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
Phase: PHASE1
Conditions: Healthy
Sponsor: Boehringer Ingelheim

001-MCS-40-106-RD-13 (5.0) / Saved on: 25 Jun 2014
Clinical Trial Protocol
TITLE PAGE
c19245536-03
EudraCT No.:
BI Trial No.:
2017-003452-23 
1305-0015
BI Investigational
Product:
BI 1015550 
Title:
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
Lay Title:
This study in healthy men tests how itraconazole influences the amount of 
BI 1015550 in the blood
Clinical Phase:
I
Trial Clinical Monitor:
Phone:
Fax:
Principal Investigator:
Phone:
Fax: 
Status:
Final Protocol (Revised Protocol (based on global amendment 1))
Version and Date:
Version: 2.0 
Date: 15 January 2018
Page 1 of 72
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This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission

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CLINICAL TRIAL PROTOCOL SYNOPSIS
Name of company:
Tabulated
Trial Protocol
Boehringer Ingelheim
Name of finished product:
Not applicable
Name of active ingredient:
BI 1015550
Protocol date:
Trial number:
Revision date:
15 January 2018
14 November 2017
1305-0015
Title of trial:
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  
Principal Investigator:
Trial site:
 
Clinical phase:
I
Objective:
To investigate whether and to what extent co-administration of multiple doses of 
itraconazole affect single dose pharmacokinetics of BI 1015550 in healthy male 
subjects
Methodology:
Open-label, fixed-sequence trial with two treatments (R and T)
No. of subjects: 
total entered:
16
each treatment:
16 (at least 12 completed)
Diagnosis:
Not applicable
Main criteria
for inclusion:
Healthy male subjects, age of 18 to 55 years, body mass index (BMI) of 18.5 to 
29.9 kg/m2
Trial product 1:
BI 1015550 tablet 
dose:
6 mg
mode of admin.:
Oral with 240 mL of water after an overnight fast of at least 10 h 
Trial product 2:
Itraconazole solution (Sempera® Liquid 10 mg/mL Lösung zum Einnehmen)
dose:
200 mg for 12 days in treatment T 
mode of admin.:
Oral with 240 mL of water after an overnight fast of at least 9 h
Duration of treatment: Treatment R (BI 1015550 alone):
Single dose of 6 mg BI 1015550 on Day 1
Treatment T (itraconazole + BI 1015550):
12 days of itraconazole treatment (200 mg itraconazole once daily) combined with a 
single dose of 6 mg BI 1015550 on the fourth day (Day 1) of the itraconazole 
treatment (1 h after the itraconazole administration).
The BI 1015550 single doses of treatments R and T will be separated by a wash-out 
period of at least 10 days

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Name of company:
Tabulated
Trial Protocol
Boehringer Ingelheim
Name of finished product:
Not applicable
Name of active ingredient:
BI 1015550
Protocol date:
Trial number:
Revision date:
15 January 2018
14 November 2017
1305-0015
Criteria for
pharmacokinetics:
Primary endpoints:
AUC0-119 and Cmax of BI 1015550 in plasma
Secondary endpoints: 
AUC0-of BI 1015550 in plasma
 
 
 
 
Criteria for safety:
Adverse events (AEs) including clinically relevant findings from the physical 
examination, safety laboratory tests including fecal occult blood and fecal calprotectin
testing, 12-lead electrocardiogram (ECG), vital signs (blood pressure [BP], pulse rate
[PR]) 
Statistical methods:
Relative bioavailability will be estimated for BI 1015550 based on the point 
estimators of the intra-subject ratio (test to reference treatments) of the geometric 
means (gMeans) of the primary and secondary endpoints. Additionally their 
corresponding two-sided 90% confidence intervals will be provided. This method 
corresponds to the two one-sided t-tests procedure, each at the 5% significance level. 
Since the main focus is on estimation and not testing, an acceptance range will not be 
specified. The statistical model will be a (mixed effects) ANOVA on log transformed 
parameters, including effects for 'subjects' and 'treatment'. Confidence intervals will 
be based on the residual error from the ANOVA.
Descriptive statistics will be calculated for all endpoints.

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TABLE OF CONTENTS
TITLE PAGE ......................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS ................................................2
TABLE OF CONTENTS ...................................................................................7
ABBREVIATIONS.......................................................................................... 11
1.
INTRODUCTION.................................................................................... 14
1.1
MEDICAL BACKGROUND............................................................................14
1.2
DRUG PROFILE...............................................................................................14
1.2.1
BI 1015550 .............................................................................................14
1.2.1.1
14
1.2.1.5.1
18
1.2.2
Itraconazole ...........................................................................................24
1.2.2.1
Clinical safety ..........................................................................24
1.2.2.2
Pharmacokinetics and drug metabolism ..................................25
2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT ......................................................................................... 26
2.1
RATIONALE FOR PERFORMING THE TRIAL........................................26
2.2
TRIAL OBJECTIVES.......................................................................................26
2.3
BENEFIT - RISK ASSESSMENT ...................................................................26
2.3.1
Procedure-related risks ........................................................................26
2.3.3
Itraconazole-related risks and safety measures .................................28
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.............. 30
3.1
OVERALL TRIAL DESIGN AND PLAN ......................................................30
3.1.1
Administrative structure of the trial...................................................30
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUPS........................................................................................31
3.3
SELECTION OF TRIAL POPULATION ......................................................32
3.3.1
Main diagnosis for study entry............................................................32
3.3.2
Inclusion criteria...................................................................................32
3.3.3
Exclusion criteria ..................................................................................32

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3.3.4
Removal of subjects from therapy or assessments.............................34
3.3.4.1
Removal of individual subjects................................................34
3.3.4.2
Discontinuation of the trial by the sponsor..............................35
3.3.5
Replacement of subjects .......................................................................35
4.
TREATMENTS........................................................................................ 36
4.1
TREATMENTS TO BE ADMINISTERED....................................................36
4.1.2
Method of assigning subjects to treatment groups ............................36
4.1.3
Selection of doses in the trial................................................................37
4.1.4
Drug assignment and administration of doses for each subject .......37
4.1.5
Blinding and procedures for unblinding ............................................37
4.1.6
Packaging, labelling, and re-supply ....................................................38
4.1.7
Storage conditions.................................................................................38
4.1.8
Drug accountability ..............................................................................38
4.2
OTHER TREATMENTS, EMERGENCY  PROCEDURES,
RESTRICTIONS ...............................................................................................39
4.2.1
Other treatments and emergency procedures....................................39
4.2.2
Restrictions............................................................................................39
4.2.2.1
Restrictions regarding concomitant treatment .........................39
4.2.2.2
Restrictions on diet and life style.............................................40
4.3
TREATMENT COMPLIANCE.......................................................................40
5.
VARIABLES AND THEIR ASSESSMENT ......................................... 41
5.1
EFFICACY - CLINICAL PHARMACOLOGY.............................................41
5.1.1
Endpoints of efficacy.............................................................................41
5.1.2
Assessment of efficacy...........................................................................41
5.2
SAFETY..............................................................................................................41
5.2.1
Endpoints of safety................................................................................41
5.2.2
Assessment of adverse events...............................................................41
5.2.2.1
Definitions of adverse events...................................................41
5.2.2.2
Adverse event collection and reporting ...................................44
5.2.3
Assessment of safety laboratory parameters......................................46
5.2.4
Electrocardiogram................................................................................49
5.2.5
Assessment of other safety parameters...............................................49
5.2.5.1
Vital signs ................................................................................49
5.2.5.2
Medical examinations..............................................................49
5.3
OTHER...............................................................................................................50
5.3.1
Pharmacogenomic evaluation..............................................................50
5.4
APPROPRIATENESS OF MEASUREMENTS.............................................50
5.5
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS..................................................................................50
5.5.1
Pharmacokinetic endpoints..................................................................50
5.5.1.1
Primary endpoints....................................................................50

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5.5.1.2
Secondary endpoints................................................................51
5.5.2
Methods of sample collection...............................................................52
5.5.2.2
Plasma sampling for pharmacokinetic analysis of itraconazole 
and OH-itraconazole................................................................52
5.5.3
Analytical determinations ....................................................................53
5.5.3.1
Analytical determination of analyte plasma concentration......53
6.
INVESTIGATIONAL PLAN.................................................................. 54
6.1
VISIT SCHEDULE............................................................................................54
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS ................54
6.2.1
Screening period....................................................................................54
6.2.2
Treatment periods.................................................................................54
6.2.3
End of trial period.................................................................................55
7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE......................................................................................... 56
7.1
STATISTICAL DESIGN – MODEL ...............................................................56
7.1.1
Objectives...............................................................................................56
7.1.2
Endpoints...............................................................................................56
7.1.3
Model......................................................................................................56
7.2
NULL AND ALTERNATIVE HYPOTHESES ..............................................57
7.3
PLANNED ANALYSES....................................................................................57
7.3.1
Primary analyses...................................................................................57
7.3.2
Secondary analyses ...............................................................................58
7.3.3
Safety analyses.......................................................................................58
7.3.4
Interim analyses ....................................................................................59
7.3.5
Pharmacokinetic analyses ....................................................................59
7.4
HANDLING OF MISSING DATA ..................................................................59
7.4.1
Safety......................................................................................................59
7.4.2
Plasma drug concentration - time profiles..........................................59
7.4.3
Pharmacokinetic parameters...............................................................60
7.5
RANDOMISATION ..........................................................................................60
7.6
DETERMINATION OF SAMPLE SIZE ........................................................60
8.
INFORMED CONSENT, DATA PROTECTION, TRIAL
RECORDS ................................................................................................ 63
8.1
STUDY APPROVAL, SUBJECT INFORMATION, AND INFORMED 
CONSENT ..........................................................................................................63
8.2
DATA QUALITY ASSURANCE .....................................................................63
8.3
RECORDS..........................................................................................................64
8.3.1
Source documents .................................................................................64

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8.3.2
Direct access to source data and documents.......................................64
8.3.3
Storage period of records.....................................................................64
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS .................................65
8.5
STATEMENT OF CONFIDENTIALITY.......................................................65
8.5.1
Collection, storage and future use of biological samples and 
corresponding data ...............................................................................65
8.6
COMPLETION OF TRIAL..............................................................................65
9.
REFERENCES......................................................................................... 66
9.1
PUBLISHED REFERENCES...........................................................................66
9.2
UNPUBLISHED REFERENCES.....................................................................69
10. APPENDICES .......................................................................................... 71
11. DESCRIPTION OF GLOBAL AMENDMENT(S).............................. 72

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ABBREVIATIONS
AE
Adverse event
AESI
Adverse events of special interest
ANOVA
Analysis of variance
AUC0-∞
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity
AUCt1-t2
Area under the concentration-time curve of the analyte in plasma over the 
time interval t1 to t2
AUC0-tz
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to the last quantifiable data point
BA
Bioavailability
BI
Boehringer Ingelheim
b.i.d.
Bis in die, twice daily
BLQ
Below limit of quantification
BMI
Body mass index (weight divided by height squared)
BP
Blood pressure
CA
Competent authority
CI
Confidence interval
CL
Total clearance of the analyte in plasma after intravascular administration
 
Cmax
Maximum measured concentration of the analyte in plasma
 
CK
CRF
Creatine kinase
Case report form
CTP
Clinical trial protocol
CTR
Clinical trial report
CV
CYP3A
DDI
Arithmetic coefficient of variation
Cytochrome P450, family 3, subfamily A
drug-drug-interaction 
DILI
Drug induced liver injury

Bioequivalence margin
ECG
Electrocardiogram
EDTA
Ethylenediaminetetraacetic acid
EOT
End of trial
gCV
Geometric coefficient of variation

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GI
Gastro-intestinal
gMean
Geometric mean
HPLC-MS/MS
High performance liquid chromatography with tandem mass spectrometry
HR
Heart rate
IEC
Independent Ethics Committee
IPF
idiopathic pulmonary fibrosis
IRB
Institutional Review Board
ISF
Investigator site file
z
Terminal rate constant of the analyte in plasma
LLOQ
Lower limit of quantification
MedDRA
Medical Dictionary for Regulatory Activities
MRD
Multiple-rising dose
NIMP
Non-investigational medicinal product
NOA
Not analysed
NOAEL
No observed adverse effect level
NOP
No peak detectable
NOR
No valid result
NOS
No sample available
PD
Pharmacodynamic(s)
PfOS
P-gp 
Powder for reconstitution of an oral solution
P-glycoprotein
PK
Pharmacokinetic(s)
PKS
Pharmacokinetic set
PR
Pulse rate
q.d.
Quaque die, once daily
QT
Time between start of the Q-wave and the end of the T-wave in an 
electrocardiogram
R
Reference treatment
REP
Residual effect period
SAE
Serious adverse event
SCR
Screening
SmPC
Summary of Product Characteristics
SRD
Single-rising dose
SUSAR
Suspected Unexpected Serious Adverse Reaction
T
TEAEs
Test product or treatment
treatment emergent adverse events 
TMF
Trial master file

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TDMAP
Trial Data Management and Analysis Plan
TSAP
UGT
Trial statistical analysis plan
Uridine 5'-diphospho-glucuronosyltransferase

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1.
INTRODUCTION
 
 
1.1
MEDICAL BACKGROUND
 
 
 
 
 
For a more detailed description of the BI 1015550 profile please refer to the current 
Investigator’s Brochure [c02094779-02].
1.2
DRUG PROFILE
1.2.1
BI 1015550
1.2.1.1
 
 
For details on nonclinical pharmacology refer to the nonclinical pharmacology section in the 
Investigator’s Brochure [c02094779-02].

