Clinical trial NCT04716894
Conditions: Healthy
Sponsor: Boehringer Ingelheim
Start date: 2021-02-01; Completion date: 2021-04-01
Enrollment: 14 participants; Allocation: NA; Intervention model: SEQUENTIAL

Brief summary:
The main objective of this trial is to investigate the effect on the exposure of BI 474121 in plasma when given as oral single dose together with multiple oral doses of itraconazole (Test, T) as compared to when given alone as oral single dose (Reference, R).

Detailed description:

Arms: arm 1: Period 1:

Reference (R) treatment: Healthy subjects received a single dose of 0.5 milligram (Powder for oral solution, 0.5 milligram (mg)/milliliter (mL) formulation) BI 474121 on day 1 of period 1.

Period 2:

Test (T) treatment: Healthy subjects received a daily dose of 200 milligram (oral solution, 10 mg/mL) Itraconazole for 14 days (days -3 - 11 of period 2) and a single dose of 0.5 milligram (Powder for oral solution, 0.5 milligram mg/mL formulation) BI 474121 on day 1 of period 2.

BI 474121 administrations in treatment R and treatment T were separated by a wash-out period of at least 10 days.

Administration of trial medication with 240 mL of water was performed after subjects had fasted overnight; fasting was to start no later than 10 hours before the scheduled dosing of BI 474121 or 9 hours before itraconazole administration.
Interventions: intervention 1: BI 474121 intervention 2: Itraconazole
Intervention descriptions: intervention 1: BI 474121 oral solution intervention 2: Itraconazole oral solution

Protocol documents:
Prot_000.pdf: 
001-MCS-40-106-RD-13 (6.0) / Saved on: 13 Jun 2018
Clinical Trial Protocol
TITLE PAGE
Document Number:
c30888994-02
EudraCT No.
2019-003630-16
BI Trial No.
1411-0010
BI Investigational
Medicinal Product
BI 474121
Title
Effect of itraconazole on the pharmacokinetics of a single oral 
dose of BI 474121 in healthy male subjects (an open-label, 
two-period fixed sequence design study)
Lay Title
A study in healthy men to test how itraconazole influences the 
amount of BI 474121 in the blood
Clinical Phase
I
Clinical Trial Leader
Principal Investigator
Status
Final Protocol (Revised Protocol (based on global amendment 
1))
Version and Date
Version: 2.0
Date: 16 Dec 2020
Page 1 of 72
Proprietary confidential information
© 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission


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CLINICAL TRIAL PROTOCOL SYNOPSIS
Company name
Boehringer Ingelheim
Protocol date
01 Jul 2020
Revision date
16 Dec 2020
BI trial number
1411-0010
Title of trial
Effect of itraconazol on the pharmacokinetics of a single oral dose of BI 474121 in 
healthy male subjects (an open-label, two-period fixed sequence design study)
Principal Investigator:
Trial site:
Clinical phase
I
Trial rationale
Based on in vitro data, CYP3A4 is involved in metabolism of BI 474121. It is 
therefore necessary to explore the effect on the pharmacokinetics of BI 474121 in 
plasma when given alone versus when given together with a strong CYP3A4
inhibitor.
Trial objective
To investigate the effect on the pharmacokinetics of a single oral dose of BI 474121
when given alone (treatment R) or in combination with itraconazole (treatment T).
Trial design
Open-label, two-treatment, two-period fixed sequence design
Trial endpoints:
Primary endpoints: AUC0-and Cmax of BI 474121 in plasma
Secondary endpoints: AUC0-tz of BI 474121 in plasma
Number of subjects 
total entered
14
each treatment
14
Diagnosis
Not applicable
Main criteria
for inclusion
Healthy male subjects, age of 18 to 50 years (inclusive), body mass index (BMI) of 
18.5 to 29.9 kg/m2 (inclusive)
Test product 1
BI 474121 as a powder for oral solution (PfoS, 0.5 mg/mL formulation) 
dose
0.5 mg
mode of admin.
Oral with 240 mL of water after an overnight fast of at least 10 h


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Test product 2
Itraconazole oral solution (Sempera® Liquid 10 mg/mL)
dose
200 mg q.d.
mode of admin.
Oral with 240 mL of water after an overnight fast of at least 9 h
Duration of treatment
Treatment R (BI 474121 alone):
Single dose of 0.5 mg BI 474121 (Day 1)
Treatment T (itraconazole + BI 474121):
14 days of itraconazole treatment (200 mg itraconazole once daily from Day -3 to 
Day 11) combined with a single dose of 0.5 mg BI 474121 on the fourth day of the 
itraconazole treatment (Day 1, 1 h after the itraconazole administration)
Wash-out period:
Administrations of BI 474121 will be separated by a wash-out phase of at least 
10 days
Statistical methods
Extent of drug-drug-interaction will be estimated by the ratios of the geometric 
means (test/reference) for the primary and secondary endpoints. Additionally, their 
two-sided 90% confidence intervals (CIs) will be provided. This method 
corresponds to the two one-sided t-test procedure, each at a 5% significance level. 
Since the main focus is on estimation and not testing, a formal hypothesis test and 
associated acceptance range are not specified. The statistical model will be an 
analysis of variance (ANOVA) on the logarithmic scale including effects for 
‘subject’ and ‘treatment’. CIs will be calculated based on the residual error from the 
ANOVA.
Descriptive statistics will be calculated for all endpoints.


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FLOW CHART
Period
Visit
Day
Planned time (relative to 
first drug administration
of BI474121) [h:min]
Approximate clock time  
of actual day [h:min]
Event and comment
Safety laboratory5
PK blood BI 474121
PK blood, Itraconazole
12-lead ECG
Vital signs (BP, PR)
Questioning for AEs and 
concomitant therapy 7
SCR
1
-21 to -3
Screening (SCR)1
xA
x
x
Period 1/ Treatment R (BI 474121 alone)8
2
-3 to -1
-75:00
06:00
Ambulatory visit
xB
x
1
-3:00
06:00
Admission to trial site2
x2,3
x2
x2
x2
x2
x2
0:00
09:00
BI 474121 administration
0:15
09:15
x
0:30
09:30
x
0:45
09:45
x
1:00
10:00
x
1:30
10:30
x
2:00
11:00
240 mL fluid intake
x
3:00
12:00
x
4:00
13:00
240 mL fluid intake, thereafter lunch4
x
x
x
x
6:00
15:00
x
7:00
16:00
Snack (voluntary)4
x
8:00
17:00
x
10:00
19:00
Dinner4
x
12:00
21:00
x
x 
2
24:00
09:00
Breakfast (voluntary)4, 
discharge from trial site
xB
x
x
x
x
34:00
19:00
Ambulatory visit
x
x
3
46:00
07:00
Ambulatory visit
x
x
4
70:00
07:00
Ambulatory visit
xB
x
x
5
94:00
07:00
Ambulatory visit
x
x
6
118:00
07:00
Ambulatory visit
x
x
7
142:00
07:00
Ambulatory visit
x
x


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FLOW CHART (cont’d)
Period
Visit
Day
Planned time (relative to 
administration of 
BI474121) [h:min]
Approximate clock time  of 
actual day [h:min]
Event and comment
Safety laboratory5
PK blood, BI 474121
PK blood, Itraconazole
12-lead ECG
Vital signs (BP, PR)
Questioning for AEs and 
concomitant therapy 7
Period 2/ Treatment T (BI 474121 + itraconazole) 8
3
-3
-73:00
08:00
Ambulatory visit, itraconazole 
administration
xB,2,3
x2
-2
-49:00
08:00
Ambulatory visit, itraconazole 
administration
x
-1
-25:00
08:00
Ambulatory visit, itraconazole 
administration
xC,2
x9
x2
1
-3:00
06:00
Admission to trial site2
x2
x2
x2
x2
-1:00
08:00
Itraconazole administration
x9
0:00
09:00
BI 474121 administration
0:15
09:15
x
0:30
09:30
x
0:45
09:45
x
1:00
10:00
x
1:30
10:30
x
2:00
11:00
240 mL fluid intake
x
3:00
12:00
x
4:00
13:00
240 mL fluid intake, thereafter lunch4
x
x
x
x
6:00
15:00
x
7:00
16:00
Snack (voluntary)4
x
8:00
17:00
x
10:00
19:00
Dinner4
x
12:00
21:00
x
x 
2
23:00
08:00
Itraconazole administration
x
24:00
09:00
Breakfast (voluntary)4
Discharge from trial site
xB
x
x
x
x
34:00
19:00
Ambulatory visit
x
x
3
46:00
07:00
Ambulatory visit, itraconazole 
administration
x9
x9
x
4
70:00
07:00
Ambulatory visit, itraconazole 
administration
xC
x9
x
5
94:00
07:00
Ambulatory visit, itraconazole 
administration
x9
x
6
118:00
07:00
Ambulatory visit, itraconazole 
administration
xC
x9
x
7
142:00
07:00
Ambulatory visit, itraconazole 
administration
x9
x9
x
8
166:00
07:00
Ambulatory visit, itraconazole 
administration
xB
x9
x
9
190:00
07:00
Ambulatory visit, itraconazole 
administration
x9
x9
x
10
214:00
07:00
Ambulatory visit, itraconazole
administration
x9
x
11
238:00
07:00
Ambulatory visit, itraconazole 
administration
x9
x9
x
12
262:00
07:00
Ambulatory visit
x
x
FU
4
17 to 
24
End-of-trial (EoTrial) examination6
xD
x
x
x


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1.
Subject must be informed and written informed consent obtained prior to starting any screening procedures. Screening 
procedures include physical examination, check of vital signs, ECG, safety laboratory (including drug screening), 
demographics (including determination of body height and weight, smoking status and alcohol history), relevant 
medical history, concomitant therapy and review of inclusion/exclusion criteria. Pharmacogenetic samples for general 
ADME genotyping will be collected if needed.
2.
The time is approximate; the procedure is to be performed and completed within the 3 h prior to drug administration
(relative to the intake of BI 474121).
3.
Urine drug screening and alcohol breath test
4.
If several actions are indicated at the same time, the intake of meals will be the last action.
5.
Letters A, B, C, and D define different sets of safety laboratory examinations (for details refer to Section 5.1.3)
6.
At the end of trial visit the EoTrial examination includes physical examination, vital signs, ECG, safety laboratory, 
recording of AEs and concomitant therapies. 
7.
AEs and concomitant therapies will be recorded throughout the trial, but will be specifically asked for at the times 
indicated in the Flow Chart above.
8.
Administration of BI 474121 in treatment R and T will be separated by a washout of at least 10 days.
9.
Blood sampling takes place at the indicated times. Itraconazole will be administered immediately thereafter..


