treatment 5-period crossover design can be determined as 3/4 

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of the sample size for the corresponding 4-period crossover design (i.e., with the number of 
treatments and periods being equal); see formula (2) in [R12-0517].
Thus, in a first step the sample sizes for a crossover tQT trial with equal number of treatments 
and periods will be determined, which then lead to the sample size for the selected 5-period 
design through multiplication by 0.75 in a second step.
Using a one-sided confidence level of α = 0.05 and a power of 90%, Table 7.5: 1 displays the 
required sample sizes for showing that the mean difference between BI 1015550 and placebo 
in the QTcF change from baseline is smaller than 10 msec under various assumptions for the 
within-subject variability and expected differences between the means.
Table 7.5: 1
Sample sizes assuming a power of 90% for concluding that the mean 
difference between BI 1015550 and placebo is less than 10 msec 
LEL for difference
-999
-999
-999
-999
-999
-999
UEL for difference
10
10
10
10
10
10
Expected difference
4
4
4
5
5
5
Standard deviation of 
differences
10
11
12
10
11
12
Total N
26
32
36
36
44
52
LEL: Lower equivalence limit, UEL: Upper equivalence limit (one-sided α = 0.05)
The calculations were performed using the MTE1co routine from commercial software nQuery Advisor7.0[R15-1331].
Therefore, in a standard crossover design with equal number of treatments and periods, a total 
sample size of 52 subjects will provide a power of 90% to conclude that the mean difference 
between BI 1015550 and placebo in QTcF change from baseline is smaller than 10 msec, if 
the true difference is even up to 5 msec and the standard deviation of the differences is at 
most 12 msec. Accounting for up to 8 potential drop outs, a total of 60 subjects would be 
required.
As the sample size for the 5-period crossover with 2 placebo periods can be determined as 3/4 
of the sample size of the corresponding 4-period crossover, the required sample size for this 
trial is 45 subjects. A power of roughly 90% will be achieved under the assumptions specified 
above, even if up to 6 subjects are to discontinue the trial prematurely.
Regarding the assessment of assay sensitivity, the maximum mean difference in the QTcF 
change from baseline between moxifloxacin and placebo can be expected to be around 
12 msec, with a standard deviation of up to 10 msec, based on previous BI tQT trials. If just 
one single test (for one time point out of the three; see Section 7.2.3) was performed at level 
α/3=1.667%, and taking into account the design with 2 placebo periods, the power to reject 
the corresponding null hypothesis given a sample size of 45 would be 99.7%. If the true value 
of the maximum placebo-corrected change from baseline would be only 11 msec, still the 
power for the single test would be 98.2 %. The power to reject the overall null hypothesis 
stated in Section 7.1 using the Bonferroni method would be larger than the above values in 
each scenario, since in that case all three single tests would be performed at level α/3, and 

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only one would have to be significant. The power of the Hochberg method described in 
Section 7.2.3 is again larger than that of the Bonferroni method [R97-1003].

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8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY, AND
ADMINISTRATIVE STRUCTURE
The trial will be carried out in compliance with the protocol, the ethical principles laid down 
in the Declaration of Helsinki, in accordance with the ICH Harmonized Guideline for Good 
Clinical Practice (GCP), relevant BI Standard Operating Procedures (SOPs), The Medicines 
for Human Use (Clinical Trials) Regulations SI 2004, No 1031, as amended 2006 (SI No. 
1928 and No. 2984), 2008 (SI No 941) and 2019 (SI No. 744), and other relevant regulations. 
Investigators and site staff must adhere to these principles. Deviation from the protocol, the 
principles of ICH GCP or applicable regulations will be treated as ‘protocol deviation’.
Standard medical care (prophylactic, diagnostic, and therapeutic procedures) remains the 
responsibility of the subject’s treating physician.
The investigator will inform the sponsor immediately of any urgent safety measures taken to 
protect the trial subjects against any immediate hazard, as well as of any serious breaches of 
the protocol or of ICH GCP.
The Boehringer Ingelheim transparency and publication policy can be found on the following 
web page: trials.boehringer-ingelheim.com. The rights of the investigator and of the sponsor 
with regard to publication of the results of this trial are described in the investigator contract. 
As a general rule, no trial results should be published prior to finalisation of the CTR.
The terms and conditions of the insurance coverage are made available to the investigator and 
the subjects and are stored in the ISF.
8.1
TRIAL APPROVAL, SUBJECT INFORMATION, INFORMED CONSENT
This trial will be initiated only after all required legal documentation has been reviewed and 
approved by the respective Institutional Review Board (IRB / Independent Ethics Committee 
(IEC and competent authority (CA) according to national and international regulations. The 
same applies for the implementation of changes introduced by amendments.
Prior to a subject’s participation in the trial, written informed consent must be obtained from 
each subject 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 retained by the investigator as 
part of the trial records. A signed copy of the informed consent and any additional subject 
information must be given to each subject.
The subject must be given sufficient time to consider participation in the trial. The 
investigator or delegate obtains written consent of the subject’s own free will with the 
informed consent form after confirming that the subject understands the contents. The 
investigator or 
 delegate must sign (or place a seal on) and date the informed consent form. 
If a trial collaborator has given a supplementary explanation, the trial collaborator also signs 
(or places a seal on) and dates the informed consent.
Re-consenting may become necessary when new relevant information becomes available and 
should be conducted according to the sponsor’s instructions.