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For further details on safety pharmacology refer to the Investigator’s Brochure [c02094779-
02].
 
 
                  
            
 
 
 
 

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For further information please refer to the Investigator’s Brochure [c02094779-02].
1.2.1.5.1
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Further details can be found in the Investigator’s Brochure [c02094779-02].
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Clinical experience with other PDE4 inhibitors
Selective PDE4 inhibitors have been approved for COPD with chronic bronchitis and a 
history of exacerbations (roflumilast), and for moderate to severe plaque psoriasis and active 
psoriatic arthritis (apremilast). No PDE4 inhibitor has been tested in IPF, yet.

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The most common AEs reported for these marketed PDE4 inhibitors were gastrointestinal 
events (diarrhea, weight loss, nausea, and vomiting, abdominal pain) and headache. For 
roflumilast, there was an increased incidence of neuropsychiatric adverse reactions such as 
insomnia, anxiety, nervousness, and depression; in rare instances suicidal ideation or 
behavior (including completed suicide). The product information of Otezla® (apremilast) also 
recommends cautious use in patients with a history of depression and/or suicidal thoughts or 
behavior [R14-1795].
Among the AEs leading to death, cardiac arrest was reported in a higher number of patients 
who received roflumilast [R10-1555]. Clinical manifestation of mesenteric vasculitis, an 
adverse effect that has been a concern with PDE4 inhibition in general, was not reported in 
these clinical studies with roflumilast.
 
 
 
 
 
 

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1.2.2
Itraconazole
Itraconazole is an oral broad-spectrum imidazole antifungal agent, indicated for the treatment 
of systemic fungal infections at doses up to 200 mg twice daily. In-vitro studies suggest that 
itraconazole impairs the synthesis of ergosterol, a vital component of fungal cell membranes, 
by inhibiting the fungal CYP450 (CYP51). It is also a competitive inhibitor for CYP3A4, the 
major drug metabolizing enzyme in the liver, both in-vitro and in-vivo [R12-5255] as well as 
an inhibitor of P-gp [P12-05791] [R17-3744].
1.2.2.1
Clinical safety
The most common (listed occurrence ≥1%, but <10%) side effects of itraconazole are rash, 
pyrexia and symptoms of the CNS (headache, dizziness, dysgeusia), the respiratory (dyspnea, 
cough) or the gastrointestinal (abdominal pain, diarrhea, nausea, vomiting, dyspepsia, 
uncommonly also obstipation) system. As uncommon (listed occurrence ≥0.1%, but <1%) 
changes in clinical laboratory and hematology (leukopenia, thrombocytopenia and 
hypokalemia, also single cases of hypertriglyceridaemia and increased blood creatine 
phosphokinase), visual (including diplopia and blurred vision) and CNS disturbances 
(peripheral neuropathy, paresthesia, hypoesthesia), tinnitus, hypersensitivity, urticaria and 
pruritus, are listed. Further uncommon adverse reactions are hyperbilirubinemia and liver 
failure, congestive heart failure, as well as myalgia and arthralgia, menstrual disorders and 
edema. The most serious adverse drug reactions were serious allergic reactions (serum 
sickness, angioneurotic edema, anaphylactic reactions), serious skin reactions (e.g. toxic 
epidermal necrolysis, Stevens-Johnson-Syndrome), cardiac failure/congestive heart 
failure/pulmonary edema, pancreatitis, and serious hepatotoxicity, including some cases of 
fatal acute liver failure. In most of these cases of serious hepatotoxicity patients suffered from 
concomitant liver diseases, had other significant diseases, or took concomitant hepatotoxic 
drugs. Some of these cases have been observed within the first month of treatment, including 
some within the first week. Single cases of hearing loss (in most cases reversible after 
cessation of itraconazole treatment) and tinnitus are known. Furthermore, itraconazole may 

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cause negative inotropic effects, if administered intravenously or at doses exceeding 400 mg 
per day [R17-3740].
For further information regarding itraconazol solution including additional adverse drug 
reactions associated with itraconazole in clinical trials please refer to the SmPC [R17-3741]
and [R17-3740].
In trials with healthy volunteers, multiple doses of 200 mg itraconazole q.d. over a period of 
10-15 days were well tolerated ([R17-3742], R12-5316, c02336088, c03355329, c08928447). 
1.2.2.2
Pharmacokinetics and drug metabolism
Absorption of itraconazole solution is fast with maximum plasma concentration being 
reached within 2.5 h after oral administration in a fasted condition. In contrast to itraconazole 
administered as capsules where food increases the oral bioavailability of itraconazole, 
bioavailability of itraconazole liquid is increased by 30% when given in a fasted condition 
compared to administration together with food (bioavailability in fed condition: 55%) [R17-
3740]. Mean peak plasma levels were 547.7 ng/mL after a single dose of 200 mg itraconazole 
solution (fasted) and 1965 ng/mL after 15 days of daily treatment with 200 mg itraconazole 
(solution, fasted). Itraconazole has a non-linear kinetics. The half-life of itraconazole after 
multiple doses of 200 mg once daily with solution formulation was about 40 h [R17-3742].
A large number of itraconazole metabolites with minimal antifungal activities exist and are 
primarily excreted in the bile since only 0.03% of itraconazole are eliminated unchanged in 
the urine [R12-5317, [R17-3740]. In the liver, itraconazole is metabolised extensively to 
more than 30 metabolites [R17-3743]. Its main metabolite, hydroxyitraconazole, accounts for 
about twice the amount of plasma itraconazole. It has been shown in-vitro that CYP3A4 is 
mainly responsible for the formation of this metabolite [R17-3740]. Itraconazole is a known 
and classified potent in-vivo inhibitor of CYP3A4 and P-gp [P15-06991], FDA-webside:
fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabel
ing/ucm093664.htm). However, not only itraconazole contributes to the in vivo inhibition of 
CYP3A4 observed after itraconazole administration but also three of its metabolites
(hydroxyitraconazole, ketoitraconazole and N-desalkyl-itraconazole) [R10-1102].
Due to the inhibitory effect of itraconazol on CYP3A4, co-administration of itraconazole 
with drugs primarily metabolized by the CYP3A4 should result in increased plasma 
concentrations over a longer period of time for the affected drugs due to inhibited metabolism 
and thereby elimination. Co-administration of 200 mg itraconazole once daily with 7.5 mg 
midazolam, a CYP3A4 substrate, resulted in a decreased plasma clearance of midazolam by 
69%, a 6.6-fold increase in AUC0-∞, and a 2.5-fold in Cmax. Accordingly, the half-life of 
midazolam was almost doubled [R06-2665].
For a more detailed description of the itraconazole profile please refer to the SmPC [R17-
3741] and [R17-3740].

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2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT
2.1
RATIONALE FOR PERFORMING THE TRIAL
 
Therefore this trial should investigate whether and to what extent the inhibition of CYP3A 
mediated by itraconazole affects kinetics of BI 1015550. Itraconazole is a strong CYP3A4 
inhibitor and a recommended probe drug to test in-vivo inhibition of CYP3A4 [P15-06991], 
[P12-05791].
2.2
TRIAL OBJECTIVES
The primary objective of this trial is to investigate whether and to what extent co-
administration of multiple doses of itraconazole affect single dose pharmacokinetics of BI 
1015550, i.e. to compare the relative bioavailability of 6 mg BI 1015550 when given alone 
(reference, treatment R) to the relative bioavailability of 6 mg of BI 1015550 given on the 4th
day of a 12-day-treatment with itraconazole (test, treatment T) following oral administration
in healthy male subjects.
The assessment of safety and tolerability will be an additional objective of this trial.
A description of the endpoints to be determined, and the observations along with specific 
information as how to collect the data for that information, is provided in Section 5.
2.3
BENEFIT - RISK ASSESSMENT
Participation in this study is without any (therapeutic) benefit for healthy subjects. Their 
participation in the study, however, is of major importance to the development of BI 1015550 
as a treatment for IPF. The subjects are exposed to the risks of the study procedures and the 
risks related to the exposure to the trial medication.
2.3.1
Procedure-related risks
The use of an indwelling venous catheter for the purpose of blood sampling may be 
accompanied by mild bruising and also, in rare cases, by transient inflammation of the wall of 
the vein. In addition, in rare cases a nerve might be injured while inserting the venous 
catheter, potentially resulting in paresthesia, reduced sensibility, and/or pain for an indefinite 
period. The same risks apply to venipuncture for blood sampling.
ECG electrodes may cause local and typically transient skin reactions.

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2.3.3
Itraconazole-related risks and safety measures
In this trial itraconazole will be used in a standard dose of 200 mg once daily for 12 days.
Multiple dosing of 200 mg itraconazole up to 15 days has been well tolerated by healthy 
subjects [c02336088, c03355329, c08928447, R17-3742]. 
Considering the risk of hepatotoxicity, only subjects with normal liver enzyme values will be 
included into the study. Safety laboratory parameters will be monitored closely. An 
individual subject will be removed from the trial if the subject shows an elevation of AST 
and/or ALT ≥3-fold ULN combined with an elevation of total bilirubin ≥2-fold ULN 
(measured in the same blood sample, see Section 3.3.4.1). Further, most of the reported cases 
of serious hepatotoxicity during Itraconazole treatment occurred in patients suffering from 
concomitant liver diseases, had other significant diseases, or took concomitant hepatotoxic 
drugs. Therefore only healthy subjects with no history of relevant liver diseases as specified 
in exclusion criterion 27 (ref exclusion criteria) will be eligible for trial participation.
Considering these safety measures and taking into account the reported good tolerability of 
itraconazole in healthy subjects, the planned administration of itraconazole does not represent 
an undue risk to healthy volunteers.