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TABLE OF CONTENTS
TITLE PAGE ......................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS ................................................2
FLOW CHART...................................................................................................4
TABLE OF CONTENTS ...................................................................................7
ABBREVIATIONS.......................................................................................... 11
1.
INTRODUCTION.................................................................................... 14
1.1
MEDICAL BACKGROUND............................................................................14
Itraconazole ...........................................................................................21
1.2.2
1.3
RATIONALE FOR PERFORMING THE TRIAL........................................21
1.4
BENEFIT - RISK ASSESSMENT ...................................................................22
Procedure-related risks ........................................................................22
1.4.1
Drug-related risks and safety measures..............................................22
1.4.2
1.4.2.2
Itraconazole..............................................................................23
1.4.2.3
Potential drug-drug interaction between itraconazole and BI 
474121 ...................................................................................23
1.4.2.4
Drug-induced liver injury ........................................................23
2.
TRIAL OBJECTIVES AND ENDPOINTS........................................... 24
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS ......24
Main objectives......................................................................................24
2.1.1
Primary endpoints ................................................................................24
2.1.2
Secondary endpoint ..............................................................................24
2.1.3
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.............. 26
3.1
OVERALL TRIAL DESIGN AND PLAN ......................................................26


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3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP..........................................................................................26
3.3
SELECTION OF TRIAL POPULATION ......................................................27
Main diagnosis for trial entry..............................................................27
3.3.1
Inclusion criteria...................................................................................27
3.3.2
Exclusion criteria ..................................................................................27
3.3.3
Withdrawal of subjects from treatment or assessments ...................29
3.3.4
3.3.4.1
Discontinuation of trial treatment............................................29
3.3.4.2
Withdrawal of consent to trial participation ............................30
3.3.4.3
Discontinuation of the trial by the sponsor..............................30
Replacement of subjects .......................................................................31
3.3.5
4.
TREATMENTS........................................................................................ 32
4.1
INVESTIGATIONAL TREATMENTS ..........................................................32
Identity of the Investigational Medicinal Products ...........................32
4.1.1
Selection of doses in the trial................................................................33
4.1.2
Method of assigning subjects to treatment groups ............................33
4.1.3
Drug assignment and administration of doses for each subject .......34
4.1.4
Blinding and procedures for unblinding ............................................34
4.1.5
Packaging, labelling, and re-supply ....................................................35
4.1.6
Storage conditions.................................................................................35
4.1.7
Drug accountability ..............................................................................35
4.1.8
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS ...............................................................................................36
Other treatments and emergency procedures....................................36
4.2.1
Restrictions............................................................................................36
4.2.2
4.2.2.1
Restrictions regarding concomitant treatment .........................36
4.2.2.2
Restrictions on diet and life style.............................................36
4.3
TREATMENT COMPLIANCE.......................................................................37
5.
ASSESSMENTS....................................................................................... 38
5.1
ASSESSMENT OF SAFETY............................................................................38
Physical examination ............................................................................38
5.1.1
Vital signs...............................................................................................38
5.1.2
Safety laboratory parameters..............................................................38
5.1.3
Electrocardiogram................................................................................41
5.1.4
Assessment of adverse events...............................................................42
5.1.5
5.1.5.1
Definitions of adverse events...................................................42


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Adverse event ............................................................42
5.1.5.1.1
Serious adverse event ................................................42
5.1.5.1.2
AEs considered ‘Always Serious’.............................43
5.1.5.1.3
Adverse events of special interest .............................43
5.1.5.1.4
Intensity (severity) of AEs.........................................44
5.1.5.1.5
Causal relationship of AEs ........................................44
5.1.5.1.6
5.1.5.2
Adverse event collection and reporting ...................................45
AE collection.............................................................45
5.1.5.2.1
AE reporting to the sponsor and timelines ................46
5.1.5.2.2
Information required..................................................46
5.1.5.2.3
Pregnancy ..................................................................46
5.1.5.2.4
5.2
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS..................................................................................46
Assessment of pharmacokinetics .........................................................46
5.2.1
Methods of sample collection...............................................................47
5.2.2
5.2.2.1
Blood sampling for pharmacokinetic analysis.........................47
5.4
APPROPRIATENESS OF MEASUREMENTS.............................................48
6.
INVESTIGATIONAL PLAN.................................................................. 49
6.1
VISIT SCHEDULE............................................................................................49
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS ................49
Screening................................................................................................49
6.2.1
Treatment periods.................................................................................49
6.2.2
Follow-up period and trial completion ...............................................50
6.2.3
7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE......................................................................................... 51
7.1
STATISTICAL DESIGN – MODEL ...............................................................51
7.2
NULL AND ALTERNATIVE HYPOTHESES ..............................................51
7.3
PLANNED ANALYSES....................................................................................51
Primary endpoint analyses...................................................................52
7.3.1
Secondary endpoint analyses ...............................................................53
7.3.2
7.4
INTERIM ANALYSES .....................................................................................55
7.5
HANDLING OF MISSING DATA ..................................................................55
Safety......................................................................................................55
7.5.1
Pharmacokinetics..................................................................................55
7.5.2


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7.6
RANDOMISATION ..........................................................................................55
7.7
DETERMINATION OF SAMPLE SIZE ........................................................55
8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY, AND 
ADMINISTRATIVE STRUCTURE...................................................... 57
8.1
TRIAL APPROVAL, SUBJECT INFORMATION, INFORMED 
CONSENT ..........................................................................................................57
8.2
DATA QUALITY ASSURANCE .....................................................................58
8.3
RECORDS..........................................................................................................58
Source documents .................................................................................58
8.3.1
Direct access to source data and documents.......................................59
8.3.2
Storage period of records.....................................................................60
8.3.3
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS .................................60
8.5
STATEMENT OF CONFIDENTIALITY AND SUBJECT PRIVACY.......60
Collection, storage and future use of biological samples and 
8.5.1
corresponding data ...............................................................................60
8.6
TRIAL MILESTONES .....................................................................................61
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL ..................................61
9.
REFERENCES......................................................................................... 63
9.1
PUBLISHED REFERENCES...........................................................................63
9.2
UNPUBLISHED REFERENCES.....................................................................64
10. APPENDICES .......................................................................................... 66
11. DESCRIPTION OF GLOBAL AMENDMENT(S).............................. 71
11.1
GLOBAL AMENDMENT 1 .............................................................................71


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ABBREVIATIONS
AD
Alzheimer’s Disease
ADME
Absorption, distribution, metabolism, and excretion
AE
Adverse event
AESI
Adverse events of special interest
AMP
Auxiliary Medicinal Product
ALT
Alanine transaminase
ANOVA
Analysis of variance
AST
Aspartate transaminase
AUC0-∞
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity
%AUCtz-∞
Percentage of AUC0-∞obtained by extrapolation
AUCt1-t2
Area under the concentration-time curve of the analyte in plasma over the 
time interval t1 to t2
AUC0-24
Area under the concentration-time curve of the analyte in plasma over the 
time interval 0 to 24 h
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
BMI
Body mass index (weight divided by height squared)
BP
Blood pressure
CA
Competent authority
cAMP
Cyclic adenosine monophosphate
cGMP
Cyclic guanosine monophosphate
CI
Confidence interval
CIAS
Cognitive Impairment Associated with Schizophrenia
CL
Total clearance of the analyte in plasma after intravascular administration
CL/F
Apparent clearance of the analyte in plasma after extravascular 
administration
Cmax
Maximum measured concentration of the analyte in plasma
CRF
Case Report Form, paper or electronic (sometimes referred to as ‘eCRF’)
CTP
Clinical trial protocol


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CTR
Clinical trial report
CV
Arithmetic coefficient of variation
DDI
Drug-drug interaction
DILI
Drug induced liver injury
ECG
Electrocardiogram
eCRF
Electronic case report form
eDC
Electronic data capture 
EDTA
Ethylenediaminetetraacetic acid
EoTrial
End of trial
EudraCT
European Clinical Trials Database
FU
Follow-up
GCP
Good Clinical Practice
gCV
Geometric coefficient of variation
gMean
Geometric mean
IB
Investigator’s brochure
IC50
Half-maximal inhibitory concentration
IEC
Independent Ethics Committee
IRB
Institutional Review Board
ISF
Investigator Site File
LC-MS/MS
Liquid chromatography with tandem mass spectrometry
MDA
Methylenedioxyamphetamine
MDMA
Methylenedioxymethamphetamine
MedDRA
Medical Dictionary for Regulatory Activities
PfOS
Powder for reconstitution of an oral solution
NMDA
N-methyl-D-aspartate
NOAEL
No adverse effect level
PDE2
PhosphoDiEsterase 2
PK
Pharmacokinetic(s)
PKS
Pharmacokinetic set
PR
Pulse rate
QT
Time between start of the Q-wave and the end of the T-wave in an 


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electrocardiogram
QTc
QT interval corrected for heart rate using the method of Fridericia (QTcF) 
or Bazett (QTcB)
R
Reference treatment
RAAS
Renin-angiotensin-aldosterone system
RBC
Red blood cell count
REP
Residual effect period
SAE
Serious adverse event
SCR
Screening
SmPC
Summary of Product Characteristics
SOP
Standard operating procedure
SRD
Single-rising dose
ss
(at) steady state
T
Test product or treatment
t1/2
Terminal half-life of the analyte in plasma
tmax
Time from (last) dosing to the maximum measured concentration of the 
analyte in plasma
TS
Treated set
tz
Time of last measurable concentration of the analyte in plasma
TSAP
Trial statistical analysis plan
ULN
Upper limit of normal
Vz/F
Apparent volume of distribution during the terminal phase after 
extravascular administration
XTC
Ecstasy 


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1.
INTRODUCTION
BI 474121 is a PhosphoDiEsterase 2 (PDE2) inhibitor that is being developed for the 
symptomatic treatment of mild to moderate Alzheimer’s disease (AD) and cognitive 
impairment associated with schizophrenia (CIAS).
1.1
MEDICAL BACKGROUND
AD and schizophrenia are chronic, severe, and disabling brain disorders affecting both men 
and women. Available symptomatic treatments for AD consist of acetylcholinesterase 
inhibitors (AChEIs) and memantine which, however, are widely acknowledged as having 
very limited efficacy. More effective symptomatic treatment remains a major unmet medical 
need. Existing treatment options for schizophrenia (i.e., first- and second-generation 
antipsychotics) are primarily efficacious in treating positive symptoms, but have limited 
efficacy for treating the cognitive and negative symptoms of the disorder. No pharmacologic 
therapies have been approved for the symptomatic treatment of the cognitive impairment seen 
in patients with schizophrenia. 


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Itraconazole
1.2.2
Absorption of itraconazole solution is fast with maximum plasma concentration being 
reached within 2.5 h after oral administration in fasting condition. Bioavailability of 
itraconazole liquid increases by 30% when given under fasting condition compared to 
administration together with food [R20-2709]. Mean peak plasma concentrations were 
547.7 ng/mL after a single dose of 200 mg itraconazole solution (fasting) and 1965 ng/mL 
after 15 days of daily treatment with 200 mg itraconazole solution (fasting). 
Pharmacokinetics of itraconazole is non-linear. The half-life of itraconazole after multiple 
doses of 200 mg once daily with solution formulation was about 40 h [R17-3742].
In the liver, itraconazole is metabolised extensively to more than 30 metabolites [R17-3743]. 
Its main metabolite, OH-itraconazole, accounts for about twice the concentration of plasma 
itraconazole at trough. It has been shown in vitro that CYP3A4 is mainly responsible for the 
formation of this metabolite [R20-2709]. FDA classifies itraconazole as strong index 
inhibitor of CYP3A and as inhibitor of P-glycoprotein (P-gp) [R18-0241]. However, not only 
itraconazole contributes to the in vivo inhibition of CYP3A observed after itraconazole 
administration but also three of its metabolites (OH-itraconazole, keto-itraconazole, and N 
desalkyl-itraconazole) [R10-1102].
For a more detailed description of itraconazole, please refer to the German (Sempera®) and 
UK (Sporanox®) Summary of Product Characteristics (SmPC):
For Sporanox 10 mg/ml Oral Solution [R18-2643], for Sempera ®Liquid 10 mg/ml [R20-
2709].
1.3
RATIONALE FOR PERFORMING THE TRIAL
Based on in vitro data, BI 474121 is mainly metabolized via CYP 3A4. 