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The consent and re-consenting process should be properly documented in the source 
documentation.
8.2
DATA QUALITY ASSURANCE
A risk-based approach is used for trial quality management. It is initiated by the assessment 
of critical data and processes for trial subject protection and reliability of the results as well as 
identification and assessment of associated risks. An Integrated Quality and Risk 
Management Plan or alternative plan, in line with the guidance provided by ICH Q9 and 
ICH-GCP E6, for fully outsourced trials, documents the rationale and strategies for risk 
management during trial conduct including monitoring approaches, vendor management and 
other processes focusing on areas of greatest risk. 
Continuous risk review and assessment may lead to adjustments in trial conduct, trial design 
or monitoring approaches. 
A quality assurance audit/inspection of this trial may be conducted by the sponsor, sponsor’s 
designees, or by IRB / IEC or by regulatory authorities. The quality assurance auditor will 
have access to all medical records, the investigator’s trial-related files and correspondence, 
and the informed consent documentation of this clinical trial.
8.3
RECORDS
CRFs for individual subjects will be provided by the sponsor. For drug accountability, refer 
to Section 4.1.8.
8.3.1
Source documents
In accordance with regulatory requirements, the investigator should prepare and maintain 
adequate and accurate source documents and trial records for each trial subject that include 
all observations and other data pertinent to the investigation. Source data as well as reported 
data should follow the ‘ALCOA principles’ and be attributable, legible, contemporaneous, 
original, and accurate. Changes to the data should be traceable (audit trail).
Data reported on the CRF must be consistent with the source data or the discrepancies must 
be explained.
The current medical history of the subject may not be sufficient to confirm eligibility for the 
trial and the investigator may need to request previous medical histories and evidence of any 
diagnostic tests. In this case, the investigator must make at least one documented attempt to 
retrieve previous medical records. If this fails, a verbal history from the subject, documented 
in their medical records, would be acceptable.
Before providing any copy of subjects’ source documents to the sponsor, the investigator 
must ensure that all subject identifiers (e.g., subject’s name, initials, address, phone number, 
and social security number) have properly been removed or redacted to ensure subject 
confidentiality.
If the subject is not compliant with the protocol, any corrective action (e.g. re-training) must 
be documented in the subject file.

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For the CRF, data must be derived from source documents, for example:

Subject identification: sex, year of birth (in accordance with local laws and 
regulations)

Subject participation in the trial (substance, trial number, subject number, date subject 
was informed)

Dates of subject’s visits, including dispensing of trial medication

Medical history (including trial indication and concomitant diseases, if applicable)

Medication history

AEs and outcome events (onset date [mandatory], and end date [if available])

SAEs (onset date [mandatory], and end date [if available])

Concomitant therapy (start date, changes)

Originals or copies of laboratory results and other imaging or testing results, with 
proper documented medical evaluation (in validated electronic format, if available)

ECG results (original or copies of printouts)

Completion of subject’s participation in the trial (end date; in case of premature 
discontinuation, document the reason for it, if known)