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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN AND PLAN
The study will be performed as an open-label, fixed-sequence trial with two treatments (R 
and T) in healthy male subjects in order to compare the test treatment (T) to the reference 
treatment (R). 
Each subject will receive the reference treatment at Visit 2 and the test treatment in Visit 3. 
The two treatments are described below. The administrations of the single dose of BI 
1015550 in treatment R (Visit 2) and in the following treatment T (Visit 3) will be separated 
by a wash-out period of at least 10 days.
Visit 4 will be the end of trial examination.
Treatment R (BI 1015550 alone):
6 mg (1x 6 mg tablet) of BI 1015550 will be given as a single dose on Day 1.
Treatment T (itraconazole + BI 1015550):
200 mg itraconazol (20 mL of Sempera Liquid 10 mg/mL) will be given once daily from Day 
-3 to Day 9 (12 days of itraconazole treatment in total). In addition, 6 mg (1x 6 mg tablet) of 
BI 1015550 will be given as a single dose 1 h after the itraconazole administration on Day 1
(corresponding to the fourth day of the 12-day itraconazole treatment).
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.
3.1.1
Administrative structure of the trial
The trial is sponsored by Boehringer Ingelheim (BI) Pharma GmbH & Co. KG, Germany.
BI has appointed a Trial Clinical Monitor, responsible for coordinating all required activities, 
in order to 

manage the trial in accordance with applicable regulations and internal SOPs,

direct the clinical trial team in the preparation, conduct, and reporting of the trial,

ensure appropriate training and information of local clinical monitors (CML), 
Clinical Research Associates (CRAs), and participating trial sites.
The trial medication BI 1015550 will be provided by the Clinical Trial Supplies Unit 
(CTSU), BI Pharma GmbH & Co. KG, Biberach, Germany. Itraconazole (Sempera® Liquid 
10 mg/mL) will be provided by a public pharmacy.
The trial will be conducted at the Human Pharmacology Centre (HPC) of BI Pharma GmbH 
& Co. KG, Biberach, Germany, under the supervision of the Principal Investigator.

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Safety laboratory tests will be performed by the local laboratory of the trial site 
 
The analyses of BI 1015550 and its metabolites concentrations in plasma will be performed at 
a suitable contract research organization (CRO) under the responsibility of the Department of 
Drug Metabolism and Pharmacokinetics, BI Pharma GmbH & Co. KG, Biberach, Germany. 
The analyses of itraconazole and its metabolites concentrations in plasma will be performed 
at a suitable contract research organization (CRO) under the responsibility of the Department 
of Drug Metabolism and Pharmacokinetics, BI Pharma GmbH & Co. KG, Biberach, 
Germany. 
On-site monitoring will be performed by BI or a contract research organization appointed by 
BI.
Statistical evaluation will be done by BI or by a suitable contract research organization 
(CRO) under the responsibility of BI and according to BI SOPs.
Data management will be done by BI according to BI SOPs.
Tasks and functions assigned in order to organize, manage, and evaluate the trial are defined 
according to BI SOPs. A list of responsible persons and relevant local information can be 
found in the ISF.
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUPS
This is an open-label trial to investigate the potential effect of multiple dose itraconazole on 
the single dose pharmacokinetics of BI 1015550. Two treatments will be compared in a 
descriptive way: a single dose of BI 1015550 given alone (treatment R) and in combination 
with multiple dose itraconazole (treatment T).
Due to the long half-life of itraconazole (about 40 hours) and its metabolites (ND-
itraconazole)
 
a fixed sequence design was selected, with 
administration of itraconazole in the second study period only. The fixed-sequence design is 
not expected to lead to systematic errors in the estimation of the treatment effects, because 
the trial duration is short enough so that nonspecific time-effects are not expected. This 
design is also the design for itraconazole DDI studies that is recommended by the Innovation 
and Quality in Pharmaceutical Development’s Clinical Pharmacology Leadership Group 
(CPLG) [R17-3744].
Blinding is not possible because the treatments are distinguishable.
The open-label treatment is not expected to bias results, since the study endpoints are derived 
from measurement of plasma concentrations of BI 1015550 provided by a bioanalytical
laboratory which is blinded to treatment allocation.

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During the test treatment, subjects will receive itraconazole once daily from Day -3 onwards
to achieve a sufficient exposure of the perpetrator drug (itraconazole) on Day 1. Predosing of
itraconazole is a standard dosing regimen that has been described by several authors [R13-
4571, R13-4572, R13-4573]. 
 
 Itraconazole will be 
administered 1 h before BI 1015550 on Day 1 of the test treatment to allow for a local 
inhibition of intestinal CYP 3A4 and P-gp prior to BI 1015550 drug intake.
The single dose administrations of BI 1015550 in the 2 treatments will be separated by a 
wash-out period of at least 10 days, which should be sufficient for a complete washout of BI 
1015550 between treatments.
3.3
SELECTION OF TRIAL POPULATION
It is planned that 16 healthy male subjects (at least 12 completed) will enter the study. They 
will be recruited from the volunteers' pool of the trial site.
Only male subjects will be included into the study because hitherto no data on reproductive 
toxicology are available.
A log of all subjects enrolled into the trial (i.e. having given informed consent) will be 
maintained in the ISF at the investigational site irrespective of whether they have been treated 
with investigational drug or not.
3.3.1
Main diagnosis for study entry
The study will be performed in healthy subjects.
3.3.2
Inclusion criteria
Subjects will only be included into the trial, if they meet the following criteria:
1. Healthy male subjects according to the assessment of the investigator, based on a 
complete medical history including a physical examination, vital signs (BP, PR), 12-lead 
ECG, and clinical laboratory tests 
2. Age of 18 to 55 years (incl.)
3. BMI of 18.5 to 29.9 kg/m2 (incl.)
4. Signed and dated written informed consent prior to admission to the study in accordance 
with GCP and local legislation
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, PR or ECG) is deviating from 
normal and judged as clinically relevant by the investigator

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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 pulse rate outside the 
range of 45 to 90 bpm
3. Any laboratory value outside the reference range that the investigator considers to be of
clinical relevance
4. Any evidence of a concomitant disease judged as clinically relevant by the investigator
5. Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological or 
hormonal disorders
6. Cholecystectomy and/or surgery of the gastrointestinal tract that could interfere with the 
pharmacokinetics of the trial medication (except appendectomy and 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 mood disorders and any history of suicidality.
8. History of relevant orthostatic hypotension, fainting spells, or blackouts
9. Chronic or relevant acute infections
10. History of relevant allergy or hypersensitivity (including allergy to the trial medication or 
its excipients or other Azoles ) 
11. Use of drugs within 30 days prior to administration of trial medication if that might 
reasonably influence the results of the trial (incl. QT/QTc interval prolongation)
12. Participation in another trial where an investigational drug has been administered within 
60 days prior to planned administration of trial medication, or current participation in
another trial involving administration of investigational drug
13. Smoker (more than 10 cigarettes or 3 cigars or 3 pipes per day)
14. Inability to refrain from smoking on specified trial days
15. Alcohol abuse (consumption of more than 20 g per day)
16. Drug abuse or positive drug screening
17. Blood donation of  more than 100 mL within 30 days prior to administration of trial 
medication or intended donation during the trial
18. Intention to perform excessive physical activities within one week prior to administration 
of trial medication or during the trial
19. Inability to comply with dietary regimen of trial site
20. A marked baseline prolongation of QT/QTc interval (such as QTc intervals that are 
repeatedly greater than 450 ms in males) or any other relevant ECG finding at screening
21. A history of additional risk factors for Torsades de Pointes (such as heart failure, 
hypokalemia, or family history of Long QT Syndrome)
22. Subject is assessed as unsuitable for inclusion by the investigator, for instance, because 
considered not able to understand and comply with study requirements, or has a condition 
that would not allow safe participation in the study 
23. Male subjects who do not agree to minimize the risk of female partners becoming 
pregnant from the first dosing day until two months after the study completion.
Acceptable methods of contraception comprises barrier contraception and a medically 

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accepted contraceptive method for the female partner (intra-uterine device, hormonal 
contraceptive since at least two months)
In addition, the following trial-specific exclusion criteria apply:
 
 
 
For study restrictions, refer to Section 4.2.2.
3.3.4
Removal of subjects from therapy or assessments
3.3.4.1
Removal of individual subjects
An individual subject is to be removed from the trial if:
1. The subject withdraws consent for trial treatment or trial participation, without the need to 
justify the decision
2. The subject needs to take concomitant drugs that interfere with the investigational  
product or other trial medication
3. The subject is no longer able to participate for other medical reasons (such as surgery, 
adverse events, or diseases)
4. An AE or clinically significant laboratory change or abnormality occurred that the 
investigator judges to warrant discontinuation of treatment. This may include cases of 
sustained symptomatic hypotension (BP <90/50 mmHg) or hypertension (BP >180/100 
mmHg) or of clinically relevant changes in ECG requiring intervention as well as 
unexplained liver enzyme elevations at any time during the trial.
5. The subject shows an elevation of AST and/or ALT ≥3-fold ULN combined with an 
elevation of total bilirubin ≥2-fold ULN (measured in the same blood sample) and/or 
needs to be followed up according to the ‘DILI checklist’ provided in the ISF.
In addition to these criteria, the physician may discontinue subjects at any time based on his 
or her clinical judgment.
A subject can also be removed from the trial if eligibility criteria are being violated or if the 
subject fails to comply with the protocol (for instance, by non-adherence to dietary rules, or 
non-attendance at study assessments).

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If a subject is removed from or withdraws from the trial prior to first administration of trial 
medication, the data of this subject will not be entered in the case report form (CRF) or trial 
database and will not be reported in the clinical trial report (CTR). If a subject is removed 
from or withdraws from the trial after first administration of trial medication, this will be 
documented and the reason for discontinuation must be recorded in the CRF. In this case, the 
data will be included in the CRF/trial database and will be reported in the CTR. At the time 
of discontinuation a complete end of trial examination will be performed if possible and the 
information will be recorded in the CRFs. If the discontinuation occurs before the end of the 
REP (see Section 5.2.2.2), the discontinued subject should if possible be questioned for AEs
and concomitant therapies at or after the end of the REP in order to ascertain collection of 
AEs and concomitant therapies throughout the REP, if not contrary to any consent 
withdrawal of the subject. These discontinuations will be discussed in the CTR.
3.3.4.2
Discontinuation of the trial by the sponsor
Boehringer Ingelheim reserves the right to discontinue the trial overall or at a particular trial 
site at any time for any of the following reasons:
1. New toxicological findings or serious adverse events invalidate the earlier positive 
benefit-risk-assessment. More specifically, the trial will be terminated if more than 50% 
of the subjects show drug-related and clinically relevant adverse events of moderate or 
severe intensity, or if at least one drug-related serious adverse event is reported.
2. The expected enrolment goals overall or at a particular trial site are not met
3. Violation of GCP, or the CTP by a trial site or investigator, disturbing the appropriate 
conduct of the trial
4. The sponsor decides to discontinue the further development of the investigational 
product.
3.3.5
Replacement of subjects
In case some subjects do not complete the trial, the trial clinical monitor together with the 
trial pharmacokineticist and the trial statistician are to decide if and how many subjects will 
be replaced. A replacement subject will be assigned a unique study subject number, and will 
be assigned to the same treatment as the subject he or she replaces.

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4.
TREATMENTS
4.1
TREATMENTS TO BE ADMINISTERED
 
 
 
Trial product 2:
Name:
Sempera® Liquid 10 mg/mL Lösung zum Einnehmen
Substance:
Itraconazole 
Pharmaceutical formulation: Oral solution
Source:
Janssen-Cilag, Neuss, Germany
Unit strength:
10 mg/mL
Posology:
20 mL - 0 mL - 0 mL
Route of administration:
p.o.
Duration of use:
12 days (in treatment T only) 
4.1.2
Method of assigning subjects to treatment groups
There is only one treatment sequence in this trial, and each subject will be allocated to the 
same treatment sequence (R-T). The subjects will be allocated to a study subject number by 
drawing lots prior to first administration of trial medication in the morning of Day 1 of Visit 
2. The randomization list of study subject numbers and assigned treatment sequence will be 
provided to the trial site in advance. Note that the randomization list is just needed for 
logistical reasons in this non-randomized, fixed-sequence and open-label trial. Hence, no bias
is introduced when providing the randomization list in advance to the site. Test and reference 
treatments will be administered in the sequence specified in the Flow Chart.