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Therefore, in this trial, the focus is on the drug-drug interaction (DDI) victim potential of 
BI 474121 with regard to CYP3A4 as this may lead to clinically relevant increases in 
exposures with potential impact on patient safety.
Itraconazole is chosen for this trial as perpetrator drug, as this drug is recommended as strong 
inhibitor of CYP3A by EMA and PMDA [P15-06991, P15-06298], and as strong index 
inhibitor of CYP3A by FDA [R18-0241]. . 
Moreover, safety and tolerability of itraconazole were acceptable in previous DDI trials 
[c02336088, c03355329, c08928447].
1.4
BENEFIT - RISK ASSESSMENT
Participation in this clinical trial is without any (therapeutic) benefit for healthy subjects. 
Their participation, however, is of major importance for the development of a drug which 
might improve the therapy of patients with AD or CIAS.
Subjects are exposed to risks of study procedures and risks related to the exposure to the trial 
medication.
Procedure-related risks
1.4.1
The use of an indwelling venous catheter or venepuncture for e.g. blood sampling may result 
in mild bruising, and in rare cases, in transient inflammation of the wall of the vein, or nerve 
injury, potentially resulting in paraesthesia, reduced sensibility, and/or pain for an indefinite 
period, as well as in feeling of lightheadedness or in syncope.
The total volume of blood withdrawn per subject during the entire study will not exceed the 
volume of a normal blood donation (500 mL). No health-related risk to healthy subjects is 
expected from withdrawal of this volume of blood.
Drug-related risks and safety measures
1.4.2


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1.4.2.2
Itraconazole
In this trial, itraconazole will be used in a standard clinical dose of 200 mg once daily for 14
days. Multiple dosing of 200 mg itraconazole up to 15 days was of acceptable tolerability in 
healthy subjects [c02336088, c03355329, c08928447, R17-3742]. 
For a detailed description of the potential risks of itraconazole treatment, please refer to the 
German Summary of Product Characteristics (SmPC) for Sempera® Liquid 10 mg/ml [R20-
2709].
In order to address 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 ≥2-fold ULN, see Section 3.3.4.1). 
Further, most of the reported cases of serious hepatotoxicity during itraconazole treatment 
occurred in patients that suffered from concomitant liver diseases, had other significant 
diseases, or took concomitant hepatotoxic drugs. Subjects with liver diseases or a medical 
history of drug-induced liver failure are excluded from trial participation.
Itraconazole has shown a dose-related increase in maternal toxicity, embryotoxicity and 
teratogenicity in nonclinical studies at high doses, and therefore itraconazole must not be 
used during pregnancy. Woman of childbearing potential have to use a highly effective 
method of contraception until the menstrual period after the last itraconazole dose [R20-2709, 
R18-2643]. For risk mitigation, only male subjects will be included into this clinical trial.
Considering these safety measures and taking into account the reported acceptable tolerability 
of itraconazole, the planned administration of itraconazole does not represent an undue risk to 
healthy male volunteers.
1.4.2.3
Potential drug-drug interaction between itraconazole and BI 474121
It is likely that concomitant administration of BI 474121 with itraconazole leads to an 
increase of plasma concentrations and t1/2 of BI 474121. The effect of itraconazole in 
increasing Cmax and AUC of other drugs can be as high as 3.4-fold and 11-fold, respectively, 
as seen with oral midazolam, a sensitive CYP3A4 substrate, when co-administered with oral 
itraconazole 200 mg/d [R01-0516, R20-2709]. 
1.4.2.4
Drug-induced liver injury
Although rare, a potential for drug-induced liver injury (DILI) is under constant surveillance 
by sponsors and regulators. Therefore, this trial requires timely detection, evaluation, and 
follow-up of laboratory alterations in selected liver laboratory parameters to ensure subjects´ 
safety; see also Section 5.1.5.1.4, adverse events of special interest.


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2.
TRIAL OBJECTIVES AND ENDPOINTS
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS
Main objectives
2.1.1
The main objective of this trial is to investigate the effect on the exposure of BI 474121 in 
plasma when given as oral single dose together with multiple oral doses of itraconazole (Test, 
T) as compared to when given alone as oral single dose (Reference, R).
Primary endpoints
2.1.2
The following pharmacokinetic parameters will be determined for BI 474121:

AUC0-∞(area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity)

Cmax (maximum measured concentration of the analyte in plasma)
Secondary endpoint
2.1.3
The following pharmacokinetic parameter will be determined for BI 474121:

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)


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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, two-treatment, two-period, fixed sequence 
design trial in healthy male subjects in order to compare the test treatment (T) to the reference 
treatment (R). The treatments will be one oral single dose of 0.5 mg BI 474121 administered 
as PfOS (concentration; 0.5 mg/mL) together with multiple oral doses of 200 mg itraconazole 
as oral solution formulation (concentration: 10 mg/mL) (T) and one single dose of 0.5 mg 
BI 474121 as PfOS given alone (R).
In both treatments, BI 474121 is administered to subjects in the fasting state. In the first 
treatment period (Period 1, Visit 2), all subjects are planned to undergo treatment R, and in 
the second treatment period (Period 2, Visit 3), all subjects are planned to undergo treatment 
T. For details, refer to Section 4.1.
There will be a washout period of at least 10 days between the administrations of BI 474121.
Figure 3.1: 1
Trial design
An overview of all relevant trial activities is provided in the Flow Chart. For visit schedule 
and details of trial procedures at selected visits, refer to Sections 6.1 and 6.2, respectively.
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP
For relative bioavailability trials, the crossover design is preferred because of its efficiency: 
since each subject serves as his/her own control, the comparison between treatments is based 
on an intra-subject comparison, thus removing inter-subject variability from the comparison 
between treatments [R94-1529]. Because of the long half-life (about 40 h) of itraconazole and 
its metabolites, a two-period fixed sequence design was selected, with administration of 
itraconazole in the second study period only. This design is not expected to lead to systematic 
errors in the estimation of the treatment effects since nonspecific time-effects are unlikely 
due to the short trial duration. For itraconazole studies, this design is recommended by the 
Screening
Period 1
Period 2
End-of-trial
BI 474121
Itraconazole
≥1 day


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Innovation and Quality in Pharmaceutical Development’s 
 
[R17-3744].
For this PK drug-drug interaction trial, open-label treatment is acceptable, because the 
primary and secondary endpoints of this trial are PK endpoints derived from measurement of 
plasma concentrations of BI 474121. These endpoints are not expected to be affected by 
knowledge of treatment.
3.3
SELECTION OF TRIAL POPULATION
It is planned that 14 healthy male subjects will enter the study. They will be recruited from 
the volunteers' pool of the trial site. 
Due to the reproduction toxicity itraconazole has shown in nonclinical studies, only male 
subjects will be included in this trial.
A log of all subjects enrolled into the trial (i.e. who have signed informed consent) will be 
maintained in the ISF irrespective of whether they have been treated with investigational drug 
or not.
Main diagnosis for trial entry
3.3.1
The study will be performed in healthy subjects.
Inclusion criteria
3.3.2
Subjects will only be included in the trial if they meet the following criteria:
1. Healthy male subjects according to the assessment of the investigator, as based on a 
complete medical history including a physical examination, vital signs (BP, PR), 12-
lead ECG, and clinical laboratory tests 
2. Age of 18 to 50 years (inclusive) 
3. BMI of 18.5 to 29.9 kg/m2 (inclusive) 
4. Signed and dated written informed consent prior to admission to the study, in 
accordance with GCP and local legislation
Exclusion criteria
3.3.3
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) deviating from 
normal and assessed as clinically relevant by the investigator
2. Repeated measurement of systolic blood pressure outside the range of 100 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


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4. Any evidence of a concomitant disease assessed as clinically relevant by the 
investigator
5. Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological 
or hormonal disorders
6. Cholecystectomy or other surgery of the gastrointestinal tract that could interfere with 
the pharmacokinetics of the trial medication (except appendectomy or simple hernia 
repair)
7. Diseases of the central nervous system (including but not limited to any kind of
seizures or stroke), and other relevant neurological or psychiatric disorders 
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) 
11. Use of drugs within 30 days of planned administration of trial medication that might 
reasonably influence the results of the trial (including drugs that cause QT/QTc 
interval prolongation)
12. Intake of an investigational drug in another clinical trial within 60 days of planned  
administration of investigational drug in the current trial, or concurrent participation 
in another clinical trial in which investigational drug is administered
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 24 g per day for males)
16. Drug abuse or positive drug screening
17. Blood donation of more than 100 mL within 30 days of planned administration of trial 
medication or intended blood donation during the trial
18. Intention to perform excessive physical activities within one week prior to the 
administration of trial medication or during the trial
19. Inability to comply with the dietary regimen of the trial site
20. A marked baseline prolongation of QT/QTc interval (such as QTc intervals that are 
repeatedly greater than 450 ms or any other relevant ECG finding at screening)
21. A history of additional risk factors for Torsade de Pointes (such as heart failure, 
hypokalaemia, or family history of Long QT Syndrome)
22. Subject is assessed as unsuitable for inclusion by the investigator, for instance, 
because the subject is not considered able to understand and comply with study 
requirements, or has a condition that would not allow safe participation in the study
23. Liver enzymes (ALT, AST, GGT) above upper limit of normal at the screening 
examination, confirmed by a repeat test 
24. History of drug induced liver injury
25. History of heart failure, or any evidence of ventricular dysfunction 
26. Known sorbitol/polyols intolerance


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27. Male subjects with WOCBP partner who are unwilling to use a highly effective 
method of birth control from time point of administration of trial medication until 
30 days thereafter. Highly effective methods of birth control are:
-
Male subject is sexually abstinent
-
Male subjects is vasectomised (vasectomy at least 1 year prior to enrolment), plus 
condom in male subject
-
Use of intrauterine device (IUD) or intrauterine hormone-releasing system (IUS)
-
Use of progestogen-only hormonal contraception by female partner that inhibits 
ovulation (only injectables or implants), plus condom in male subject
-
Use of combined (estrogen and progestogen containing) hormonal contraception by 
female partner that prevents ovulation (oral, intravaginal or transdermal), plus 
condom in male subject
-
Female partner is surgically sterilised (including hysterectomy)
-
Female partner is postmenopausal, defined as no menses for 1 year without an 
alternative medical cause (in questionable cases a blood sample with FSH above 
40 U/L and estradiol below 30 ng/L is confirmatory)
Sperm donation is not allowed from the time point of drug administration until 30 days 
thereafter.
28. During COVID-19 pandemic: laboratory test indicative of an ongoing SARS-CoV-2 
infection
For study restrictions, refer to Section 4.2.2.
Withdrawal of subjects from treatment or assessments
3.3.4
Subjects may discontinue trial treatment or withdraw consent to trial participation as a whole 
(‘withdrawal of consent’) with very different implications; please see Sections 3.3.4.1 and 
3.3.4.2 below.
If a subject is removed from or withdraws from the trial prior to the first administration of 
trial medication, the data of this subject will not be entered in the case report form (CRF) and 
will not be reported in the clinical trial report (CTR). If a subject is removed from or 
withdraws from the trial after the first administration of trial medication, this will be 
documented and the reason for discontinuation must be recorded in the CRF; in addition, the 
data will be included in the CRF 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 CRF. If the discontinuation occurs before the end of the 
REP (see Section 1.2.3), the discontinued subject should if possible be questioned for AEs 
and concomitant therapies at or after the end of the REP in order to ensure collection of AEs 
and concomitant therapies throughout the REP, if not contrary to any consent withdrawal of 
the subject.
3.3.4.1
Discontinuation of trial treatment
An individual subject will discontinue trial treatment if:


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1. The subject wants to discontinue trial treatment, without the need to justify the 
decision
2. The subject has repeatedly shown to be non-compliant with important trial procedures 
and, in the opinion of both, the investigator and sponsor representative, is not willing 
or able to adhere to the trial requirements in the future.
3. The subject needs to take concomitant medication that interferes with the 
investigational medicinal product or other trial treatment
4. The subject can no longer receive trial treatment for medical reasons (such as surgery, 
adverse events [AEs], or diseases)
5. The subject has an elevation of AST and/or ALT ≥2-fold ULN
6. The subject has an elevation of AST and/or ALT ≥3-fold ULN and 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.
7. The subject has a serious adverse reaction or a severe non-serious adverse reaction.
In addition to these criteria, the investigator may discontinue subjects at any time based on 
his or her clinical judgment.
Even if the trial treatment is discontinued, the subject remains in the trial and, given his/her 
agreement, will undergo the procedures for early treatment discontinuation and follow up as 
outlined in the Flow Chart and section 6.2.3.
3.3.4.2
Withdrawal of consent to trial participation
Subjects may withdraw their consent to trial participation at any time without the need to 
justify the decision. If a subject wants to withdraw consent, the investigator should be 
involved in the discussion with the subject and explain the difference between trial treatment 
discontinuation and withdrawal of consent to trial participation, as well as explain the options 
for continued follow up after trial treatment discontinuation, please see section 3.3.4.1 above
3.3.4.3
Discontinuation of the trial by the sponsor
Boehringer Ingelheim reserves the right to discontinue the trial at any time for any of the 
following reasons (# 2 mandatory reason for discontinuation):
1. Failure to meet expected enrolment goals overall or at a particular trial site
2. New toxicological findings, serious adverse events, or any safety information
invalidating the earlier positive benefit-risk-assessment. More specifically, the trial 
will be terminated if more than 50% of the subjects have drug-related and clinically 
relevant adverse events of moderate or severe intensity, or if at least 1 drug-related 
serious adverse event is reported
3. Violation of GCP, or the CTP impairing the appropriate conduct of the trial
4. The sponsor decides to discontinue the further development of the investigational 
product


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Replacement of subjects
3.3.5
Subjects withdrawn due to drug related adverse events will not be replaced. In case more than
2 subjects do not complete the trial, the Clinical Trial Leader together with the Trial 
Pharmacokineticist and the Trial Statistician are to decide, if and how many subjects will be 
replaced. A replacement subject will be assigned a unique trial subject number.