Prior to allocation of a subject to a treatment into a clinical trial, there must be 
documented evidence in the source data (e.g. medical records) that the trial participant 
meets all inclusion criteria and does not meet any exclusion criteria. The absence of 
records (either medical records, verbal documented feedback of the subject or testing 
conducted specific for a protocol) to support inclusion/exclusion criteria does not 
make the subject eligible for the clinical trial.
8.3.2
Direct access to source data and documents
The investigator/institution will allow site trial-related monitoring, audits, IRB / IEC review 
and regulatory inspections. Direct access must be provided to the CRF and all source 
documents/data, including progress notes, copies of laboratory and medical test results, which 
must be available at all times for review by the Clinical Research Associate, auditor and 
regulatory inspector (e.g. FDA). They may review all CRFs and informed consents. The 
accuracy of the data will be verified by direct comparison with the source documents 
described in Section 8.3.1. The sponsor will also monitor compliance with the protocol and 
GCP.
8.3.3
Storage period of records
Trial site:
The trial site(s) must retain the source and essential documents (including ISF) according to 
contract or the local requirements valid at the time of the end of the trial (whatever is longer).
Sponsor:
The sponsor must retain the essential documents according to the sponsor’s SOPs.

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8.4
EXPEDITED REPORTING OF ADVERSE EVENTS
BI is responsible to fulfil their legal and regulatory reporting obligation in accordance with 
regulatory requirements.
8.5
STATEMENT OF CONFIDENTIALITY AND SUBJECT PRIVACY
Data protection and data security measures are implemented for the collection, storage and 
processing of subject data in accordance with the principles 7 and 12 of the WHO GCP 
handbook.
To ensure confidentiality of records and personal data, only pseudonymised data will be 
transferred to the sponsor by using a participant identification number instead of the trial 
participant’s name. The code is only available at the site and must not be forwarded to the 
sponsor. In case participant’s records will be forwarded e.g. for SAE processing or 
adjudication committees, personal data that can identify the trial participant will be redacted 
by the site prior to forwarding.
Individual subject data obtained as a result of this trial is considered confidential and 
disclosure to third parties is prohibited with the following exceptions: 
Personalised treatment data may be given to the subject’s personal physician or to other 
appropriate medical personnel responsible for the subject’s welfare. Data generated at the site 
as a result of the trial need to be available for inspection on request by the participating 
physicians, the sponsor’s representatives, by the IRB / IEC and the regulatory authorities.
A potential data security breach will be assessed regarding the implications for rights and 
privacy of the affected person(s). Immediate actions as well as corrective and preventive 
actions will be implemented. Respective regulatory authorities, IRBs/IECs and trial 
participants will be informed as appropriate.
8.5.1
Collection, storage and future use of biological samples and corresponding 
data
Measures are in place to comply with the applicable rules for the collection, storage and 
future use of biological samples and clinical data, in particular

Sample and data usage have to be in accordance with the informed consent

The BI-internal facilities storing biological samples from clinical trial participants as 
well as the external storage facility are qualified for the storage of biological samples 
collected in clinical trials.

An appropriate sample and data management system, incl. audit trail for clinical data 
and samples to identify and destroy such samples according to ICF is in place

A fit for the purpose documentation (e.g. biomarker proposal, analysis plan and 
report) ensures compliant usage

A fit for purpose approach will be used for assay/equipment validation depending on 
the intended use of the biomarker data

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
Samples and/or data may be transferred to third parties and other countries as 
specified in the ICF
8.6
TRIAL MILESTONES
The start of the trial is defined as the date when the first subject in the whole trial signs 
informed consent.
The end of the trial is defined as the date of the last visit (or last contact) of the last subject in 
the whole trial (‘Last Subject Completed’).
Early termination of the trial is defined as the premature termination of the trial due to any 
reason before the end of the trial as specified in this protocol.
Temporary halt of the trial is defined as any unplanned interruption of the trial by the sponsor 
with the intention to resume it.
Suspension of the trial is defined as an interruption of the trial based on a Health Authority 
request.
The IEC / competent authority in each participating EU member state will be notified about 
the trial milestones according to the laws of each member state. 
A final report of the clinical trial data will be written only after all subjects have completed 
the trial in all countries (EU or non-EU), so that all data can be incorporated and considered 
in the report.
The sponsor will submit to the EU database a summary of the final trial results within one 
year from the end of a clinical trial as a whole, regardless of the country of the last subject 
(EU or non-EU).
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL
The trial is sponsored by Boehringer Ingelheim (BI).
The trial will be conducted at the contract research organisation
under the 
supervision of the Principal Investigator. Relevant documentation on the participating 
(Principal) Investigators (e.g. their curricula vitae) will be filed in the ISF. The investigators 
will have access to the BI web portal Clinergize to access documents provided by the 
sponsor.
BI has appointed a Clinical Trial Leader (CT Leader), responsible for coordinating all 
required trial activities, in order to 