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Once a subject number has been assigned, it cannot be reassigned to any other subject.
4.1.3
Selection of doses in the trial
The dose of itraconazole selected for this trial reflects standard clinical doses, is considered 
sufficient to yield significant CYP3A4 inhibition and has been successfully and safely used in 
previous drug-interaction trials that investigate the effect of CYP3A4 inhibition (c02336088, 
c03355329, c08928447).
 
 
 
 
 
 (see section 2.3.4).
4.1.4
Drug assignment and administration of doses for each subject
All subjects will receive two treatments in a fixed-sequence order (R-T). The treatments to be 
evaluated are outlined in Table 4.1.4: 1 below.
Table 4.1.4: 1
Dosage and treatment schedule
Treatment
Substance
Formulation
Unit strength Dosage
Total  dose
T (Test)
BI 1015550 
Tablet
6 mg
1 tablet on Day 1, Visit 3
6 mg
Itraconazole
Oral solution 10 mg/mL
20 mL (200 mg) on Day -3 to Day 9, Visit 3
2.4 g
R (Reference)
BI 1015550 
Tablet
6 mg
1 tablet on Day 1, Visit 2
6 mg
Trial medication (BI 1015550 and itraconazole) will be administered together with about 240 
mL of water to a subject in the standing position under supervision of the investigating 
physician or an authorized designee. The so-called four-eye principle (two-person rule) 
should be applied for administration of trial medication and – if applicable – its preparation 
(e.g. reconstitution), if correct dosage cannot be ensured otherwise. Trial medication will be 
administered at the time points listed in the Flow Chart, following an overnight fast starting 
no later than 9 h before itraconazole administration or 10 h before scheduled BI 1015550
administration.
Subjects will be kept under close medical surveillance until 24 h following drug 
administration of BI 1015550. During the first 2 h after drug administration of BI 1015550, 
they are not allowed to lie down (i.e. no declination of the upper body of more than 45 
degrees from upright posture). For restrictions with regard to diet see Section 4.2.2.2.
BI 1015550 administrations in Visit 2 and 3 will be separated by a wash-out phase of at least 
10 days.
4.1.5
Blinding and procedures for unblinding
No blinding was performed because the treatments are distinguishable from each another.
This Phase I trial will be handled in an open fashion throughout (that is, during the conduct,

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including data cleaning and preparation of the analysis). This is considered acceptable 
because the potential for bias seems to be low and does not outweigh practical considerations.
Emergency envelopes will not be provided, since all subjects receive the same dose of 
different formulations in an open label design.
4.1.6
Packaging, labelling, and re-supply
Itraconazole will be obtained from a public pharmacy. The drug will be dispensed out of the 
original, unmodified packages.
BI 1015550 will be provided by the Department of Pharmaceutical Development of 
Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany.
The clinical trial supply consists of containers holding the trial medication which are labelled 
with trial identification. The required information according to the German Drug Law as well 
as Annex 13/EU GMP Guideline will be provided on the containers. Containers will be 
labelled with:

BI trial number

Name of product and strengths or identification code

Pharmaceutical dosage form, quantity of dosage units 

Route and mode of administration

Term ‘For Clinical Trial Use’ (domestic language)

Sponsor name and address

Storage conditions

Use-by date

Batch number
The telephone number of the sponsor and name, address and telephone number of the trial 
site are given in the subject information form. The EudraCT number is indicated on the title 
page of this protocol as well as on the subject information and informed consent forms. 
Examples of the labels will be available in the ISF.
No re-supply is planned.
4.1.7
Storage conditions
Drug supplies will be kept in their original packaging and in a secure limited access storage 
area according to the recommended (labelled) storage conditions. Where necessary, a 
temperature log must be maintained to make certain that the drug supplies are stored at the 
correct temperature. If the storage conditions are found to be outside the specified range, the 
local clinical monitor (as provided in the list of contacts) is to be immediately contacted.
4.1.8
Drug accountability
The investigator will receive the investigational drugs delivered by the sponsor when the 
following requirements are fulfilled:

Approval of the trial protocol by the IRB/ethics committee 

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
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 authorized personnel as documented in the form ‘Trial Staff List’ may dispense
medication to trial subjects. The trial medication must be administered in the manner 
specified in the CTP. All unused medication will be disposed locally by the trial site upon 
written authorization by the clinical monitor. Receipt, usage and disposal must be
documented on the respective forms. Account must be given for any discrepancies. 
The investigator 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 products and trial subjects. The 
investigator will maintain records that document adequately that the subjects were provided 
the doses specified by the CTP, and that reconcile all investigational products received from 
the sponsor. At the time of disposal, the investigator must verify that no remaining supplies
are in the investigator’s possession.
4.2
OTHER TREATMENTS, EMERGENCY  PROCEDURES,
RESTRICTIONS
4.2.1
Other treatments and emergency procedures
There are no special emergency procedures to be followed. No additional treatment is 
planned. However, in case of adverse events in need of treatment, the investigator can 
authorize 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 medical 
evaluation results have returned to an acceptable level.
4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
In principle, no concomitant therapy is allowed. All concomitant or rescue therapies will be
recorded (including time of intake on study days) on the appropriate pages of the CRF.
 

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4.2.2.2
Restrictions on diet and life style
While admitted to the trial site the subjects are restricted from consuming any other foods or 
drinks than those provided by the staff. Standardized meals will be served at the time points 
described in the Flow Chart. No food is allowed for at least 4 h after drug intake in case of BI 
1015550 and for at least 1 h in case of itraconazole administration.
On PK profile days (Day 1, Visit 2 and 3), fluid intake is restricted from 2 h before drug 
intake of BI 1015550 until lunch 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 of BI 1015550, total fluid intake is restricted to 3000 mL.
Alcoholic beverages are not permitted starting 5 days before the first administration of trial 
medication until the last PK sample is collected; grapefruits, Seville oranges (sour or bitter 
oranges) and their juices, and dietary supplements and products including St. John's wort 
(Hypericum perforatum) are not allowed from 7 days before the first administration until 
collection of the last PK sample.
Smoking is not allowed during in-house confinement at the trial site.
Methylxanthine-containing drinks or foods (such as coffee, tea, cola, energy drinks, and 
chocolate) are not allowed from 24 h before until 24 h after administration of BI 1015550.
Excessive physical activity (such as competitive sport) should be avoided starting 7 days 
before the first administration of trial medication until the end of trial examination.
Direct exposure to the sun or exposure to solarium radiation should be avoided during the 
entire study.
4.3
TREATMENT COMPLIANCE
Compliance will be assured by administration of all trial medication in the study center under 
supervision of the investigating physician or a designee. The measured plasma concentrations 
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.
VARIABLES AND THEIR ASSESSMENT
5.1
EFFICACY - CLINICAL PHARMACOLOGY
5.1.1
Endpoints of efficacy
No efficacy endpoints will be evaluated in this trial.
5.1.2
Assessment of efficacy
Not applicable.
5.2
SAFETY
5.2.1
Endpoints of safety
Safety and tolerability of the investigational drugs will be assessed based on:

Adverse events (including clinically relevant findings from the physical examination)

Safety laboratory tests

12-lead ECG

Vital signs (blood pressure, pulse rate)
These parameters will be evaluated in a descriptive way only, and are therefore considered to 
be ‘further parameters of interest’. A confirmatory analysis is not planned (see Section 7.3). 
5.2.2
Assessment of adverse events
5.2.2.1
Definitions of adverse events
Adverse event
An adverse event (AE) is defined as any untoward medical occurrence 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 unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product.
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,

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
requires inpatient hospitalization or 

requires prolongation of existing hospitalization,

results in persistent or significant disability or incapacity, or

is a congenital anomaly/birth defect, 
or 

is deemed serious for any other reason if it is an important medical event when based 
upon appropriate medical judgment which may jeopardize 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 hospitalization or 
development of dependency or abuse. 
AEs considered ‘Always Serious’
Cancers of new histology and exacerbations of existing cancer must be classified as a serious 
event regardless of the duration between discontinuation of the drug and must be reported as 
described in 5.2.2.2, subsections “AE Collection” and “AE reporting to sponsor and 
timelines”.
In accordance with the European Medicines Agency initiative on Important Medical Events, 
Boehringer Ingelheim has set up a list of further AEs, which by their nature, can always be 
considered to be ‘serious’ even though they may not have met the criteria of an SAE as 
defined above.
The latest list of ‘Always Serious AEs’ can be found in the RDC system. These events should 
always be reported as SAEs as described above.
Adverse events of special interest (AESIs)
The term AESI relates to any specific AE that has been identified at the project level as being 
of particular concern for prospective safety monitoring and safety assessment within this trial, 
e.g. the potential for AEs based on knowledge from other compounds in the same class. 
AESIs need to be reported to the sponsor’s Pharmacovigilance Department within the same 
timeframe that applies to SAEs, please see above.
The following are considered as AESIs:

Hepatic injury
A Hepatic injury is defined by the following alterations of hepatic laboratory 
parameters: 
o
an elevation of AST and/or ALT ≥3-fold ULN combined with an elevation of 
total bilirubin ≥2-fold ULN measured in the same blood sample, and/or
o
aminotransferase (ALT, and/or AST) elevations ≥10 fold ULN
These lab findings constitute a hepatic injury alert and the patients showing these lab 
abnormalities need to be followed up according to the ‘DILI checklist’ provided in the ISF. In 
case of clinical symptoms of hepatic injury (icterus, unexplained encephalopathy, 

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unexplained coagulopathy, right upper quadrant abdominal pain, etc.) without lab results 
(ALT, AST, total bilirubin) available, the Investigator should make sure these parameters are 
analyzed, if necessary in an unscheduled blood test. Should the results meet the criteria of 
hepatic injury alert, the procedures described in the DILI checklist should be followed.
With the exception of hepatic injury, no AESIs have been defined for this trial.
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
Causal relationship of AEs
Medical judgment should be used to determine the relationship, considering all relevant 
factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge, 
confounding factors such as concomitant medication, concomitant diseases and relevant 
history.
Arguments that may suggest that there is a reasonable possibility of a causal relationship 
could be:

The event is consistent with the known pharmacology of the drug 

The event is known to be caused by or attributed to the drug class

A plausible time to onset of the event relative to the time of drug exposure

Evidence that the event is reproducible when the drug is re-introduced

No medically sound alternative etiologies that could explain the event (e.g. pre-
existing or concomitant diseases, or co-medications)

The event is typically drug-related and infrequent in the general population not 
exposed to drugs (e.g. Stevens-Johnson syndrome)

An indication of dose-response (i.e. greater effect size if the dose is increased, smaller 
effect size if dose is diminished)
Arguments that may suggest that there is no reasonable possibility of a causal relationship 
could be:

No plausible time to onset of the event relative to the time of drug exposure is evident 
(e.g. pre-treatment cases, diagnosis of cancer or chronic disease within days / weeks 
of drug administration; an allergic reaction weeks after discontinuation of the drug 
concerned)

Continuation of the event despite the withdrawal of the medication, taking into 
account the pharmacological properties of the compound (e.g. after 5 half-lives). Of 
note, this criterion may not be applicable to events whose time course is prolonged 
despite removing the original trigger

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
Additional arguments amongst those stated before, like alternative explanation (e.g. 
situations where other drugs or underlying diseases appear to provide a more likely 
explanation for the observed event than the drug concerned)

Disappearance of the event even though the trial drug treatment continues or remains 
unchanged
5.2.2.2
Adverse event collection and reporting
AE collection
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 as well as the time of onset, end, 
and intensity of these events. 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 careful 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, and intensity of the event as 
well as 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: 
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 or trial database 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 AEs but 
should only report related SAEs and related AESIs of which the investigator
may become aware of by any means of communication, e.g. phone call. Those 
AEs should, however, not be reported in the CRF.