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4.
TREATMENTS
4.1
INVESTIGATIONAL TREATMENTS
 
Identity of the Investigational Medicinal Products
4.1.1
The characteristics of the test product are given below:


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Selection of doses in the trial
4.1.2
Perpetrator (itraconazole)
The dose of itraconazole selected for this trial reflects standard clinical doses, is considered 
sufficient to yield significant CYP3A inhibition and has been used successfully and safely in 
previous drug-drug-interaction trials [c02336088, c03355329, c08928447].
Method of assigning subjects to treatment groups
4.1.3
There is only one treatment sequence investigated 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. Once a subject number has been assigned, it cannot be reassigned to any 
other subject.
All subjects may be treated in one cohort, i.e. all subjects may receive treatment on the same
calendar day. In case this is not feasible (e.g., due to logistical or recruitment reasons), the
group may be split into several cohorts as required. Treatment of all subjects on the same
calendar day is acceptable (for safety margin to exposure reached in previous SRD trial 1411-
0001 refer to Section 4.1.2, for discussion of study-associated risks and safety measures see
Section 1.4.2.1).


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Drug assignment and administration of doses for each subject
4.1.4
This trial is a two-period fixed sequence design study. All subjects will receive the 2 
treatments in fixed order. The treatments to be evaluated are outlined in Table 4.1.4: 1 below. 
Administration of trial medication will be performed after subjects have fasted overnight; 
fasting is to start no later than 10 h before the scheduled dosing of BI 474121 or 9 hours 
before itraconazole administration. The investigator (or authorised designee) will administer 
the trial medication as an oral dose together with about 240 mL of water to subjects who are 
in a standing position. For drug administration, the so-called four-eye principle (two-person
rule) should be applied. For this, one authorised employee of the trial site should witness the 
administration of trial medication, and – if applicable – its preparation (e.g. reconstitution), if 
correct dosage cannot be ensured otherwise.
Subjects will be kept under close medical surveillance until at least 24 hours after 
administration of BI 474121 in period 1 and at least 24 hours in period 2. During the first 4 h 
after administration of BI 474121, subjects are not allowed to lie down (i.e. no declination of 
the upper body of more than 45 degrees from upright posture).
The treatments with BI 474121 will be separated by a wash-out phase of at least 10 days.
Blinding and procedures for unblinding
4.1.5
This Phase I trial is not randomized and will be handled in an open fashion throughout (that 
is, during the conduct, 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, because the dose of trial medication is known to 
investigators and subjects.


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Packaging, labelling, and re-supply
4.1.6
BI 474121
BI 474121 PfOS will be provided by BI. They will be packaged and labelled in accordance 
with local law and the principles of Good Manufacturing Practice. For details of packing and 
the description of the label, refer to the ISF.
The telephone number of the sponsor and the name, address and telephone number of the trial 
site are provided in the subject information form. The EudraCT number is indicated on the 
title page of this protocol as well as on the subject information and informed consent forms. 
No re-supply is planned.
Itraconazole oral solution
Itraconazole oral solution will be obtained by the clinical trial site from a public pharmacy. 
The drug will be dispensed out of the original, unmodified packages.
Storage conditions
4.1.7
Drug supplies will be kept in their original packaging and in a secure limited access storage 
area in accordance with the recommended (labelled) storage conditions. If necessary, a 
temperature log must be maintained to make certain that the drug supplies are stored at the 
correct temperature. If the storage conditions are found to be outside the specified range, the 
clinical trial manager (as provided in the list of contacts) is to be contacted immediately.
Drug accountability
4.1.8
The investigator or designee will receive the investigational drugs delivered from the sponsor
following requirements are fulfilled:

Approval of the clinical trial protocol by the IRB / ethics committee

Approval/notification of the regulatory authority,  e.g. competent authority

Availability of the curriculum vitae of the Principal Investigator

Availability of a signed and dated clinical trial protocol  

Availability of FDA Form 1572
Only authorised personnel 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.
The investigator or designee must maintain records of the product’s delivery to the trial site, 
the inventory at the site, the use by each subject, and the disposal of unused products.These 
records will include dates, quantities, batch / serial numbers, expiry ('use-by') dates, and the 
unique code numbers assigned to the investigational medicinal product and trial subjects. The 
investigator or designee will maintain records that document adequately that the subjects 
were provided the doses specified by the CTP and reconcile all investigational medicinal 
products received from the sponsor. At the time of disposal of remaining trial medication, the 


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investigator or designee must verify that no remaining supplies are in the investigator’s 
possession.
All unused medication will be disposed of locally by the trial site upon written authorisation 
of the Clinical Trial Leader. Receipt, usage and disposal of trial medication must be 
documented on the appropriate forms. Account must be given for any discrepancies.
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES,
RESTRICTIONS
Other treatments and emergency procedures
4.2.1
There are no special emergency procedures to be followed. No additional treatment is
planned. However, if adverse events require treatment, the investigator can authorise 
symptomatic therapy. In those cases, subjects will be treated as necessary and, if required, 
kept under supervision at the trial site or transferred to a hospital until all results of medical 
evaluations are acceptable.
Restrictions
4.2.2
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.
Known inhibitors/inducers of CYP3A4 activity, drugs with a known hepatotoxicity profile, 
drugs which are contraindicated to be co-administered with itraconazole [R20-2709] should 
be avoided during the entire study; if necessary, short term use of ibuprofen is acceptable.
4.2.2.2
Restrictions on diet and life style
Poppy-seeds containing foods should not be consumed starting 3 days before the first drug 
administration in each treatment period, in order to avoid false-positive results in the drug-
screen.
While admitted to the trial site, the subjects will be instructed not to consume any foods or 
drinks other than those provided by the staff. Standardised meals will be served at the times
indicated in the Flow Chart.
No food is allowed within 10 h before and for at least 4 h after intake of BI 474121. Subjects 
will be advised to not consume any food within 9 h before and 1 h after itraconazole 
administrations.
On Day 1, from 1 h before intake of BI 474121 (Period 1) or itraconazole (Period 2), 
respectively, fluid intake is restricted to the water administered with the drug intake, and an 
additional 240 mL of water at 2 h and 4 h after administration of BI 474121 (mandatory for 
all subjects). From lunch until 23 h post administration of BI 474121, total fluid intake is 
restricted to 3000 mL.


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Alcoholic beverages, grapefruits, Seville oranges (sour or bitter oranges) and their juices, and 
dietary supplements and products containing St. John's wort (Hypericum perforatum) are not 
permitted from 7 days before the first administration of trial medication in Period 1 until after 
the last PK sample in period 2 is collected.
Methylxanthine-containing drinks or foods (such as coffee, tea, cola, energy drinks, or 
chocolate) are not allowed from 24 h before administration of BI 474121 until discharge from 
trial site.
Smoking is not allowed during in-house confinement.
Excessive physical activity (such as competitive sport) should be avoided from 7 days before
the first administration of trial medication until the end of trial examination.
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 centre under 
supervision of the investigating physician or a designee. The measured plasma concentrations 
of trial medication will provide additional confirmation of compliance.
Subjects who are non-compliant (for instance, who do not appear for scheduled visits or 
violate trial restrictions) may be removed from the trial and the CRF will be completed 
accordingly (for further procedures, please see Section 3.3.4.1).


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5.
ASSESSMENTS
5.1
ASSESSMENT OF SAFETY
Physical examination
5.1.1
At screening, the medical examination will include demographics, height and body weight, 
smoking and alcohol history (results not mandatory to be entered into CRF or to be reported), 
relevant medical history and concomitant therapy, review of inclusion and exclusion criteria, 
review of vital signs (BP, PR), 12-lead ECG, laboratory tests, and a physical examination. At 
the end of trial examination, it will include review of vital signs, 12-lead ECG, laboratory 
tests, and a physical examination.
Vital signs
5.1.2
Systolic and diastolic blood pressures (BP) as well as pulse rate (PR) will be measured by a 
blood pressure monitor (Dinamap Pro 100, 
) 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.
Safety laboratory parameters
5.1.3
For the assessment of laboratory parameters, blood and urine samples will be collected by the 
trial site at the times indicated in the Flow Chart after the subjects have fasted for at least 
10 h. For retests, at the discretion of the investigator or designee, overnight fasting is not 
required.
The parameters that will be determined are listed in Tables 5.1.3: 1 and 5.1.3: 2. Reference 
ranges will be provided in the ISF, Section 10. 
Manual differential white blood cell count or urine sediment examinations will only be 
performed if there is an abnormality in the automatic blood cell count or in the urinalysis, 
respectively.


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Table 5.1.3: 1
Routine laboratory tests
Functional lab group
BI test name [comment/abbreviation]
A
B
C
D
Haematology
Haematocrit
Haemoglobin
Red Blood Cell Count/Erythrocytes 
White Blood Cells/Leucocytes
Platelet Count/Thrombocytes (quant)
X
X
X
X
X
X
X
X
X
X
--
--
--
--
--
X
X
X
X
X
Automatic WBC 
differential, relative
Neutrophils/Leukocytes; Eosinophils/Leukocytes; Basophils/ 
Leukocytes; Monocytes/Leukocytes; 
Lymphocytes/Leukocytes 
X
X
--
X
Automatic WBC 
differential, absolute 
Neutrophil, absol.; Eosinophils, absol.; Basophils, absol.; 
Monocytes, absol.; Lymphocytes, absol.
X
X
--
X
Manual differential 
WBC (if automatic
differential WBC is 
abnormal)
Neut. Poly (segs); Neut. Poly (segs), absol.; Neutrophils 
Bands;  Neutrophils Bands, absol.; Eosinophils/Leukocytes; 
Eosinophils, absol.; Basophils/ Leukocytes; Basophils, absol.; 
Monocytes/ Leukocytes; Monocytes, absol.; 
Lymphocytes/Leukocytes; Lymphocytes, absol.
X
X
--
X
Coagulation
Activated Partial Thromboplastin Time 
Prothrombin time/ INR (International Normalization Ratio)
Fibrinogen
X
X
X
X
X
--
--
--
--
X
X
--
Enzymes
AST [Aspartate transaminase] /GOT, SGOT 
ALT [Alanine transaminase] /GPT, SGPT
Alkaline Phosphatase
Gamma-Glutamyl Transferase 
Glutamate Dehydrogenase (GLDH)
Creatine Kinase [CK]
Creatine Kinase Isoenzyme MB [only if CK is elevated] 
Lactic Dehydrogenase
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 
X
--
--
--
Substrates
Glucose (Plasma)
Creatinine 
Bilirubin, Total 
Bilirubin, Direct
Protein, Total
Albumin
C-Reactive Protein (Quant)  
X
X
X
X
X
X
X
X
X
X
X
X
X
X
--
--
X
X
--
--
--
X
X
X
X
X
X
X


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Table 5.1.3: 1
Routine laboratory tests (cont.)
Functional lab group
BI test name [comment/abbreviation]
A
B
C
D
Electrolytes
Sodium
Potassium
X
X
X
X
--
--
X
X
Urinalysis1 (Stix)
Urine Nitrite (qual)
Urine Protein (qual)
Urine Glucose (qual)
Urine Ketone (qual)
Urobilinogen (qual)
Urine Bilirubin (qual)
Urine RBC/Erythrocytes (qual)
Urine WBC/Leucocytes (qual)
Urine pH
X
X
X
X
X
X
X
X
X
--
--
--
--
--
--
--
--
--
--
--
--
--
--
--
--
--
--
X
X
X
X
X
X
X
X
X
Urine sediment1
(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)
A: parameters to be determined at Visit 1 (screening examination) 
B: parameters to be determined at Visit 2 and 3 (for time points refer to Flow Chart)
C: parameters to be determined at Visit 3 (for time points refer to Flow Chart)
D: parameters to be determined at Visit 4 (end of trial examination)
The tests listed in Table 5.1.3: 2 are exclusionary laboratory tests that 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 each treatment period.