Manage the trial in accordance with applicable regulations and internal SOPs

Direct the clinical trial team in the preparation, conduct, and reporting of the trial

Ensure appropriate training and information of local Clinical Trial Mangers 
(CT Managers), Clinical Research Associates (CRAs), and investigators of 
participating trial sites

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The trial medication will be provided by the Clinical Trial Supplies Unit, BI Pharma GmbH 
& Co. KG, Biberach, Germany, or will be obtained by the clinical trial site from public 
pharmacy (Moxifloxacin (Avelox®
 plc)).
Safety laboratory tests will be performed by the local laboratory of the trial site (
Analyses of BI 1015550 concentrations in plasma will be performed at
On-site monitoring will be performed by BI or a contract research organisation appointed by 
BI.
Data management and statistical evaluation will be done by BI, or a contract research
organisation appointed by BI, according to BI SOPs.
Tasks and functions assigned in order to organise, manage, and evaluate the trial are defined 
according to BI SOPs. A list of responsible persons and relevant local information can be 
found in the ISF.

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9.
REFERENCES 
9.1
PUBLISHED REFERENCES
P11-07084
Raghu G et al ATS/ERS/JRS/ALAT Committee on Idiopathic Pulmonary 
Fibrosis. An official ATS/ERS/JRS/ALAT statement: idiopathic 
pulmonary fibrosis: evidence-based guidelines for diagnosis and 
management. Am J Respir Crit Care Med; 183(6), p._788-824; 2011.
P15-07539
Raghu G, Rochwerg B, Zhang Y, et al. 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.
P17-10582
Flaherty KR, Brown KK, Wells AU, et al. Design of the PF-ILD trial: a
double-blind, randomised, placebo-controlled phase III trial of nintedanib
in patients with progressive fibrosing interstitial lung disease. BMJ Open
Respir Res 2017; 4: e000212.
P18-04729
Wells AU, Brown KK, Flaherty KR, et al. IPF Consensus Working Group.
What's in a name? That which we call IPF, by any other name would act
the same. Eur Respir J 2018; 51:1800692.
P18-06345
Sisson TH, Christensen PJ, Muraki Y, et al. Phosphodiesterase 4 inhibition
reduces lung fibrosis following targeted type II alveolar epithelial cell
injury. Physiol Rep 2018; 6(12): e13753.
P19-01738
Cottin V, Wollin L, Fischer A, et al. Fibrosing interstitial lung diseases:
knowns and unknowns. Eur Respir Rev 2019; 28:180100.
P20-01299
Wong AW, Ryerson CJ, Guler SA. Progression of fibrosing interstitial
lung disease. Respir Res 2020; 21(1):32.
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.
R08-0437
Garnett CE, Beasley N, Bhattaram VA, Jadhav PR, Madabushi R,
Stockbridge N, Tornoe CW, Wang Y, Zhu H, Gobburu JV. Concentration-
QT relationships play a key role in the evaluation of proarrhythmic risk
during regulatory review. J Clin Pharmacol. 2008;48:13-18.
R09-4830
Brown BD, Badilini F. HL7 aECG implementation guide (March 21,
2005). 2005
R10-0867
Bloomfield DM, Kost JT, Ghosh K, Hreniuk D, Hickey LA, Guitierrez
MJ, Gottesdiener K, Wagner JA. The effect of moxifloxacin on QTc and
implications for the design of thorough QT studies. Clin Pharmacol Ther.
2008;84(4):475-480.