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In Treatment T, the REP of itraconazole is
about 9 days after last administration of itraconazole on day 9, i.e. up to day 18 (Treatment 
T). Therefore, all AEs which occurred through the treatment phase and throughout the REP 
will be considered as on treatment; please see Section 7.3.3. Events which occurred after the 
REP will be considered as follow-up events.
AE reporting to sponsor and timelines
The Investigator must report SAEs, AESIs, and non-serious AEs which are relevant for the 
reported SAE or AESI, on the BI SAE form via fax immediately (within 24 hours) to the 
sponsor’s unique entry point (country specific contact details will be provided in the ISF). 
The same timeline applies if follow-up information becomes available. In specific occasions 
the Investigator could inform the sponsor upfront via telephone. This does not replace the 
requirement to complete and fax 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.
Information required
For each AE, the investigator should provide the information requested on the appropriate 
CRF pages and the BI SAE form (if applicable). The investigator should determine the causal 
relationship to the trial medication.
The following should also be recorded as an (S)AE in the CRF and BI SAE form (if 
applicable):

Worsening of the underlying disease or of other pre-existing conditions 

Changes in vital signs, ECG, physical examination and laboratory test results, if they 
are judged clinically relevant by the investigator.
If such abnormalities already pre-exist prior to trial inclusion they will be considered as 
baseline conditions and should be collected in the CRF only.

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All (S)AEs, including those persisting after individual subject’s end of trial must be followed 
up until they have resolved, have been assessed as ‘chronic’ or ‘stable’, or no further 
information can be obtained.
Pregnancy
Once the male subject has been enrolled in the clinical trial and has taken trial medication, 
and if a partner of the male trial participant becomes pregnant, the investigator must report 
any drug exposure during pregnancy in a partner of the male trial participant immediately 
(within 24 hours) by means of Part A of the Pregnancy Monitoring Form to the sponsor’s 
unique entry point, after a written consent of the pregnant partner.
The outcome of the pregnancy associated with the drug exposure during pregnancy must be 
followed up and reported to the sponsor’s unique entry point on the Pregnancy Monitoring 
Form for Clinical Trials (Part B).
The ISF will contain the Pregnancy Monitoring Form for Clinical Trials (Part A and 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 Trials and not the SAE form 
is to be completed. If there is an SAE and/or AESI associated with the pregnancy an SAE 
form must be completed in addition.
5.2.3
Assessment of safety laboratory parameters
For the assessment of laboratory parameters, blood and urine samples will be collected by the 
trial site at the time points indicated in the Flow Chart after the subjects have fasted for at 
least 10 h. Overnight fasting is not required at the discretion of the investigator or designee
for retests.
The parameters that will be determined 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 will only be performed if there is an abnormality 
in the automatic blood cell count, i.e. if automatic count is not feasible or differential WBC is 
abnormal (i.e. pathological or atypical cells) and clinically relevant in the opinion of the 
investigator. In case the urinalysis is positive for erythrocytes, leukocytes, nitrite or protein, 
microscopic examination of the urine sediment will be performed. Positive findings of the 
urine sediment examination will be monitored and if needed based on the medical judgment 
of the investigator an urologist may be consulted.
Fecal occult blood testing, using an immunochemical test kit for hemoglobin, and fecal 
calprotectin testing will be performed by the laboratory at the time points indicated in the 
Flow Chart.
As subjects may not be able to defecate at the trial site in the morning of Visit 1 (Screening) 
and during the ambulatory phase of Visits 2 and 3, they may collect the specimen at home 
and bring the test specimen to the trial site.
In case of gastrointestinal AEs (e.g. diarrhea, constipation), additional testing for fecal
occult blood and fecal calprotectin may be carried out at the discretion of the investigator.
If a subject tests positive for occult blood in feces, further tests will be performed and the 
subject will be monitored closely.

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Table 5.2.3: 1
Routine laboratory tests
Functional lab 
group
Test name 
A1
B2
C2
D3
Hematology
Hematocrit
Hemoglobin
Red blood cell count (RBC)
Reticulocyte count
White blood cell count (WBC)
Platelet count
Erythrocyte sedimentation rate (ESR)
x
x
x
x
x
x
x
x
x
x
--
x
x
x
--
--
--
--
--
--
--
x
x
x
x
x
x
x
Automatic WBC 
differential 
(relative and absolute)
Neutrophils, eosinophils, basophils, monocytes, 
lymphocytes
x
x
--
x
Manual differential 
WBC (if automatic 
count is not feasible or 
differential WBC is 
abnormal and clinically 
relevant in the opinion of 
the investigator)
Polymorphnuclear neutrophils (segs), band 
neutrophils (stabs), eosinophils, basophils, 
monocytes, lymphocytes 
Coagulation
Activated partial thromboplastin time (aPTT)
Prothrombin time (Quick’s test and INR)
Fibrinogen
x
x
x
x
x
x
--
--
--
x
x
x
Enzymes
Aspartate transaminase (AST/GOT)
Alanine transaminase (ALT/GPT)
Alkaline phosphatase (AP)
Gamma-glutamyl transferase (GGT)
Glutamate dehydrogenase (GLDH)
Creatine kinase (CK); CK-MB only if CK is elevated 
Lactate dehydrogenase (LDH)
Lipase
Amylase
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
x
x
x
Hormones
Thyroid stimulating hormone (TSH)
x
--
--
--
Substrates
Plasma glucose
Creatinine 
Total bilirubin 
Direct bilirubin
Total protein
High sensitivity C-Reactive Protein (hsCRP) 
Uric acid 
Total cholesterol 
Triglycerides
Albumin 
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
Electrolytes
Sodium
Potassium
Calcium
Chloride
Inorganic phosphate
x
x
x
x
x
--
--
--
--
--
--
--
--
--
--
x
x
x
x
x
1 Parameters of Set A will be determined at the screening examination.
2 Parameters of Set B and C will be determined at selected time points during Visit 2 and Visit 3 (ref. Flow Chart)
3 Parameters of Set D will be determined during the end of trial examination

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Table 5.2.3: 1
Routine laboratory tests (cont.)
Functional lab 
group
Test name 
A1
B2
C2
D3
Urinalysis (Stix)
Urine nitrite
Urine protein
Urine glucose
Urine ketone
Urobilinogen
Urine bilirubin
Urine erythrocytes
Urine leukocytes
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)
1 Parameters of Set A will be determined at the screening examination.
2 Parameters of Set B and C will be determined at selected time points during Visit 2 and Visit 3 (ref. Flow Chart)
3 Parameters of Set D will be determined during the end of trial examination
The tests listed in Table 5.2.3: 2 are exclusionary laboratory tests which may be repeated as 
required. The results will not be entered in the CRF/database and will not be reported in the 
CTR. Except for drug screening, it is planned to perform these tests during screening only. 
Drug screening will be performed at screening and prior to drug administration on Day 1 of 
each treatment period.
Table 5.2.3: 2
Exclusionary laboratory tests
Functional lab group
Test name 
Drug screening (urine)
Amphetamine/MDA
Barbiturates
Benzodiazepine
Cannabis
Cocaine 
Methadone
Methamphetamines/MDMA/XTC
Opiates 
Phencyclidine
Tricyclic antidepressants
Infectious serology (blood)
Hepatitis B surface antigen (qualitative)
Hepatitis B core antibody (qualitative)
Hepatitis C antibodies (qualitative)
HIV-1 and HIV-2 antibody (qualitative)
To encourage compliance with alcoholic restrictions, a breath alcohol test (Alcotest® 7410, 
Dräger AG, Lübeck, Germany) will be performed prior to drug administration on Day 1 of 
each treatment period, and may be repeated at any time during the study at the discretion of 
an investigator or designee. The results will not be included in the CTR.

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The laboratory tests listed in Table 5.2.3: 1 and 5.2.3: 2 will be performed 
 
 with the exception of 
the drug screening tests. These tests will be performed at the trial site using AccuSign® DOA
10 or a comparable test.
Laboratory data will be transmitted electronically from the laboratory to the trial site.
5.2.4
Electrocardiogram
Twelve-lead ECGs (I, II, III, aVR, aVL, aVF, V1 - V6) will be recorded using a
computerized electrocardiograph (CardioSoft EKG System, GE Medical Systems, Freiburg,
Germany) at the time points given in the Flow Chart.
All ECGs will be recorded for a 10-sec duration after the subjects have rested for at least 5
min in a supine position. ECG assessment will always precede all other study procedures of 
the same time point (except blood drawing from an intravenous cannula which is already in 
place) to avoid impact of sampling on the ECG quality.
All ECGs will be stored electronically on the Muse CV Cardiology System (GE Medical 
Systems, Freiburg, Germany). Electrode placement will be performed according to the 
method of Wilson, Goldberger and Einthoven modified by Mason and Likar (hips and 
shoulders instead of ankles and wrists). 
All locally printed ECGs will be evaluated by the investigator or a designee. ECGs may be
repeated for quality reasons (like alternating current artefacts, muscle movements, electrode 
dislocation) and the repeated ECG will be used for analysis. Additional (unscheduled) ECGs 
may be collected by the investigator for safety reasons. 
Abnormal findings will be reported as AEs (during the trial) or baseline conditions (at 
screening) if judged clinically relevant by the investigator. Any ECG abnormalities will be 
monitored carefully and, if necessary, the subject will be removed from the trial and will 
receive the appropriate medical treatment. 
5.2.5
Assessment of other safety parameters
5.2.5.1
Vital signs
Systolic and diastolic 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 
(Dinamap Pro 100, GE Medical Systems, Freiburg, Germany) 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.
5.2.5.2
Medical examinations
At screening, the medical examination will include demographics including height and body 
weight, smoking and alcohol history, relevant medical history and concomitant therapy, 
review of inclusion and exclusion criteria, review of vital signs (BP, PR), 12-lead ECG, 

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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.
5.3
OTHER
5.3.1
Pharmacogenomic evaluation
Pharmacogenomic investigations explore the role of genetic variation in determining an 
individual’s response to drugs. For this purpose, a sample of at most 10 mL of blood will be 
taken at the screening examination from each subject whose genotype has not been 
previously determined. Separate informed consent for genotyping will be obtained from each 
volunteer prior to sampling.
DNA will be extracted from the blood sample in order to sequence genes coding for proteins 
that are involved in the absorption, distribution, metabolism, and excretion (ADME) of drugs. 
The gene sequences to be determined include known and likely functional variations of key 
ADME genes and incorporate more than 90% of ADME-related genetic markers identified by 
the PharmaADME group (weblink.pharmaadme.org). It is not intended to include the
pharmacogenomic data in the final report. However, the data may be part of the report if 
necessary.
5.4
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 5.5 are 
generally used assessments of drug exposure.
5.5
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS
Date and clock time of drug administration and pharmacokinetic sampling will be recorded.
Exact time points of plasma sampling will be derived from the study management system 
ClinBase™ and documented in the CRFs by the medical personnel or sent as electronic files
to the trial data manager. The actual sampling times will be used for determination of 
pharmacokinetic parameters.
5.5.1
Pharmacokinetic endpoints
5.5.1.1
Primary endpoints
The following primary endpoints will be determined for BI 1015550:

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
AUC0-119 (area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to 119 h)

Cmax (maximum measured concentration of the analyte in plasma)
5.5.1.2
Secondary endpoints
The following secondary endpoints will be evaluated for BI 1015550:

AUC0-∞(area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity)
 
 
 
 
 
Plasma concentrations of itraconazole and OH-itraconazole will be assessed at the time points 
given in the Flow Chart to confirm sufficient itraconazole/OH-itraconazole exposure and 
might be used for modeling to assess the effect of other CYP3A inhibitors (e.g. moderate 
inhibitors) on BI 1015550 pharmacokinetics.