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Table 5.1.3: 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 (e.g. 
 True 
M®, 
) will be performed prior to 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.
The laboratory tests listed in Tables 5.1.3: 1 and 5.1.3: 2 will be performed at 
 
, with the exception of 
drug screening tests. These tests will be performed at the trial site using M-10/14-PDT test, 
Diagnostic Nord, or a comparable test system.
Laboratory data will be transmitted electronically from the laboratory to the trial site.
Electrocardiogram
5.1.4
Twelve-lead ECGs (I, II, III, aVR, aVL, aVF, V1 - V6) will be recorded using a 
computerised electrocardiograph (CardioSoft EKG System, 
, 
) at the times provided in the Flow Chart.
To achieve a stable heart rate at rest and to assure high quality recordings, the site personnel 
will be instructed to assure a relaxed and quiet environment, so that all subjects are at 
complete rest.
All ECGs will be recorded for a 10 sec duration after subjects have rested for at least 5 min in 
a supine position. ECG assessment will always precede all other study procedures scheduled 
for the same time to avoid compromising ECG quality. 
All ECGs will be stored electronically on the Muse CV Cardiology System (
 
). 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. Abnormal 
findings will be reported as AEs (during the trial) or baseline conditions (at screening) if 
assessed to be clinically relevant by the investigator. Any ECG abnormalities will be 


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carefully monitored and, if necessary, the subject will be removed from the trial and will 
receive the appropriate medical treatment. 
ECGs may be repeated for quality reasons (for instance, due to alternating current artefacts, 
muscle movements, or electrode dislocation) and the repeated ECG will be used for analysis. 
Additional (unscheduled) ECGs may be collected by the investigator for safety reasons. 
Assessment of adverse events
5.1.5
5.1.5.1
Definitions of adverse events
Adverse event
5.1.5.1.1
An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a medicinal product and which does not necessarily have 
to have a causal relationship with this treatment.
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product.
The following should also be recorded as an AE in the CRF and BI SAE form (if applicable):

Worsening of the underlying disease or of other pre-existing conditions 

Changes in vital signs, ECG, physical examination, and laboratory test results, if they 
are judged clinically relevant by the investigator
If such abnormalities already pre-exist prior to trial inclusion, they will be considered as 
baseline conditions and should be collected in the eCRF only.
Serious adverse event
5.1.5.1.2
A serious adverse event (SAE) is defined as any AE which fulfils at least one of the 
following criteria:

Results in death 

Is life-threatening, which refers to an event in which the patient was at risk of death 
at the time of the event; it does not refer to an event that hypothetically might have 
caused death if more severe 

Requires inpatient hospitalisation  

Requires prolongation of existing hospitalisation

Results in persistent or significant disability or incapacity 

Is a congenital anomaly/birth defect 

Is deemed serious for any other reason if it is an important medical event when based 
upon appropriate medical judgment which may jeopardise the patient and may 
require medical or surgical intervention to prevent one of the other outcomes listed in 
the above definitions. Examples of such events are intensive treatment in an 


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emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalisation or development of dependency or 
abuse
AEs considered ‘Always Serious’
5.1.5.1.3
Cancers of new histology and exacerbations of existing cancer must be classified as a serious 
event regardless of the time since discontinuation of the trial medication and must be reported 
as described in 5.1.5.2, 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 eDC system, an electronic data 
capture system which allows the entry of trial data at the trial site. These events should 
always be reported as SAEs as described above.
Adverse events of special interest
5.1.5.1.4
The term adverse events of special interest (AESI) relates to any specific AE that has been 
identified at the project level as being of particular concern for prospective safety monitoring 
and safety assessment within this trial, e.g. the potential for AEs based on knowledge from 
other compounds in the same class. AESIs need to be reported to the sponsor’s 
Pharmacovigilance Department within the same timeframe that applies to SAEs, please see 
section 5.1.5.2.2.
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 (aspartate transaminase) and/or ALT (alanine 
transaminase) ≥3-fold ULN combined with an elevation of total bilirubin 
≥2-fold ULN measured in the same blood sample, or
o
Aminotransferase (ALT, and/or AST) elevations ≥10 fold ULN
These lab findings constitute a hepatic injury alert and the subjects showing these lab 
abnormalities need to be followed up according to the ‘DILI checklist’ provided in the 
ISF. In case of clinical symptoms of hepatic injury (icterus, unexplained 
encephalopathy, unexplained coagulopathy, right upper quadrant abdominal pain, 
etc.) without lab results (ALT, AST, total bilirubin) available, the Investigator should 
make sure that these parameters are analysed, if necessary in an unscheduled blood 
test. Should the results meet the criteria of hepatic injury alert, the procedures 
described in the DILI checklist should be followed.


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Intensity (severity) of AEs
5.1.5.1.5
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
5.1.5.1.6
Medical judgment should be used to determine the relationship, considering all relevant 
factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge, 
confounding factors such as concomitant medication, concomitant diseases and relevant 
history.
Arguments that may suggest that there is a reasonable possibility of a causal relationship 
could be:

The event is consistent with the known pharmacology of the drug 

The event is known to be caused by or attributed to the drug class

A plausible time to onset of the event relative to the time of drug exposure

Evidence that the event is reproducible when the drug is re-introduced

No medically sound alternative aetiologies that could explain the event (e.g. pre-
existing or concomitant diseases, or co-medications)

The event is typically drug-related and infrequent in the general population not 
exposed to drugs (e.g. Stevens-Johnson syndrome)

An indication of dose-response (i.e. greater effect size if the dose is increased, smaller 
effect size if dose is reduced)
Arguments that may suggest that there is no reasonable possibility of a causal relationship 
could be:

No plausible time to onset of the event relative to the time of drug exposure is evident 
(e.g. pre-treatment cases, diagnosis of cancer or chronic disease within days / weeks 
of drug administration; an allergic reaction weeks after discontinuation of the drug 
concerned)

Continuation of the event despite the withdrawal of the medication, taking into 
account the pharmacological properties of the compound (e.g. after 5 half-lives). Of 
note, this criterion may not be applicable to events whose time course is prolonged 
despite removing the original trigger

Additional arguments amongst those stated before, like alternative explanation (e.g. 
situations where other drugs or underlying diseases appear to provide a more likely 
explanation for the observed event than the drug concerned)

Disappearance of the event even though the trial drug treatment continues or remains 
unchanged


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5.1.5.2
Adverse event collection and reporting
AE collection
5.1.5.2.1
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
time, 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 carefully written record of all AEs shall be kept by the investigator in charge of the trial. 
Records of AEs shall include data on the time of onset, end time, intensity of the event, and 
any treatment or action required for the event and its outcome.
The following must be collected and documented on the appropriate CRF(s) by the 
investigator:

From signing the informed consent onwards until an individual subject’s end of trial: 
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 any occurrence of cancer and 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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AE reporting to the sponsor and timelines
5.1.5.2.2
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
5.1.5.2.3
All (S)AEs, including those persisting after the individual subject’s end of trial, must be 
followed up until they have resolved, have been sufficiently assessed as ‘chronic’ or ‘stable’, 
or no further information can be obtained.
Pregnancy
5.1.5.2.4
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 well as non-trial specific information and consent for the pregnant partner.
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
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS
Assessment of pharmacokinetics
5.2.1
For the assessment of pharmacokinetics, blood samples will be collected at the time points 
indicated in the Flow Chart. The actual sampling times will be recorded and used for 
determination of pharmacokinetic parameters. 


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Methods of sample collection
5.2.2
5.2.2.1
Blood sampling for pharmacokinetic analysis
For quantification of BI 474121 and Itraconazole concentrations in plasma, 2.7 mL of blood 
for each analyte will be drawn from an antecubital or forearm vein into an K2-EDTA 
(dipotassium ethylenediaminetetraacetic acid)-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 venepuncture with a metal needle.
The EDTA-anticoagulated blood samples will be centrifuged for approximately 10 min at 
approximately 2000 x g to 4000 x g and at 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 of plasma. 
The process from blood collection until transfer of plasma aliquots into the freezer should be 
completed in less than 120 minutes. During this period, samples can be stored and handled at 
room temperature. The time each aliquot was placed in the freezer will be documented. Until 
transfer on dry ice to the analytical laboratory, the aliquots will be stored upright at 
approximately -20°C or below at the trial site. The second aliquot will be transferred to the 
analytical laboratory after the bioanalyst has acknowledged safe arrival of the first aliquot. At 
the analytical laboratory, the plasma samples will be stored at approximately -20°C or below 
until analysis.
At a minimum, the sample tube labels should list BI trial number, subject number, visit, and 
planned sampling time. 
After completion of the trial, the plasma samples may be used for further methodological 
investigations (e.g. for stability testing or assessment of metabolites. However, only data 
related to the analyte and/or 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 after the CTR is archived.


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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 5.2 are 
generally used assessments of drug exposure.


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6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
Exact times of measurements outside the permitted time windows will be documented. The 
acceptable time windows for screening and the end of trial examination are provided in the 
Flow Chart.
Study measurements and assessments scheduled to occur ‘before’ trial medication 
administration on Day 1 are to be performed and completed within a 3 h-period prior to the 
administration of 474121.
If not stated otherwise in the flow chart, the acceptable deviation from the scheduled time of 
safety assessments (e.g. vital signs, ECG, and laboratory tests) will be ± 60 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 venepuncture are scheduled for the same time, venepuncture should be the last of 
the measurements due to its inconvenience to the subject and possible influence on 
physiological parameters.
For planned blood 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 
the determination of pharmacokinetic parameters.
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
Screening
6.2.1
After having been informed about the trial, all subjects will provide written informed consent 
in accordance with GCP and local legislation prior to enrolment in the study.
For information regarding laboratory tests (including drug and virus screening), ECG, vital 
signs, and physical examination, refer to Sections 5.1.1 to 5.1.4.
Genotyping will be performed in those volunteers whose genotypes have not been previously 
determined (for details, see Section 5.3).
Treatment periods
6.2.2
Each subject is expected to participate in 2 treatment periods. At least a wash-out of 10 days
will separate BI 474121drug administrations in the first and second treatment period.
On Day 1 of treatment period 1, study participants will be admitted to the trial site and kept 
under close medical surveillance for at least 24 h following drug administration. 
On Day 1 of treatment period 2, study participants will be admitted to the trial site and kept 
under close medical surveillance for at least 24 h following drug administration. 


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The subjects will then be allowed to leave the trial site after formal assessment and 
confirmation of their fitness. On all other study days, subjects will be treated 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 5.2.2.
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 times of 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.
Follow-up period and trial completion
6.2.3
For AE assessment, laboratory tests, recording of ECG and vital signs, and physical 
examination during the follow-up period, see Sections 5.1.2 to 5.1.5.
Subjects who discontinue treatment before the end of the planned treatment period should 
undergo the EoTrial Visit.
All abnormal values (including laboratory parameters) that are assessed as clinically relevant 
by the investigator will be monitored using the appropriate tests until a return to a medically 
acceptable level is achieved. (S)AEs persisting after a subject’s EoTrial Visit must be 
followed until they have resolved, have been sufficiently characterised, or no further 
information can be obtained. 


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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
7.1
STATISTICAL DESIGN – MODEL
The main objective of this trial is to investigate the effect on the pharmacokinetics of BI 
474121 in plasma when given as oral single dose together with multiple oral doses of 
itraconazole (Test, T) as compared to when given alone as oral single dose (Reference, R) on 
the basis of the primary and secondary pharmacokinetic endpoints, as listed in Section 2.1.2
and 2.1.3. The trial is designed to allow intra-subject comparisons and will be evaluated 
statistically by use of a linear model for logarithmically transformed PK endpoints.
 
 
 
7.2
NULL AND ALTERNATIVE HYPOTHESES
The bioavailability of BI 474121 given in combination with itraconazole compared with BI 
474121 given alone will be estimated by the ratios of the geometric means (test/reference),
and their corresponding 2-sided 90% confidence intervals (CIs) will be provided. This 
method corresponds to the two one-sided t-test procedure, each at the 5% significance level. 
Since the main focus is on estimation and not testing, a formal hypothesis test and associated 
acceptance range is not specified.
7.3
PLANNED ANALYSES
Analysis sets
Statistical analyses will be based on the following analysis sets:

Treated set (TS): The treated set includes all subjects who were treated with at least 
one dose of study drug. The treated set will be used for safety analyses.
Pharmacokinetic parameter analysis set (PKS): This set includes all subjects in the 
treated set (TS) who provide at least one PK endpoint that was defined as primary or 
secondary and was not excluded due to a protocol deviation relevant to the evaluation 
of PK or due to PK non-evaluability (as specified in the following subsection 
‘Pharmacokinetics’). Thus, a subject will be included in the PKS, even if he 
contributes only one PK parameter value for one period to the statistical assessment. 
Descriptive and model based analyses of PK parameters will be based on the PKS.
Adherence to the protocol will be assessed by the trial team. Important protocol deviation
(IPD) categories will be suggested in the IQRM plan, IPDs will be identified no later than in 
the Report Planning Meeting, and the IPD categories will be updated as needed.