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BI-VQD-11906_40-106_AD-13 (8.0)
R10-4391
Kenward MG, Roger JH. The use of baseline covariates in crossover
studies. Biostatistics. 2010;11(1):1-17.
R10-5353
Schall R, Ring A. Mixed models for data from thorough QT studies: part
1. Assessment of marginal QT prolongation. Pharm Stat. 2011;10(3):265-
276.
R12-0517
Ring A, Walter B, Larbalestier A, Chanter D. An efficient crossover
design for thorough QT studies. GMS Med Inform Biometr Epidemiol.
2010;6(1): Doc 05.
R12-1392
Levey AS Stevens LA Schmid CH Zhang Y Castro AF Feldman HI Kusek 
JW Eggers P Lente F van Greene T Coresh J Chronic Kidney Disease 
Epidemiology Collaboration (CKD-EPI). A new equation to estimate 
glomerular filtration rate. Ann Intern Med; 150(9), p. 604-612; 2009.
R14-5088
Jones B, Kenward MG. Design and analysis of cross-over trials.
(Monographs on Statistics and Applied Probability; 138). 3rd ed. Boca 
Raton: CRC Press; 2015.
R15-1331
Elashoff JD. nQuery Advisor version 7.0 user's guide. 
website.statsols.com/wp-
content/uploads/2013/10/nQ70_version2_manual.pdf 
(access date: 20 March 2015); Los Angeles: Statistical Solutions; 2007.
R17-2617
Winthrop KL, Novosad SA, Baddley JW, Calabrese L, Chiller T, Polgreen
P, et al. Opportunistic infections and biologic therapies in 
immunemediated inflammatory diseases: consensus recommendations for
infection reporting during clinical trials and postmarketing surveillance.
Ann Rheum Dis 2015; 74.
R17-2903
Guidance for industry: E14 clinical evaluation of QT/QTc interval
prolongation and proarrhythmic potential for non-antiarrhythmic drugs -
questions and answers (R3) (June 2017, ICH, revision 2).
website.fda.gov/ucm/groups/fdagov-public/atfdagov-drugsgen/
documents/documen t/ucm073161.pdf (access date: 14 August 2017); 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); 2017.
R18-0143
Garnett C, Bonate PL, Dang Q, Ferber G, Huang D, Liu J, et al. Scientific
white paper on concentration-QTc modeling. J Pharmacokinet
Pharmacodyn. 2018;45(3):383-397.
R19-0854 
Kolb M Vasakova M. The natural history of progressive fibrosing 
interstitial lung diseases. Respir Res (Lond); 20(1), p. 57; 2019.
R23-2891
Avelox® 400 mg film coated tables. Summary of Product Characteristics 
Updates 09-Nov-2020. 
R94-1529 
Chow SC, Liu JP, editors. Design and analysis of bioavailability and 
bioequivalence studies. New York: Marcel Dekker Inc., 1992.

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BI-VQD-11906_40-106_AD-13 (8.0)
R97-1003
Hochberg Y. A sharper Bonferroni procedure for multiple tests of
significance. Biometrika. 1988;75(4):800-802.
9.2
UNPUBLISHED REFERENCES
c02094779
 Investigator's Brochure BI 1015550 for
1305.P3, current version.
c02191718
Safety, tolerability and pharmacokinetics of multiple rising oral doses of
BI 1015550 powder for oral solution in healthy male volunteers q.d. or bid
for 14 days (a randomised, double-blind, placebo-controlled within dose
groups Phase I trial). 1305.0002.
c22991937
Safety, tolerability and pharmacokinetics of single and multiple rising oral
doses of BI 1015550 in healthy subjects. 1305-0011.
c24902949
Relative bioavailability of a single oral dose of BI 1015550 when
administered alone or in combination with multiple oral doses of
itraconazole in healthy male subjects. 1305-0015.
c25085412
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. 1305-0012.
c30409140-01
Thorough QT study to evaluate the effects of BI 409306 as single doses on 
cardiac safety parameters in healthy male and female subjects. A 
randomized, placebo controlled, double-blind, five-period crossover study 
with (open-label) moxifloxacin as positive control. 1289-0038.
c36151567
A Phase I, open-label, non-
randomized, single-dose, single-arm, singleperiod study to investigate the 
metabolism and pharmacokinetics of [C 14]- labelled BI 1015550 after 
oral administration in healthy male subjects. 1305-0016.
c37065416
A randomised, double-blind, placebo-controlled parallel group study in 
IPF patients over 12 weeks evaluating efficacy, safety and tolerability of
BI 1015550 taken orally. 1305-0013.
c39775503
 Assessment of requirement for male contraception. Memo. 09
June 2022
c40013550
Relative bioavailability comparison of BI 1015550 as the intended 
commercial formulation (iCF) versus trial formulation 2 and iCF with and 
without food following oral administration in healthy subjects (an open-
label, randomised, single-dose, three-way crossover trial). 1305-0028.
c40607236
The effect of multiple oral doses of BI 1015550 on metabolism of 
midazolam administered orally in healthy male subjects (open-label, two-
period fixed sequence design trial). 1305-0033.