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5.5.2
Methods of sample collection
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5.5.2.2
Plasma sampling for pharmacokinetic analysis of itraconazole and OH-
itraconazole
For quantification of itraconazole and its metabolite plasma concentrations, 2.6 mL of blood 
will be taken from an antecubital or forearm vein into a Sodium-Heparin anticoagulant blood 
drawing tube at the times indicated in the Flow Chart. Blood will be withdrawn by means of 
either an indwelling venous catheter or by venipuncture with a metal needle.
The Sodium-Heparin-anticoagulated blood samples will be centrifuged for about 10 min at 
about 2000 g to 4000 g and at about 4° to 8 °C. Two plasma aliquots will be obtained and 
stored in polypropylene tubes. The first aliquot should contain at least 0.5 mL plasma. Plasma 
aliquots will be frozen within 2 hours after blood withdrawal (interim storage of 
blood/plasma at room temperature). For each aliquot the time when the sample was placed in 
the freezer will be documented. Until transfer on dry ice to the analytical laboratory, the 
aliquots will be stored upright at about - 20°C or below at the trial site. The second aliquot 
will be transferred to the analytical laboratory after the bioanalyst has acknowledged safe 

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arrival of the first aliquot. At the analytical laboratory the plasma samples will be stored at 
about -20°C or below until analysis.
The sample tube labels should list at least the following information: study number, subject 
number, visit, and planned time. Further information such as matrix and analyte may also be 
given.
After completion of the trial the plasma samples may be used for further methodological 
investigations for e.g. stability testing, assessment of metabolites. However, only data related 
to the analyte and its metabolite(s) will be generated by these additional investigations. The 
study samples will be discarded after completion of the additional investigations but not later 
than 5 years upon the final study report has been signed.
5.5.3
Analytical determinations
5.5.3.1
Analytical determination of analyte plasma concentration
The analysis will be performed under
the responsibility of Drug Metabolism and Pharmacokinetics, Boehringer Ingelheim Pharma 
GmbH & Co. KG, Biberach, Germany at a suitable contract research organization (CRO).

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6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
Exact times of measurements outside the permitted time windows will be documented. The 
acceptable time windows for screening and end of trial examination are given in the Flow 
Chart.
Study measurements and assessments scheduled to occur ‘before’ trial medication 
administration are to be performed and completed within a 3 h-period prior to the trial drug 
administration as indicated in the Flow Chart. 
The acceptable deviation from the scheduled time for vital signs, ECG and laboratory tests 
will be ± 30 min.
If scheduled in the Flow Chart at the same time as a meal, blood sampling, vital signs and 12-
lead ECG recordings have to be done first. Furthermore, if several measurements including 
venipuncture are scheduled for the same time, venipuncture should be the last of the
measurements due to its inconvenience to the subject and possible influence on physiological
parameters.
For planned individual plasma concentration sampling times refer to the Flow Chart. While 
these nominal times should be adhered to as closely as possible, the actual sampling times 
will be recorded and used for determination of pharmacokinetic parameter.
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 give their written informed 
consent in accordance with GCP and local legislation prior to enrolment in the study.
For information regarding laboratory tests (including drug and virus screening, fecal occult 
blood testing and fecal calprotectin testing), ECG, vital signs, and physical examination, refer 
to Sections 5.2.3 to 5.2.5.
Pharmacogenomic genotyping will be performed in those volunteers whose genotypes are not 
known (for details see Section 5.3).
6.2.2
Treatment periods
Each subject is expected to participate in two treatment periods (Treatment R, Day -5 to Day 
6 followed by Treatment T, Day -3 to Day 10). The washout period between the single dose 
BI 1015550 administrations in treatments R and T will be at least 10 days.
On Day 1 of each treatment period study participants will be admitted to the trial site and 
kept under close medical surveillance for at least 24 h following administration of BI 

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1015550. The subjects will then be allowed to leave the trial site after formal assessment and 
confirmation of their fitness. On all other study days, the study will be performed in an 
ambulatory fashion. Likewise, itraconazole administrations on Days -3, -2, -1, 3 to 9 of
treatment T will be done in an ambulatory fashion.
For details on time points and procedures for collection of plasma samples for PK analysis, 
refer to Flow Chart and Section 5.5.2.
The safety measurements performed during the treatment period are specified in Section 5.2
of this protocol and in the Flow Chart. For details on time points for all other trial procedures, 
refer to the Flow Chart. AEs and concomitant therapy will be assessed continuously from 
screening until the end of trial examination.
6.2.3
End of trial period
For AE assessment, laboratory tests, recording of ECG and vital signs, and physical 
examination during the end of trial period, see Sections 5.2.2 to 5.2.5.
Subjects who discontinue treatment before the end of the planned treatment period should 
undergo the end of trial visit.
All abnormal values (including laboratory parameters) that are judged clinically relevant by 
the investigator will be monitored using the appropriate tests until a return to a medically 
acceptable level is achieved. (S)AEs persisting after subject’s end of trial must be followed 
up until they have resolved, have been sufficiently characterized, or no further information 
can be obtained.
The end of the trial as a whole is defined by the ‘last regular visit completed by last subject’ 
or ‘end date of the last open AE’ or ‘date of the last follow-up test’ or ‘date of an AE has 
been decided as sufficiently followed-up’, whichever is latest.

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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
7.1
STATISTICAL DESIGN – MODEL
7.1.1
Objectives
The primary objective of this trial is to investigate the effect of multiple doses of itraconazole 
on the pharmacokinetics of BI 1015550 given as single dose. The reference treatment (R) is 
administration of BI 1015550 alone, test treatment (T) is the co-administration of BI 1015550 
on the fourth day of a 12-day treatment with itraconazole in healthy male volunteers. The trial 
is designed to allow intrasubject comparisons and will be evaluated statistically by use of an 
appropriate linear model.
The secondary objective is the evaluation and comparison of several pharmacokinetic 
parameters between the treatments. The secondary objective(s) will be assessed by 
descriptive statistics.
The assessment of safety and tolerability will be an additional objective of this trial, and will 
be evaluated by descriptive statistics.
7.1.2
Endpoints
Relative bioavailability is to be determined on the basis of the primary and secondary 
pharmacokinetic endpoints (see Section 5.5.1).
Safety and tolerability will be determined on the basis of the parameters specified in Section 
5.2.1.
7.1.3
Model
The statistical model used for the analysis of primary and secondary endpoints will be an 
ANOVA (analysis of variance) model on the logarithmic scale. This model will include 
effects accounting for the following sources of variation: ‘Subject’ and ‘treatment’. The 
effect ‘subject’ will be considered as random, whereas the other effect will be considered as 
fixed. The model is described by the following equation:
yij = + si + j + eij, where
yij = logarithm of response (endpoint, see Section 5.5.1) measured on subject i 
receiving treatment j,
= the overall mean,
si = the effect associated with the ith subject, i = 1, 2, ..., n
j = the jth treatment effect, j = 1, 2,

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eij = the random error associated with the ith subject who received treatment j.
In addition, the same analysis will be applied using subject as fixed effect.
7.2
NULL AND ALTERNATIVE HYPOTHESES
The relative bioavailability of BI 1015550 administered alone or in combination with 
multiple oral doses of itraconazole will be estimated by the ratios of the geometric means 
(test/reference) for the primary and secondary PK endpoints. Additionally, their two-sided 
90% confidence intervals (CIs) will be provided. This method corresponds to the two one-
sided t-tests procedure, each at the 5% significance level. Since the main focus is on 
estimation and not testing, an acceptance range was not specified, that is, no hypothesis will 
be tested.
7.3
PLANNED ANALYSES
7.3.1
Primary analyses
The pharmacokinetic endpoints listed in Section 5.5.1 will be calculated according to the BI 
Standard Operating Procedure (SOP) ‘Standards and processes for analyses performed within 
Clinical Pharmacokinetics/Pharmacodynamics’ (001-MCS-36-472).
Pharmacokinetic parameters of a subject will be included in the analysis unless the subject 
has an important protocol violation relevant for the evaluation. Whether a protocol violation 
is important will be decided no later than in the Report Planning Meeting.
Reasons for exclusion of single pharmacokinetic parameters may be:

The subject experiences emesis at or before two times median tmax. Median tmax is to 
be taken either from the median tmax for the reference product or from median tmax for 
the test product, depending on whether the subject had experienced emesis after taken 
the test or the reference product. Median tmax is to be determined excluding the 
subjects experiencing emesis

Time deviations

Use of restricted medications 
Violations may lead to exclusion of single measurements/parameters for a subject (e.g. only 
data of one study period) or even to exclusion of all data of the subject.
The subject set for the evaluation of PK endpoints (PKS) will include all treated subjects that 
provide at least one observation for at least one primary or secondary endpoint without 
important protocol violations with respect to the statistical evaluation of PK endpoints. It will 
also be decided in the Report Planning Meeting which subjects are to be included in the PKS.
Point estimates of bioavailability, the ratios of the geometric means (test/reference) for the 
primary and secondary endpoints (see 5.5.1.1, 5.5.1.2), and their two-sided 90% confidence 
intervals (CIs) will be provided.

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To this end, the PK endpoints will be log transformed (natural logarithm) prior to fitting the 
ANOVA model (cf. Section 7.1.3). For each endpoint, the difference between the expected 
means for log(T)-log(R) will be estimated by the difference in the corresponding adjusted 
means (LeastSquares Means), and a two-sided 90% confidence interval based on the 
t-distribution will be computed. These quantities will then be back-transformed to the original 
scale to provide the point estimate and 90% CIs for each endpoint.
7.3.2
Secondary analyses
The secondary parameters (refer to Section 5.5.1) will be calculated according to the BI SOP 
‘Standards and processes for analyses performed within Clinical Pharmacokinetics/ 
Pharmacodynamics’ (001-MCS-36-472) and will statistically be assessed using the same 
methods as described for the primary endpoints.
7.3.3
Safety analyses
Safety will be assessed for the endpoints listed in Section 5.2.1. All treated subjects (that is,
all subjects who received at least one dose of study drug), will be included in the safety
analysis. Safety analyses will be descriptive in nature and will be based on BI standards. No 
hypothesis testing is planned.
The analyses will be done by ‘treatment at onset’.
Treatments will be compared in a descriptive way. Tabulations of frequencies/proportions 
will be used for the evaluation of categorical (qualitative) data, and tabulations of descriptive 
statistics will be used to analyze continuous (quantitative) data.
Measurements (such as ECG, vital signs, or laboratory parameters) or AEs will be assigned to 
treatments (see Section 4.1) based on the actual treatment at the planned time of the 
measurement or on the recorded time of AE onset (concept of treatment emergent AEs).
Therefore, measurements planned or AEs recorded prior to first intake of trial medication will 
be assigned to 'screening', those between first trial medication intake until the end of its 
residual effect period (REP) will be assigned to the preceding treatment, and those after the 
REP but prior to the next intake or end of trial examination will be assigned to ‘follow-up’.
Therefore, measurements planned or AEs recorded prior to first intake of trial medication will 
be assigned to 'screening', those between first trial medication intake until end of the residual 
effect period (see 5.2.2.2) will be assigned to the treatment period. Events after the residual 
effect period but prior to next intake or end of trial examination will be summarized as
‘follow-up’. These assignments including the corresponding time intervals will be defined in 
detail in the TSAP. Please note that AEs occurring after the last per protocol contact but 
entered before database lock will be reported to drug safety only and will not be captured in 
the trial database
Additionally, further treatment intervals (analyzing treatments) may be defined in order to 
provide summary statistics for time intervals, such as combined treatments, on-treatment 
totals or periods without treatment effects (such as screening and 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 

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treatment, system organ class and preferred term. SAEs, AESIs (see Section 5.2.2.1) and 
other significant AEs (according to ICH E3) will be listed separately.
Laboratory data will be compared to their reference ranges. Values outside the reference 
range as well as values defined as clinically relevant will be highlighted in the listings. 
Additionally, differences from baseline will be evaluated.
Vital signs or other safety-relevant data observed at screening, baseline, during the course of 
the trial and at the end-of-trial evaluation will be assessed with regard to possible changes 
compared to findings before start of treatment.
Relevant ECG findings will be reported as AEs.
7.3.4
Interim analyses
No interim analysis is planned.
7.3.5
Pharmacokinetic analyses
The pharmacokinetic parameters listed in Section 5.5.1 for BI 1015550 and its relevant 
metabolites will be calculated according to the relevant SOP of the Sponsor (001-MCS-36-
472) using validated software programs (preferably Phoenix WinNonlin®).
Subjects who are not included in the PKS (refer to Section 7.3.1.) will be reported with their 
individual plasma concentrations and individual pharmacokinetic parameters; however, they 
will not be included in descriptive statistics for plasma concentrations, pharmacokinetic 
parameters or other statistical assessment.
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).
If a predose concentration value is greater than 5% of Cmax, the subject’s pharmacokinetic 
data will be not included in any statistical evaluations, in accordance with international 
guidance. The individual pharmacokinetic parameters of such a subject will be calculated and 
listed separately. If a predose concentration is above BLQ, but less than or equal to 5% of the 
subject’s Cmax value, the subject’s data without any adjustments will be included in all 
pharmacokinetic measurements and calculations.
7.4
HANDLING OF MISSING DATA
7.4.1
Safety
With respect to safety evaluations, it is not planned to impute missing values.
7.4.2
Plasma drug concentration - time profiles
Handling of missing PK data will be performed according to the relevant Corporate 
Procedure of the Sponsor (001-MCS-36-472).