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Pharmacokinetics
The pharmacokinetic parameters listed in Section 2.1 for drug BI 474121 will be calculated 
according to the relevant SOP of the Sponsor (001-MCS-36-472). 
Plasma concentration data and parameters of a subject will be included in the statistical 
pharmacokinetic (PK) analyses if they are not flagged for exclusion due to a protocol 
deviation relevant to the evaluation of PK (to be decided no later than in the Report Planning 
Meeting) or due to PK non-evaluability (as revealed during data analysis, based on the 
criteria specified below). Exclusion of a subject’s data will be documented in the CTR.
Relevant protocol deviations may be:

Incorrect trial medication taken, i.e. the subject received at least one dose of trial
medication the subject was not assigned to

Incorrect dose of trial medication taken

Use of restricted medications
Plasma concentrations and/or parameters of a subject will be considered as non-evaluable, if 
for example

The subject experienced emesis that occurred at or before two times median tmax of 
the respective treatment (Median tmax is to be determined excluding the subjects 
experiencing emesis) 

A predose concentration of BI 474121 is >5% Cmax value of that subject in the 
respective treatment period

Missing samples/concentration data at important phases of PK disposition curve
Plasma concentration data and parameters of a subject which is flagged for exclusion will be 
reported with its individual values but will not be included in the statistical analyses. 
Descriptive and inferential statistics of PK parameters will be based on the PKS.
Only concentration values within the validated concentration range and actual sampling times 
will be used for the calculation of pharmacokinetic parameters. Concentrations used in the 
pharmacokinetic calculations will be in the same format provided in the bioanalytical report, 
(that is, to the same number of decimal places provided in the bioanalytical report). 
Primary endpoint analyses
7.3.1
Primary analyses
The statistical model used for the analysis of the primary endpoints will be an analysis of 
variance (ANOVA) model on the logarithmic scale. That is, the PK endpoints will be log-
transformed (natural logarithm) prior to fitting the ANOVA model. This model will include 
effects accounting for the following sources of variation: subjects and treatment. The effect 
'subjects' will be considered as random, whereas ‘treatment’ will be considered as fixed. The 
model is described by the following equation:


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ykm = +k + sm +  ekm
where
ykm = logarithm of response measured on subject m receiving treatment k,
= the overall mean,
k = the kth treatment effect, k = 1, 2,
sm = the effect associated with the mth subject,
m = 1, 2, ..., n
ekm = the random error associated with the mth subject who received
treatment k.
where s ~ N(0, σ
) i.i.d., e ~ N(0, σ
 ) i.i.d. and sm, ekm are independent random 
variables.
Point estimates for the ratios of the geometric means (test/reference) for the primary 
endpoints (see Section 2.1) and their two-sided 90% confidence intervals (CIs) will be 
provided.
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 (Least Squares Means).
Additionally their two-sided 90% confidence intervals will be calculated based on the 
residual error from the ANOVA and quantiles from the t-distribution. These quantities will 
then be back-transformed to the original scale to provide the point estimate and 90% CIs for 
each endpoint.
 
Secondary endpoint analyses
7.3.2
The secondary endpoints (refer to Section 2.1.3) will be calculated according to the BI SOP 
‘Standards and processes for analyses performed within Clinical Pharmacokinetics/ 
Pharmacodynamics’ (001-MCS-36-472) and will be assessed statistically using the same 
methods as described for the primary endpoints.


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7.4
INTERIM ANALYSES
No interim analysis is planned.
7.5
HANDLING OF MISSING DATA
Safety
7.5.1
It is not planned to impute missing values for safety parameters.
Pharmacokinetics
7.5.2
Handling of missing PK data will be performed according to the relevant Corporate 
Procedure (001-MCS-36-472).
PK parameters that cannot be reasonably calculated based on the available drug 
concentration-time data will not be imputed.
7.6
RANDOMISATION
In this trial subjects receive all treatments in the same order, thus no randomisation for the
treatment assignment is performed (see also Section 4.1.3). The sponsor will arrange for the 
packaging and labelling of BI 474121 trial medication.
7.7
DETERMINATION OF SAMPLE SIZE
It is planned to enter a total of 14 subjects in the trial (accounting for up to 2 dropouts or non 
PK evaluable subjects), because this sample size is considered sufficient to achieve the aims 
of this exploratory trial. With this sample size, the following precision in estimating the ratio 
of geometric means (test/reference) can be expected with 95% probability. Precision is 
defined as the ratio of upper CI limit to the estimate of ratio of geometric means. Note that 
the precision is independent of the actual ratio of geometric means.
For this trial, no information on intra-subject variability is available. Therefore, Table 7.7: 1
provides an overview on the achievable precision for estimating the ratio of geometric means 
(test/reference) for three different gCV. For illustrative purposes, the expected 90% 
confidence intervals with 95% coverage probability are displayed for different values of 
geometric mean ratios T/R in the two-period fixed sequence design.


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Table 7.7: 1
Precision that can be expected with 95% probability and illustrative 
two-sided 90% confidence intervals around the ratios of geometric 
means (T/R) for different gCVs in a two-period fixed sequence design 
study (N=12)
gCV [%]
Precision upper 
CL / ratio* 
estimate
Ratio [%]*
Lower CL [%]
Upper CL [%]
15.0
1.158
80
  69.11
  92.60
15.0
1.158
100
  86.39
115.75
15.0
1.158
125
107.99
144.69
20.0
1.214
80
  65.88
  97.15
20.0
1. 214
100
  82.35
121.43
20.0
1. 214
125
102.94
151.79
25.0
1.273
80
  62.84
101.85
25.0
1. 273
100
78.55 
127.31
25.0
1. 273
125
  98.19
159.13
*Ratio of geometric means (test/reference) for a PK endpoint is defined by exp(T)/exp(R).
The expected 90% confidence interval limits in the table were derived by
CI limit, = exp(ln(θ) ± ω),
with θ being the ratio (T/R) on original scale and ω the distance from the estimate θ to either 
confidence interval limit on the log-scale, which was obtained from the achievable precision 
on the original scale.
The calculation was performed as described by Julious [R11-5230] using R Version 3.5.1.


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8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY, AND 
ADMINISTRATIVE STRUCTURE
The trial will be carried out in compliance with the protocol, the ethical principles laid down 
in the Declaration of Helsinki, in accordance with the ICH Harmonized Guideline for Good 
Clinical Practice (GCP), relevant BI Standard Operating Procedures (SOPs), the EU 
regulation 536/2014, and other relevant regulations. Investigators and site staff must adhere 
to these principles.
Standard medical care (prophylactic, diagnostic, and therapeutic procedures) remains the 
responsibility of the subject’s treating physician.
The investigator will inform the sponsor immediately of any urgent safety measures taken to 
protect the trial subjects against any immediate hazard, as well as of any serious breaches of 
the protocol or of ICH GCP.
The Boehringer Ingelheim transparency and publication policy can be found on the following 
web page: trials.boehringer-ingelheim.com. As a general rule, no trial results should be 
published prior to archiving of the CTR.
The terms and conditions of the insurance coverage are made available to the investigator and 
the  subjects, and are stored in the ISF.
8.1
TRIAL APPROVAL, SUBJECT INFORMATION, INFORMED CONSENT
This trial will be initiated only after all required legal documentation has been reviewed and 
approved by the respective Institutional Review Board (IRB / Independent Ethics Committee 
(IEC and competent authority (CA) according to national and international regulations. The 
same applies for the implementation of changes introduced by amendments.
Prior to a subject’s participation in the trial, written informed consent must be obtained from 
each subject (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 retained by the investigator as part of the trial records. A signed copy of the 
informed consent and any additional subject information must be given to each subject or the 
subject’s legally accepted representative.
The subject must be given sufficient time to consider participation in the trial. The 
investigator or delegate obtains written consent of the subject’s own free will with the 
informed consent form after confirming that the subject understands the contents. The 
investigator or 
 delegate must sign (or place a seal on) and date the informed consent form. 
If a trial collaborator has given a supplementary explanation, the trial collaborator also signs 
(or places a seal on) and dates the informed consent.
Re-consenting may become necessary when new relevant information becomes available and 
should be conducted according to the sponsor’s instructions.


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The consent and re-consenting process should be properly documented in the source 
documentation.
For subjects enrolled during the COVID-19 crisis: In addition to the study specific informed 
consent, separate written consent will be obtained for testing on SARS-CoV-2 infection.
8.2
DATA QUALITY ASSURANCE
A risk-based approach is used for trial quality management. It is initiated by the assessment 
of critical data and processes for trial subject protection and reliability of the results as well as 
identification and assessment of associated risks. An Integrated Quality and Risk 
Management Plan documents the rationale and strategies for risk management during trial 
conduct including monitoring approaches, vendor management and other processes focusing 
on areas of greatest risk. 
Continuous risk review and assessment may lead to adjustments in trial conduct, trial design 
or monitoring approaches. 
A quality assurance audit/inspection of this trial may be conducted by the sponsor, sponsor’s 
designees, or by IRB / IEC or by regulatory authorities. The quality assurance auditor will 
have access to all medical records, the investigator’s trial-related files and correspondence, 
and the informed consent documentation of this clinical trial..
8.3
RECORDS
CRFs for individual subjects will be provided by the sponsor. For drug accountability, refer 
to Section 4.1.8.
ClinBaseTM
In the 
 Phase I unit – the 
validated ClinBase
system is used 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.
Source documents
8.3.1
In accordance with regulatory requirements, the investigator should prepare and maintain 
adequate and accurate source documents and trial records for each trial subject that include 
all observations and other data pertinent to the investigation. Source data as well as reported 
data should follow the ‘ALCOA principles’ and be attributable, legible, contemporaneous, 
original, and accurate. Changes to the data should be traceable (audit trail).
Data reported on the CRF must be consistent with the source data or the discrepancies must 
be explained.
Before providing any copy of subjects’ source documents to the sponsor, the investigator 
must ensure that all subject identifiers (e.g., subject’s name, initials, address, phone number, 


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and social security number) have properly been removed or redacted to ensure subject 
confidentiality.
If the subject is not compliant with the protocol, any corrective action (e.g. re-training) must 
be documented in the subject file.
For the CRF, data must be derived from source documents, for example:

Subject identification: sex, year of birth (in accordance with local laws and 
regulations)

Subject participation in the trial (substance, trial number, subject number, date subject 
was informed)

Dates of subject’s visits, including dispensing of trial medication

Medical history (including trial indication and concomitant diseases, if applicable)

Medication history

AEs and outcome events (onset date [mandatory], and end date [if available])

SAEs (onset date [mandatory], and end date [if available])

Concomitant therapy (start date, changes)

Originals or copies of laboratory results and other imaging or testing results, with 
proper documented medical evaluation (in validated electronic format, if available)

ECG results (original or copies of printouts)

Completion of subject’s participation in the trial (end date; in case of premature 
discontinuation, document the reason for it, if known)

Prior to allocation of a subject to a treatment into a clinical trial, there must be 
documented evidence in the source data (e.g. medical records) that the trial participant 
meets all inclusion criteria and does not meet any exclusion criteria. The absence of 
records (either medical records, verbal documented feedback of the subject or testing 
conducted specific for a protocol) to support inclusion/exclusion criteria does not 
make the subject eligible for the clinical trial.
Data directly entered into ClinBaseTM (that is, without prior written or electronic record) are 
considered to be source data. The place where data are entered first will be defined in a trial 
specific Source Data Agreement. The data in ClinBaseTM are available for inspection at any 
time.
Direct access to source data and documents
8.3.2
The investigator /institution will allow site trial-related monitoring, audits, IRB / IEC review 
and regulatory inspections. Direct access must be provided to the CRF and all source 
documents/data, including progress notes, copies of laboratory and medical test results, which 
must be available at all times for review by the Clinical Research Associate, auditor and 
regulatory inspector (e.g. FDA). They may review all CRFs and informed consents. The 
accuracy of the data will be verified by direct comparison with the source documents 
described in section 8.3.1. The sponsor will also monitor compliance with the protocol and 
GCP.