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n00201162
n00201163
n00201440
n00261809
U08-1543-02

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10.
APPENDICES
Not applicable.

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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
11.1
GLOBAL AMENDMENT 1
Date of amendment
28 SEP 2023
IRAS ID No.
1008273
BI Trial number
1305-0026
BI Investigational Medicinal 
Product(s)
BI 1015550
Title of protocol
Thorough QT study to evaluate the effects of BI 
1015550 as single doses following oral 
administration on cardiac safety parameters 
(double-blind, randomized, placebo-controlled, 
five-period crossover, with open-label moxifloxacin 
as positive control) in healthy male and female 
subjects
Substantial Global Amendment due to urgent safety reasons
Substantial Global Amendment 
Non-substantial Global Amendment 
Section to be changed
1) 3.3.4.1
2) 3.3.4.3
Description of change
1) Withdrawal from trial treatment Criterion 5 is 
updated
2) Discontinuation of the trial by the sponsor
Criterion 4 is updated
Rationale for change
The CTP is amended in response to the RA/EC 
comments

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11.2
GLOBAL AMENDMENT 2
Date of amendment
21 MAR 2024
IRAS ID No.
1008273
BI Trial number
1305-0026
BI Investigational Medicinal 
Product(s)
BI 1015550
Title of protocol
Thorough QT study to evaluate the effects of BI 
1015550 as single doses following oral 
administration on cardiac safety parameters 
(double-blind, randomized, placebo-controlled, 
five-period crossover, with open-label moxifloxacin 
as positive control) in healthy male and female 
subjects
Substantial Global Amendment due to urgent safety reasons
Substantial Global Amendment 
Non-substantial Global Amendment 
Section to be changed
See below
Description of change
Title Page: Clinical Trial Leader changed
Synopsis: The pharmacokinetic analyte was 
corrected to R-BI 1015550.
Flow Chart: The time point of 30 min post dose 
(Holter ECG extraction, PK, AE) was changed to 
20 min post dose for reasons of consistency with 
the primary ECG-endpoint. The pharmacokinetic 
analyte was corrected to R- BI 1015550.
Section 1.2.1.3: Description of the chiral nature of 
BI 1015550.
Section 3.3.2:Inclusion Criterion 5 was updated: 
estradiol below 30 ng/L was removed as 
confirmatory in questionable cases of 
postmenopausal status definition, since FSH above
40 U/L alone is confirmatory.

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Section 5.2.3:Table 5.2.3: 2 is updated: G6PD 
blood test added to Exclusionary tests as per 
Exclusion Criterion 34.
Rationale for change
Change in Clinical Trial Leader.
Correction of inconsistencies, typos and obvious 
mistakes.

 
 
 
 
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clinical-trial-protocol-version-03
Thorough QT study to evaluate the effects of BI 1015550 as single doses following
oral administration on cardiac safety parameters (double-blind, randomized,
placebo-controlled, five-period crossover, with open-label moxifloxacin as positive
control) in healthy male and female subjects
Author-Clinical Trial Leader
21 Mar 2024 14:37 CET
Approval-Clinical Program 
21 Mar 2024 16:01 CET
Verification-Paper Signature
Completion
22 Mar 2024 09:40 CET
Author-Trial Statistician
22 Mar 2024 09:58 CET

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