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Drug concentration data identified with NOS (no sample available), NOR (no valid result), 
NOA (not analyzed), BLQ (below the lower limit of quantification), or NOP (no peak 
detectable) will be displayed as such and not replaced by zero at any time point (this rule also 
applies also to the lag phase, including the predose values). 
7.4.3
Pharmacokinetic parameters
For the non-compartmental analysis, concentration data identified with NOS, NOR or NOA 
will generally not be considered. Concentration values in the lag phase identified as BLQ or 
NOP will be set to zero. All other BLQ/NOP values of the profile will be ignored. The lag 
phase is defined as the period between time zero and the first time point with a concentration 
above the quantification limit.
7.5
RANDOMISATION
As this is a single sequence trial, no randomization is necessary (see also Section 4.1.2).
The sponsor will arrange for the packaging and labelling of BI 1015550 trial medication.
7.6
DETERMINATION OF SAMPLE SIZE
It is planned to enter a total of 16 subjects to have at least 12 completed in the trial. The 
planned sample size is not based on a power calculation but is judged to be adequate to attain 
reliable results and to fulfil the objectives and requirements of this exploratory trial.
The observed coefficient of variations (gCV) for AUC and Cmax in previous trials 1305.1 and 
1305-0011 [c01843325, c15772185-03] were from 12.7% to 32.0% for AUC0-∞and 12.6% -
38.9% for Cmax (Table 1.2.1.5.2: 1). The reported variability originates from parallel group
designs where the gCV is an estimate of total variability. For this study an estimate of intra-
individual variability is needed. Given the correlation between two responses of the same 
subject (ρ), the intra-individual variability can be estimated from the total variability. The 
recommended ranges for ρ in PK trials are (0.5- 0.6) for Cmax and (0.75- 0.8) for AUC. 
Assuming conservative values ρ=0.5 for Cmax and ρ =0.75 for AUC, the intra-individual gCV 
will be between 8.9% and 27% for Cmax and between 6.3% and 15.7% for AUC. Hence, four 
different scenarios are considered for gCV in this trial.
Assuming different gCVs of 15%, 20%, 25% and 30% for AUC and Cmax and given the 
chosen sample size of 16 subjects, the precision of the two-sided 90% confidence interval of 
the bioavailability ratio (upper confidence limit / relative BA estimate) will be from 1.13 to 
1.26, and for the least acceptable sample size (i.e. 12 subjects), the precision would be 
approximately between 1.16 and 1.33. Table 7.6: 1 and Table 7.6: 2 provide an overview of 
the 90% confidence intervals that are expected with 95% probability, for possible scenarios 
of the gCV and intra-subject ratios (test/reference) (T/R).

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Table 7.6: 1
Precision that can be expected with 95% tolerance probability and illustrative 
two-sided 90% confidence intervals around the ratios of geometric means 
(T/R) for different gCVs (N=16).
gCV [%]
Precision upper CL / 
relative BA estimate
Ratio [%]*
Lower CL [%]
Upper CL [%]
15
1.13
50
44.38
56.34
15
1.13
100
88.75
112.68
15
1.13
150
133.13
169.01
15
1.13
250
221.88
281.69
20
1.17
50
42.67
58.58
20
1.17
100
85.35
117.17
20
1.17
150
128.02
175.75
20
1.17
250
213.37
292.92
25
1.22
50
41.06
60.89
25
1.22
100
82.12
121.77
25
1.22
150
123.18
182.66
25
1.22
250
205.30
304.44
30
1.26
50
39.53
63.24
30
1.26
100
79.07
126.47
30
1.26
150
118.60
189.71
30
1.26
250
197.67
*Ratio of geometric means (test/reference) for a PK endpoint is defined by exp(T)/exp(R).
Table 7.6: 2
Precision that can be expected with 95% tolerance probability and illustrative 
two-sided 90% confidence intervals around the ratios of geometric means 
(T/R) for different gCVs (N=12).
gCV [%]
Precision upper CL / 
relative BA estimate
Ratio [%]*
Lower CL [%]
Upper CL [%]
15
1.16
50
43.20
57.88
15
1.16
100
86.39
115.75
15
1.16
150
129.59
173.63
15
1.16
250
215.98
289.38
20
1.21
50
41.18
60.72
20
1.21
100
82.35
121.43
20
1.21
150
123.53
182.15
20
1.21
250
205.88
303.58
25
1.27
50
39.28
63.65
25
1.27
100
78.55
127.31
25
1.27
150
117.83
190.96
25
1.27
250
196.38
318.27
30
1.33
50
37.49
66.68
30
1.33
100
74.99
133.36
30
1.33
150
112.48
200.03
30
1.33
250
187.47
333.39
*Ratio of geometric means (test/reference) for a PK endpoint is defined by exp(T)/exp(R).

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It is planned to enter 16 subjects to have at least 12 completed subjects. This means, in total 
up to 4 dropouts would be acceptable providing that the number of subjects with evaluable 
PK data should not be less than 12. 
The calculation was performed as described by Julious [R11-5230] using R Version 3.3.2.

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8.
INFORMED CONSENT, DATA PROTECTION, TRIAL
RECORDS
The trial will be carried out in compliance with the protocol, the principles laid down in the 
Declaration of Helsinki, in accordance with the ICH Harmonized Tripartite Guideline for 
Good Clinical Practice (GCP) and relevant BI SOPs.
The investigator should inform the sponsor immediately of any urgent safety measures taken 
to protect the study subjects against any immediate hazard, and also of any serious breaches 
of the protocol or of ICH GCP.
As a general rule, no trial results should be published prior to finalization of the CTR.
Insurance Coverage: The terms and conditions of the insurance coverage must be given to 
each subject and are made available to the investigator via documentation in the ISF.
8.1
STUDY APPROVAL, SUBJECT INFORMATION, AND INFORMED 
CONSENT
This trial will be initiated only after all required legal documentation has been reviewed and 
approved by the respective Institutional Review Board (IRB) / Independent Ethics Committee 
(IEC) and competent authority (CA) according to national and international regulations. The 
same applies for the implementation of changes introduced by amendments.
Prior to a subject’s participation in the trial, written informed consent must be obtained from 
each subject (or the subject’s legally accepted representative) according to ICH GCP and to 
the regulatory and legal requirements of the participating country. Each signature must be 
personally dated by each signatory and the informed consent and any additional subject 
information form are to be retained by the investigator as part of the trial records. A copy of 
the signed and dated written informed consent and any additional subject information must be 
given to each subject or the subject’s legally accepted representative.
The subject must be informed that his/her personal trial-related data will be used by 
Boehringer Ingelheim in accordance with the local data protection law. The level of 
disclosure must also be explained to the subject.
The subject must be informed that his or her medical records may be examined by authorized
monitors (Clinical Monitor Local/Clinical Research Associate) or Clinical Quality Assurance 
auditors appointed by Boehringer Ingelheim, by appropriate IRB/IEC members, and by 
inspectors from regulatory authorities.
8.2
DATA QUALITY ASSURANCE
A quality assurance audit/inspection of this trial may be conducted by the sponsor or 
sponsor’s designees, by IRBs/IECs, or by regulatory authorities. The quality assurance 
auditor will have access to all medical records, the investigator’s trial-related files and 
correspondence, and the informed consent documentation of this clinical trial.

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The data management procedures to ensure the quality of the data are described in detail in 
the trial data management and analysis plan (TDMAP) available in the TMF.
8.3
RECORDS
CRFs for individual subjects will be provided by the sponsor. For drug accountability, refer 
to Section 4.1.8.
ClinBaseTM
In the Human Pharmacology Centre (HPC) – Boehringer Ingelheim's Phase I unit – the 
validated ClinBaseTM system is operated for processing information and controlling data 
collected in clinical studies. In addition to its function as a procedure control system, 
ClinBaseTM serves as data base. Instead of being entered into CRFs, selected data are directly 
entered into the system.
8.3.1
Source documents
Source documents provide evidence for the existence of the subject and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site.
All data reported in the CRFs must be consistent with the source data or the discrepancies 
must be explained.
Data directly entered into ClinBaseTM (that is, without prior written or electronic record) are 
considered to be source data. The place where data is entered first will be defined in a trial 
specific Source Data Agreement. The data in ClinBaseTM are available for inspection at any 
time.
The investigator may need to request previous medical records or transfer records, depending 
on the trial.
8.3.2
Direct access to source data and documents
The investigator/institution will permit trial-related monitoring, audits, IRB/IEC review and 
regulatory inspection, providing direct access to all related source data/documents. CRFs and 
all source documents, including progress notes (if applicable) and copies of laboratory and 
medical test results must be available at all times for review by the sponsor’s clinical trial 
monitor, auditor and inspection by health authorities (e.g. FDA). The Clinical Research 
Associate/on site monitor and auditor may review all CRFs, and written informed consents. 
The accuracy of the data will be verified by reviewing the documents described in Section 
8.3.1.
8.3.3
Storage period of records
Trial site:
The trial site must retain the source and essential documents (including ISF) according to the 
national or local requirements (whatever is longer) valid at the time of the end of the trial.
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
Individual subject medical information obtained as a result of this trial is considered 
confidential and disclosure to third parties is prohibited with the exceptions noted below. 
Subject confidentiality will be ensured by using subject identification code numbers.
Treatment data may be provided to the subject’s personal physician or to other appropriate 
medical personnel responsible for the subject’s welfare. Data generated 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, i.e. the CA.
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 from clinical trial participants and the corresponding data, in
particular:

A Quality Management System has been implemented to ensure the adherence with 
the Principles of Good Clinical Practice as outlined in 'Note For Guidance On Good
Clinical Practice' (CPMP/ICH/13 5/95)

The BI-internal facilities storing and analyzing biological samples and data from 
clinical trial participants as well as the laboratories' activities for clinical trials 
sponsored by Boehringer Ingelheim are regularly audited. The analytical groups and 
the banking facility are therefore assessed to be qualified for the storage and use of
biological samples and data collected in clinical trials.

Samples and data are used only if an appropriate informed consent is available.
8.6
COMPLETION OF TRIAL
The EC/competent authority in each participating EU member state needs to be notified about 
the end of the trial (last subject/subject out, unless specified differently in Section 6.2.3 of the 
CTP) or early termination of the trial.