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Storage period of records
8.3.3
Trial site:
The trial site must retain the source and essential documents (including ISF) according to the 
local requirements valid at the time of the end of the trial.
Sponsor:
The sponsor must retain the essential documents according to the sponsor’s SOPs.
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS
BI is responsible to fulfil their legal and regulatory reporting obligation in accordance with 
regulatory requirements.
8.5
STATEMENT OF CONFIDENTIALITY AND SUBJECT PRIVACY
Individual subject data obtained as a result of this trial is considered confidential and 
disclosure to third parties is prohibited with the exceptions noted in section 8.7. 
Data protection and data security measures are implemented for the collection, storage and 
processing of patient data in accordance with the principles 7 and 12 of the WHO GCP 
handbook.
Personalised treatment data may be given to the subject’s personal physician or to other 
appropriate medical personnel responsible for the subject’s welfare. Data generated at the site 
as a result of the trial need to be available for inspection on request by the participating 
physicians, the sponsor’s representatives, by the IRB / IEC and the regulatory authorities.
The sponsor has implemented processes to ensure confidentiality and subject privacy. The 
processes include measures in case of breach of data security [001-MCS-00-005].
Collection, storage and future use of biological samples and 
8.5.1
corresponding data
Measures are in place to comply with the applicable rules for the collection, biobanking and 
future use of biological samples and clinical data, in particular

Sample and data usage has to be in accordance with the separate biobanking informed 
consent

The BI-internal facilities storing biological samples from clinical trial participants as 
well as the external banking facility are qualified for the storage of biological samples 
collected in clinical trials.

An appropriate sample and data management system, incl. audit trail for clinical data 
and samples to identify and destroy such samples according to ICF is in place

A fit for the purpose documentation (biomarker proposal, analysis plan and report) 
ensures compliant usage

A fit for purpose approach will be used for assay/equipment validation depending on 
the intended use of the biomarker data


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Samples and/or data may be transferred to third parties and other countries as specified in the 
ICF
8.6
TRIAL MILESTONES
The start of the trial is defined as the date of the enrolment of the first subject in the trial.
The end of the trial is defined as the ‘date of the last visit of the last subject in whole trial’ 
(‘Last Subject Completed’) 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.
Early termination of the trial is defined as the premature termination of the trial for any 
reason before the end of the trial as specified in this protocol.
Temporary halt of the trial is defined as any unplanned interruption of the trial by the 
sponsor with the intention to resume it.
Suspension of the trial is defined as an interruption of the trial based on a Health Authority 
request.
The EC/competent authority in each participating EU member state will be notified about the 
trial milestones according to the laws of each member state. 
A final report of the clinical trial data will be written only after all subjects have completed 
the trial in all countries (EU or non-EU), so that all data can be incorporated and considered 
in the report.
The sponsor will submit to the EU database a summary of the final trial results within one 
year from the end of a clinical trial as a whole, regardless of the country of the last patient 
(EU or non-EU).
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL
The trial is sponsored by Boehringer Ingelheim (BI).
The trial will be conducted at the 
 
, under the supervision of the Principal Investigator. Relevant 
documentation on the participating (Principal) Investigators (e.g. their curricula vitae) will be 
filed in the ISF.
BI has appointed a Clinical Trial Leader, responsible for coordinating all required trial 
activities, in order to 

Manage the trial in accordance with applicable regulations and internal SOPs

Direct the clinical trial team in the preparation, conduct, and reporting of the trial

ensure appropriate training and information of local Clinical Trial Manager, Clinical 
Research Associates, and investigators of participating trial sites
The trial medication will be provided by the 
 
(BI 474121) or will be obtained by the clinical trial site from 
a public pharmacy (itraconazole).
Safety laboratory tests will be performed by the local laboratory of the trial site (
 
).


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Analyses of BI 474121 and Itraconazole concentrations in plasma will be performed at
On-site monitoring will be performed by BI or a contract research organisation appointed by 
BI.
Data management and statistical evaluation will be done by BI or a contract research 
organisation appointed by BI according to BI SOPs.
Tasks and functions assigned in order to organise, manage, and evaluate the trial are defined 
according to BI SOPs. A list of responsible persons and relevant local information can be 
found in the ISF.


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9.
REFERENCES 
9.1
PUBLISHED REFERENCES
P15-06298
Ministry of Health, Labour and Welfare, Drug interaction guideline for 
drug development and labeling recommendations (2015)
P15-06991
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_guidel
ine/2012/0 7/WC500129606.pdf (access date: 8 July 2015); London: 
European Medicines Agency (EMA); 2012.
R01-0516
Olkkola KT, Backman JT, Neuvonen PJ. Midazolam should be avoided in 
patients receiving the systemic antimycotics ketoconazole or itraconazole.
Clin Pharmacol Ther 1994. 55(5):481-485. 
R03-2269
Guidance for industry: food-effect bioavailability and fed bioequivalence 
studies. In: U.S. Department of Health and Human Services, Food and Drug 
Administration, Center for Drug Evaluation and Research (CDER) 2002:1-
9.
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. Clin 
Pharmacol Ther 1994. 55(5):481-485.
R10-5092
Cooke SF, Bliss TVP. Plasticity in the human central nervous system. Brain 
129, 1659 - 1673 (2006)
R10-5102
Reymann KG, Frey JU. The late maintenance of hippocampal LTP: 
requirements, phases, 'synaptic tagging', 'late-associativity' and 
implications. Neuropharmacology 52, 24 - 40 (2007)
R11-5230
Julious SA. Sample sizes for clinical trials. Boca Raton: Taylor & Francis 
Group (2010)
R13-4518
Hu NW, Ondrejcak T, Rowan MJ. Glutamate receptors in preclinical 
research on Alzheimer's disease: update on recent advances. Pharmacol 
Biochem Behav 100, 855 - 862 (2012)
R13-4521
Lin CH, Lane HY, Tsai GE. Glutamate signaling in the pathophysiology 
and therapy of schizophrenia. Pharmacol Biochem Behav 100, 665 - 677 
(2012)
R15-1331
Elashoff JD. nQuery Advisor version 7.0 user's guide.
http://www.statsols.com/wp-
content/uploads/2013/10/nQ70_version2_manual.pdf 
(access date: 20 March 2015) ; Los Angeles: Statistical Solutions; 2007.


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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 (2017)
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.
R18-0241
Guidance for industry: clinical drug interaction studies - study design, data
analysis, and clinical implications (draft guidance, this guidance document 
is being distributed for comment purposes only) (October 2017, clinical 
pharmacology). 
https://www.fda.gov/downloads/drugs/guidances/ucm292362.pdf (access 
date: 19 January 2018); Silver Spring: U.S. Department of Health and 
Human Services, Food and Drug Administration, Center for Drug 
Evaluation and Research (CDER) 2017.
R18-2643
Sporanox 10 mg/ml oral solution (Janssen-Cilag) (summary of product 
characteristics (2018)
R20-2709
Sempera Liquid 10 mg/ml, Loesung zum Einnehmen (Janssen-Cilag) 
(Fachinformation, Stand der Information: Mai 2020).
R94-1445
Diletti E, Hauschke D, Steinijans VW. Sample size determination for 
bioequivalence assessment by means of confidence intervals. Int J Clin 
Pharmacol Ther Toxicol 1992; 30 (suppl 1): S51-S58.
R94-1529
Chow SC, Liu JP, Design and Analysis of Bioavailability and 
Bioequivalence Studies. New York: Marcel Dekker Inc (1992)
9.2
UNPUBLISHED REFERENCES
001-MCS-36-472 Standards and processes for analyses performed within Clinical   
Pharmacokinetics/Pharmacodynamics. Current version
001-MCS-00-005 Protection of Study Subject/Patient Confidentiality, current version
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, 
twoperiod, 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.
c26859057
. Investigator's Brochure BI 474121 Alzheimer's 
Disease and Schizophrenia. Current version
c32142501
1411-0001, 8-05-output-sibv1-safety-2020-04-27, 04 October 2019
n00265648
 
. 18B128. BI 474121: 4-week 
oral (gavage) toxicity study in rats
n00268539
. Prediction of 
BI 474121 Pharmacokinetics and Therapeutic Dose in Human. 02 August 
2019
n00269861
. In vitro inhibition of human, rat and monkey 
recombinant phosphodiesterase (PDE) 2A and human recombinant PDE1a, 
1b and 1c by BI 47412. 05 June 2019
n00271367
GM20LK. BI 474121. Toxicity Study by Oral Gavage 
Administration to Cynomolgus Monkeys for 4 Weeks Followed by a 4 
Week Recovery Period


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10.
APPENDICES


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
11.1
GLOBAL AMENDMENT 1
Date of amendment
16 December 2020
EudraCT number
EU number
2019-003630-16
BI Trial number
1411-0010
BI Investigational Medicinal 
Product(s)
BI 474121
Title of protocol
Effect of itraconazole on the pharmacokinetics of a 
single oral dose of BI 474121 in healthy male 
subjects (an open-label, two-period fixed sequence 
design study)
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. Flowchart
2. 1.2.2 Itraconazole
3. 1.4.2.2 Itraconazole
4. 3.1 Overall trial design and plan
5. 3.3.4.1 Discontinuation of trial treatment
6. 4.1.4 Drug assignment and administration of
doses for each subject
7. 4.2.2 Restrictions
8. 8.5. Statement of confidentiality and subject 
privacy
9. a) 9.1 Published references
b) 9.2. Unpublished references
10. 10.1 Reconstitution Instructions
Description of change
1. Minor logistical and editorial changes
2. Reference to Sporanox 10 mg/ml Oral 
Solution inserted and reference to current 
version of Sempera ®Liquid 10 mg/ml added
3. a) Reference to current version of 
Sempera ®Liquid 10 mg/ml inserted
b) Discontinuation of treatment already if 
AST and/or ALT ≥2-fold ULN
4. Washout period of 12 days replaced with 10 
days 


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5. Criterion #5 amended to trigger 
discontinuation of treatment at a lower 
threshold of liver enzyme increase
6.
a) Post-dose observation period of 34 hours 
replaced with 24 hours which is considered 
acceptable from a safety perspective. 
b) Washout period of 12 days replaced with 
10 days.
7. a) Reference to current version of 
Sempera ®Liquid 10 mg/ml inserted b) 
Specification of post-dose fluid restrictions
8. a) WHO principle 6 replaced with 7
b) Clarification on confidentiality and subject 
privacy
9. a) most current version of the German 
Summary of Product Characteristics of 
Sempera Liquid 10 mg/ml added
b) SOP for Protection of Subject/patient 
confidentiality added
10. Missing information from the reconstitution 
instruction added
Rationale for change
1. Correction
2. Correction and update
3. a) Updated SmPC is available
b) Ensure consistency with updated 
discontinuation criterion (see 5)
4. FDA feedback.
5. EC feedback regarding monitoring of liver 
function considering the adverse effect 
profile of itraconazole
6. a) and b) FDA feedback
7. a) Update b) Correction
8. a) Correction, b) Feedback from BfArM
9.
a) and b) update due to changes in the text 
body
10. Correction


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c30888994
2.0
clinical-trial-protocol-version-2
Effect of  itraconazole on the pharmacokinetics of a single oral dose of BI 474121 in
healthy male subjects (an open-label, two-period fixed sequence design study)
Author-Clinical Trial Leader
16 Dec 2020 08:48 CET
Author-Trial Clinical
Pharmacokineticist
16 Dec 2020 09:11 CET
Author-Trial Statistician
16 Dec 2020 09:38 CET
Verification-Paper Signature
Completion
16 Dec 2020 11:16 CET
Approval-Team Member Medicine
16 Dec 2020 15:07 CET
Approval-
Medicine
17 Dec 2020 22:20 CET


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c30888994
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SAP_001.pdf: 
TITLE PAGE
TRIAL STATISTICAL ANALYSIS PLAN
c35064438-01
BI Trial No.:
1411-0010
Title:
Effect of itraconazole on the pharmacokinetics of a single oral 
dose of BI 474121 in healthy male subjects (an open-label, two-
period fixed sequence design study)
(Revised Protocol including Amendment 1 [c30888994-02])
Investigational
Product(s):
BI 474121
Responsible trial 
statistician(s):
Phone: 
Fax: 
Date of statistical 
analysis plan:
12 MAY 2021 SIGNED
Version:
1
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reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.