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9.
REFERENCES 
9.1
PUBLISHED REFERENCES
P11-07084
Raghu G, et al, ATS/ERS/JRS/ALAT Committee on Idiopathic Pulmonary 
Fibrosis. An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary 
fibrosis: evidence-based guidelines for diagnosis and management. Am J 
Respir Crit Care Med 2011;183(6):788-824.
P12-05791
U.S. Department of Health and Human Services Food and Drug 
Administration Center for Drug Evaluation and Research (CDER). 
Guidance for industry: drug interaction studies - study design, data analysis, 
implications for dosing, and labeling recommendations (draft guidance, 
February 2012 (this guidance document is being distributed for comment 
purposes only)). http://www.fda.gov/downloads/Drugs/GuidanceComplianc 
eRegulatoryInformation/Guidances/ucm292362.pdf (access date: 14 May 
2012) ; U.S. Department of Health and Human Services, Food and Drug 
Administration, Center for Drug Evaluation and Research (CDER); 2012.
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European Medicines Agency (EMA). Committee for Human Medicinal 
Products (CHMP): guideline on the investigation of drug interactions (21 
June 2012, CPMP/EWP/560/95/rev. 1 corr. 2). http://www.ema.europa.eu/
docs/en_GB/document_library/Scientific_guideline/2012/07/WC50012960
6.pdf (access date: 8 July 2015); London: European Medicines Agency 
(EMA); 2012.
P15-07539
Raghu G, et al, American Thoracic Society (ATS), European Respiratory 
Society (ERS), Japanese Respiratory Society (JRS), Latin American 
Thoracic Association (ALAT). An official ATS/ERS/JRS/ALAT clinical 
practice guideline: treatment of idiopathic pulmonary fibrosis: an update of 
the 2011 clinical practice guideline. Am J Respir Crit Care Med 
2015;192(2):e3-e19.
R06-2665
Guidance for industry: drug interaction studies - study design, data analysis, 
and implications for dosing and labeling. 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); 2006.
R10-1102
Templeton IE, Thummel KE, Kharasch ED, Kunze KL, Hoffer C, Nelson 
WL, Isoherranen N. Contribution of itraconazole metabolites to inhibition 
of CYP3A4 in vivo. Clin Pharmacol Ther 2008;83(1) :77-85.

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R10-1555
Daxas (roflumilast) in chronic obstructive pulmonary disease, NDA 22-522, 
FDA Advisory Committee briefing document presented to: Pulmonary-
Allergy Drugs Advisory Committee (briefing book, April 7, 2010). 
http://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/Dr
ugs/Pulmonary-AllergyDrugsAdvisoryCommittee/ucm207376.htm (access 
date: 23 November 2010); Jersey City: Forest Research Institute; 2010.
R10-1559
Giembycz MA. Life after PDE4: overcoming adverse events with dual-
specificity phosphodiesterase inhibitors. Curr Opin Pharmacol 2005;5:238-
244.
R11-5230
Julious SA. Sample sizes for clinical trials. Boca Raton: Taylor & Francis 
Group; 2010.
R11-2587
Ley B, Collard HR, King TE. Clinical course and prediction of survival in 
idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2011;183:431-
440.
R12-5255
Sempera capsules (Janssen), Rx only (prescribing information, as at 
October 2011). 2011.
R12-5316
Barone JA, Muskovitz BL, Guarnieri J, Hassell AE, Colaizzi JL, Bierman 
RH, Jessen L. Enhanced bioavailability of itraconazole in hydroxypropyl-
beta-cyclodextrin solution versus capsules in healthy volunteers. 
Antimicrob Agents Chemother 1998;42(7) :1862-1865.
R12-5317
Hardin TC, Graybill JR, Fetchick R, Woestenborghs R, Rinaldi MG, Kuhn 
JG. Pharmacokinetics of itraconazole following oral administration to 
normal volunteers. Antimicrob Agents Chemother 1988;32(9) :1310-1313.
R12-5527
Nalysnyk L, Cid-Ruzafa J, Rotella P, Esser D. Incidence and prevalence of  
idiopathic pulmonary fibrosis: review of the literature. Eur Respir Rev 
2012; 21(126):355-361.
R13-4571
Kantola T, Kivisto KT, Neuvonen PJ. Effect of itraconazole on the 
pharmacokinetics of atorvastatin. Clin Pharmacol Ther 1998;64(1) :58-65.
R13-4572
Cooper KJ, Martin PD, Dane AL, Warwick MJ, Schneck DW, Cantarini 
MV. Effect of itraconazole on the pharmacokinetics of rosuvastatin. Clin 
Pharmacol Ther 2003;73(4) :322-329.
R13-4573
Tapaninen T, Backman JT, Kurkinen KJ, Neuvonen PJ, Niemi M. 
Itraconazole, a P-glycoprotein and CYP3A4 inhibitor, markedly raises the
plasma concentrations and enhances the renin-inhibiting effect of aliskiren. 
J Clin Pharmacol 2011; 51(3) :359-367.
R14-1795
Otezla (apremilast) tablets, for oral use (Celgene) (U.S. prescribing
information, revised: 3/2014); 2014.

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R15-3252
Jalava KM, Partanen J, Neuvonen PJ. Itraconazole decreases renal 
clearance of digoxin. Ther Drug Monit 1997;19(6) :609-613.
R17-0158
Korkmaz S, Maupoil V, Sobry C, Brunet C, Chevalier S, Freslon JL. An 
increased regional blood flow precedes mesenteric inflammation in rats 
treated by a phosphodiesterase 4 inhibitor. Toxicol Sci 2009;107(1) :298-
305.
R17-0915
Roflumilast 500 mcg tablets (Forest Research Institute): pharmacology/to 
xicology NDA/BLA review and evaluation, application number:  
022522Orig1s000. http://www.accessdata.fda.gov/drugsatfda_docs/nda/ 
2011/022522Orig1s000PharmR.pdf (access date: 13 March 2017); 
Department of Health and Human Services, Public Health Service, Food 
and Drug Administration, Center for Drug Evaluation and Research; 2011.
R17-0916
Losco PE, Evans EW, Barat SA, Blackshear PA, Reyderman L, Fine JS, et 
al. The toxicity of SCH 351591, a novel phosphodiesterase-4 inhibitor, in 
cynomolgus monkeys. Toxicol Pathol 2004;32(3) :295-308.
R17-0919
Otezla (apremilast) (Celgene): pharmacology/toxicology NDA/BLA review 
and evaluation, application number: 205437Orig1s000. 
http://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/205437Orig1s00
0PharmR.pdf (access date: 13 March 2017) ; Department of Health and 
Human Services, Public Health Service, Food and Drug Administration, 
Center for Drug Evaluation and Research; 2014.
R17-1539
Otezla 30mg tablets (Celgene) (summary of product characteristics updated 
05-Jan-2017). http://www.medicines.org.uk/emc/print-document?docume 
ntId=29792 (access date: 2 May 2017); 2017.
R17-1540
Otezla 10mg, 20mg, 30mg treatment initiation pack (Celgene) (summary of 
product characteristics updated 05-Jan-2017). http://www.medicines.org.uk/
emc/print-document?documentId=29793 (access date: 2 May 2017); 2017.
R17-1542
Daxas 500 micrograms film-coated tablets (AstraZeneca) (summary of 
product characteristics updated 06-Dec-2016). http://www.medicines. 
org.uk/emc/print-document?documentId=23416 (access date: 2 May 2017); 
2016.
R17-3740
Sempera liquid 10 mg/ml (Janssen) (prescribing information, as at March
2017). 2017.
R17-3741
Sporanox 10 mg/ml oral solution (Janssen-Cilag) (summary of product 
characteristics updated 26-Oct-2016). https://www.medicines.org.uk/ 
emc/print-document?documentId=7514 (access date :31 August 2017); 
2016.

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R17-3742
Barone JA, Moskovitz BL, Guarnieri J, Hassell AE, Colaizzi JL, Bierman 
RH, et al. Food interaction and steady-state pharmacokinetics of 
itraconazole oral solution in healthy volunteers. Pharmacotherapy 1998; 
18(2) :295-301.
R17-3743
Willems L, Geest R van der, Beule K de. Itraconazole oral solution and 
intravenous formulations: a review of pharmacokinetics and 
pharmacodynamics. J Clin Pharm Ther 2001; 26 :159-169.
R17-3744
Liu L, Bello A, Dresser MJ, Heald D, Komjathy SF, O'Mara E, et al. Best
practices for the use of itraconazole as a replacement for ketoconazole in 
drug-drug interaction studies. J Clin Pharmacol 2016; 56(2) :143-151.
9.2
UNPUBLISHED REFERENCES
001-MCS-36-472 Standards and processes for analyses performed within Clinical 
Pharmacokinetics/Pharmacodynamics. Current version
c01843325
 Safety, tolerability and 
pharmacokinetics of single rising oral doses of BI 1015550 in healthy male 
volunteers (a partially randomised, single-blinded, placebo-controlled Phase 
I study). 1305.1. 21 Jun 2013.
c20400964
. 8-04-qc-preliminary-analyses-part1-2017-10-04-final-qc-doc. 
1350.11. 23 Oct 2017.
c02094779-02
, 
Investigator's 
Brochure BI 1015550 for Idiopathic Pulmonary Fibrosis. 12 May 2017.
c02191718-02
 Safety, 
tolerability and pharmacokinetics of multiple rising oral doses of BI 
1015550 powder for oral solution in healthy male volunteers q.d. or b.i.d. 
for 14 days (a randomised, double-blind, placebo-controlled within dose 
groups Phase I trial). 1305.2. 15 Apr 2014.
c02336088
 Relative bioavailability of a 
single oral dose of BI 691751 when administered alone or in combination 
with multiple oral doses of itraconazole in healthy male subjects (an open-
label, randomised, two-period, two-sequence crossover study). 1334.10. 
09 Jan 2015.
c03355329
 Relative bioavailability of a single 
oral dose of BI 425809 when administered alone or in combination with 
multiple oral doses of itraconazole in healthy male subjects (an open-label, 
two-period, fixed-sequence trial). 1346.10. 03 Dec 2015.

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c08928447
 Effect of multiple doses of 
itraconazole on the pharmacokinetics of a single oral dose of BI 1026706 in 
healthy male subjects (an open-label, randomised, two-period, two-
sequence crossover study). 1320.20. 29 Sep 2016.
c15772185-03
. Safety, tolerability, and pharmacokinetics 
of single (Part 1) and multiple rising oral doses (Part 2) of BI 1015550 in 
healthy male subjects. 1305.11. 28 Aug 2017.
c17549115-01
Relative bioavailability of BI 1015550 
following oral administration under fed and fasted conditions in healthy 
male subjects. 1305-0020. 11 Jul 2017.

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10.
APPENDICES
Not applicable.

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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
Number of global amendment
1
Date of CTP revision
15 January 2018
EudraCT number
2017-003452-23
BI Trial number
1305-0015
BI Investigational Product(s)
BI 1015550
Title of protocol
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
To be implemented only after 
approval of the IRB / IEC /
Competent Authorities
To be implemented 
immediately in order to 
eliminate hazard –
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval
Can be implemented without 
IRB / IEC / Competent 
Authority approval as changes 
involve logistical or 
administrative aspects only
Section to be changed
1. Flow Chart, p 5
2. Section 5.5.2.1, p 52
3. Section 5.5.2.2, p 52
Description of change
Storage temperature of 20° (typo) was corrected 
to – 20° and a minor inconsistency in the Flow 
Chart was removed. 
Rationale for change
By mistake 20° instead of – 20° was written in the 
plasma sample handling instruction. This 
amendment was issued to correct the mistake and 
ensure correct sample handling. At the same time 
a minor inconsistency in the Flow Chart was 
removed.

 
 
 
 
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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
Author-Trial Statistician
15 Jan 2018 15:51 CET
Approval-Trial Clinical Monitor
15 Jan 2018 16:41 CET
Author-Trial Clinical
Pharmacokineticist
16 Jan 2018 02:28 CET
Approval-Therapeutic Area
16 Jan 2018 08:25 CET
Verification-Paper Signature
Completion
16 Jan 2018 13:29 CET
Approval-Team Member Medicine
24 Jan 2018 09:47 CET

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