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1.
TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
1.
TABLE OF CONTENTS......................................................................................2
LIST OF TABLES...................................................................................................................4
2.
LIST OF ABBREVIATIONS ..............................................................................5
3.
INTRODUCTION.................................................................................................7
4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY......................8
5.
ENDPOINTS .........................................................................................................9
5.1
PRIMARY ENDPOINTS.....................................................................................9
5.2
SECONDARY ENDPOINTS...............................................................................9
5.2.1
Key secondary endpoints......................................................................................9
5.2.2
Secondary endpoint...............................................................................................9
6.
GENERAL ANALYSIS DEFINITIONS ..........................................................11
6.1
TREATMENTS...................................................................................................11
6.2
IMPORTANT PROTOCOL DEVIATIONS....................................................13
6.3
SUBJECT SETS ANALYSED...........................................................................14
6.5
POOLING OF CENTRES .................................................................................15
6.6
HANDLING OF MISSING DATA AND OUTLIERS....................................15
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS ...................15
7.
PLANNED ANALYSIS......................................................................................17
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS.........18
7.2
CONCOMITANT DISEASES AND MEDICATION .....................................19
7.3
TREATMENT COMPLIANCE........................................................................19
7.4
PRIMARY ENDPOINTS...................................................................................19
7.4.1
Primary analysis of the primary endpoints......................................................19
 
7.5
SECONDARY ENDPOINTS.............................................................................21
7.5.1
Key secondary endpoints....................................................................................21
7.5.2
Secondary endpoint.............................................................................................21
7.7
EXTENT OF EXPOSURE.................................................................................21
7.8
SAFETY ANALYSIS..........................................................................................22
7.8.1
Adverse Events ....................................................................................................22
7.8.2
Laboratory data ..................................................................................................23
7.8.3
Vital signs.............................................................................................................23
7.8.4
ECG......................................................................................................................24
7.8.5
Others...................................................................................................................24


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8.
TIMEPOINT OF RELEASE OF TREATMENT INFORMATION.............25
9. 
REFERENCES....................................................................................................26
11.
HISTORY TABLE..............................................................................................28


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LIST OF TABLES
Table 6.1: 1
Treatments and labels used in the analysis.......................................................11
Table 6.3: 1
Subject sets analysed........................................................................................15
Table 11: 1
History table .....................................................................................................28


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2.
LIST OF ABBREVIATIONS
See Medicine Glossary: 
http://glossary
Term
Definition / description
ADPC
Analysis data pharmacokinetic concentrations
ADPP
Analysis data pharmacokinetic parameters
ADS
Analysis data set
AESI
Adverse event of special interest
ALT
Alanine transaminase
ANOVA
Analysis of variance
AST
Aspartate transaminase
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
AUC0-∞
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity
BMI
Body mass index
CI
Confidence interval
Cmax
Maximum measured concentration of the analyte in plasma
CSD
Company Standard Displays
CV
Arithmetic coefficient of variation
DILI
Drug induced liver injury
F/U
Follow Up
gCV
Geometric coefficient of variation
gMean
Geometric mean
ITZ
Itraconazole
λz
Terminal rate constant of the analyte in plasma
LLT
Lower level term
Max
Maximum
MedDRA
Medical Dictionary for Regulatory Activities
Min
Minimum
N
Number non-missing observations
P10
10th percentile


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Term
Definition / description
P90
90th percentile
PfoS
Powder for oral solution
PKS
PK parameter analysis set
Q1
1st quartile
Q3
3rd quartile
qd
Once daily
R
Reference treatment
RAGe
Report Appendix Generator system
REP
Residual Effect Period
RPM
Report Planning Meeting
SD
Standard deviation
SOC
System organ class
T
Test treatment
TS
Treated set
ULN
Upper limit of normal
WHO-DD
World Health Organization Drug Dictionary


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3.
INTRODUCTION
As per ICH E9 (1) the purpose of this document is to provide a more technical and detailed 
elaboration of the principal features of the analysis described in the protocol, and to include 
detailed procedures for executing the statistical analysis of the primary and secondary 
variables and other data.
This Trial statistical analysis plan (TSAP) assumes familiarity with the Clinical Trial Protocol 
(CTP), including Protocol Amendments. In particular, the TSAP is based on the planned 
analysis specification as written in CTP Section 7 “Statistical Methods and Determination of 
Sample Size”. Therefore, TSAP readers may consult the CTP for more background 
information on the study, e.g., on study objectives, study design and population, treatments, 
definition of measurements and variables, planning of sample size, randomisation.
Study data (including data entered in the RAVE EDC system and external data provided by 
suppliers) will be stored in a Clinical Data Repository (CDR).
Pharmacokinetic (PK) parameters will be calculated using Phoenix WinNonlinTM software 
(version 8.1 or higher, 
).
The statistical analyses will be performed within the validated working environment CARE, 
including SASTM (current Version 9.4, by 
), and a number 
of SASTM-based tools (e.g., macros for the analyses of AE data or laboratory data; Report 
Appendix Generator system (RAGe) for compilation/formatting of the CTR appendices).


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4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY
All analyses as planned in the CTP will be performed and are described in more detail in this 
TSAP.
In Section 7.3 of the CTP the following was defined: Important protocol deviation (IPD) 
categories will be suggested in the IQRM plan, IPDs will be identified no later than in the Report 
Planning Meeting, and the IPD categories will be updated as needed. Due to SOP changes, the 
IPD categories are no longer available in the IQRM plan but included in an IPD specification file
(2). The IPD categories originally defined in the IQRM plan were transferred to this IPD 
specification file. Minor changes regarding the IPD categories were performed only.
The CTP refers to a central SOP of the sponsor (SOP 001-MCS-36-472 for PK and PD 
analysis) which is no longer applicable and was superseded by other procedural documents. 
These are outlined in the respective passages of this TSAP.


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5.
ENDPOINTS
5.1
PRIMARY ENDPOINTS
Section 2.1.2 of the CTP: 
The following pharmacokinetic parameters will be determined for BI 474121:

AUC0-∞(area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity)

Cmax (maximum measured concentration of the analyte in plasma)
5.2
SECONDARY ENDPOINTS
5.2.1
Key secondary endpoints
This section is not applicable as no key secondary endpoints have been defined in the CTP.
5.2.2
Secondary endpoint
Section 2.1.3 of the CTP: 
The following pharmacokinetic parameter will be determined for BI 474121:

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)


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENTS
For basic study information on investigational products, assignment to treatment groups and 
selection of doses, please see CTP Sections 3 and 4.
The study will be performed as an open-label two-period trial with two treatments 
administered as oral solutions (T = Test treatment and R = Reference treatment). Healthy 
male subjects receive both treatments in a fixed sequence (period 1: R, period 2: T). There 
will be a washout period of at least 10 days between the administrations of BI 474121 in 
treatment period 1 and 2.
In total, it was planned to assign 14 healthy male subjects.
For details of dosage and formulation see Table 6.1: 1 below. Itraconazole will be 
administered for 14 days, starting 3 days prior to administration of BI 474121 in period 2 
until Day 11 after BI administration.
Table 6.1: 1
Treatments and labels used in the analysis
Treatment
Short label
R
BI 474121, 0.5 mg PfoS, single dose
BI 
T
BI 474121, 0.5 mg PfoS, single dose + Itraconazole 20ml, 10mg/ml, 
qd for 14 days
BI+ITZ
Section 1.2.3 of CTP:
The Residual Effect Period (REP, i.e., the period after the last dose with measurable drug 
levels and/or pharmacodynamic effects still likely to be present) of BI 474121 is 
conservatively assumed to be 7 days. […]
For the use of itraconazole in Treatment T, the REP is defined as 3 days after last 
administration of itraconazole […].
The following study phases will be defined for the safety analysis:


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
Screening
o
Ranging from 0:00h on day of informed consent until first administration time 
of BI 474121 alone in treatment period 1.

On treatment (labelled “BI”, “ITZ”, “BI+ITZ”)
o
BI alone (”BI”): Ranging from the time of first administration of BI 474121
alone in treatment period 1 until 7 days (168h) thereafter.
o
Itraconazole alone (“ITZ”): Ranging from the time of first administration of 
itraconazole until time of BI 474121 administration in treatment period 2 OR 
until 3 days (72h) after last dose of itraconazole (if subject discontinues 
treatment prior to BI 474121 drug administration in period 2).
o
BI + ITZ (“BI+ITZ”): Ranging from time of BI 474121 administration in 
treatment period 2 until 3 days (72h) after the last administration of 
itraconazole OR 7 days (168h) after the BI 474121 administration in treatment 
period 2, whatever occurs later.

Follow-up (labelled “F/U BI”, “F/U ITZ”, “F/U BI+ITZ”)
o
F/U BI: Ranging from the end of REP of BI 474121 in treatment period 1 
until the first administration of itraconazole in period 2 or until trial 
termination, whatever occurs first.
o
F/U ITZ: (only applicable if subject discontinues treatment prior to BI 474121 
drug administration in period 2) Ranging from the end of REP of itraconazole 
in treatment period 2 until trial termination.
o
F/U BI+ITZ: Ranging from the end of REP of BI 474121 or itraconazole 
(whatever occurs later) in treatment period 2 until trial termination.
“Until trial termination” is defined as 0:00h on the day after trial termination.
Section 7.3.4 of the CTP: Note that AEs occurring after the last per protocol contact but 
entered before final database lock will be reported to Pharmacovigilance only and will not be 
captured in the trial database.
The following AE displays will be provided in the report:
A) Section 15.3 and Appendix 16.1.13.1.8 (for ClinicalTrials.gov and EudraCT only) of the 
CTR displays:
In these displays, the on treatment phase will be analysed (labelled with the name of the 
study treatment (short label)). Screening and follow-up periods will not be included in 
this analysis. 
The following total will be provided in addition (Section 15.3 only):
a total over all on treatment phases involving BI ("BI Total on treatment")
a total over all on treatment phases included in this analysis ("Total on treatment")


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B) Section 15.4 and Appendix 16.1.13.1.8 (except for ClinicalTrials.gov and EudraCT) of 
the CTR displays:
Screening 
On treatment (labelled with the name of the study treatment (short label))
Follow-up BI (labelled "F/U BI")
Follow-up BI+ITZ (labelled "F/U BI+ITZ")
Follow-up ITZ (labelled "F/U ITZ") – if applicable
In Section 16.1.13.1.8 (except for ClinicalTrials.gov and EudraCT), the following totals will 
be provided in addition:
a total over all on treatment phases involving BI ("BI Total")
a total over all study phases (screening, on treatment and follow-up) ("Total")
For detailed information on the handling of the treatments refer to Technical TSAP ADS plan 
and Analysis Data Reviewers guide.
6.2
IMPORTANT PROTOCOL DEVIATIONS
Data discrepancies and deviations from the CTP will be identified for all treated subjects. 
Consistency check listings (for identification of deviations of time windows) and a list of 
protocol deviations (e.g. deviations in drug administration, in blood sampling times, etc.) will 
be provided to be discussed at the Report Planning Meeting (RPM). At this meeting, all 
manual deviations identified at the sites by the CRAs and deviations too complex to program 
will be reviewed by the trial team to decide which are considered important. For definition of 
important protocol deviations (iPD), and for the process of identification of these, refer to the 
Boehringer Ingelheim (BI) SOP "Identify and Manage Important Protocol Deviations (iPD)" 
(3).
Categories which are considered to be iPDs in this trial were defined in the integrated quality 
and risk management plan (IQRMP) prior to trial initiation. The iPD list was transferred into 
the iPD specification file (due to changes in the SOP) (2). Within this transfer some minor 
adaptations were done to comply with new naming conventions and categorisations. IPDs 
will be identified no later than in the Report Planning Meeting and the iPD categories in the 
iPD specification file will be updated as needed. If any iPDs are identified, they are to be 
summarised into categories and will be captured in the RPM minutes (the decision log) and in 
the iPD specification file. The decision on exclusion of subjects from analysis sets will be 
made after discussion of exceptional cases and implications for analyses.
The iPD specification file (e.g. the DV domain specifications) will be stored within the TMF
in EDMS.
The iPDs will be summarised and listed.


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6.3
SUBJECT SETS ANALYSED
Section 7.3 of the CTP:

Treated set (TS): The treated set includes all subjects who were treated with at least 
one dose of study drug. The treated set will be used for safety analyses.

Pharmacokinetic parameter analysis set (PKS): This set includes all subjects in the 
treated set (TS) who provide at least one PK endpoint that was defined as primary or 
secondary and was not excluded due to a protocol deviation relevant to the evaluation 
of PK or due to PK non-evaluability (as specified in the following subsection 
‘Pharmacokinetics’). Thus, a subject will be included in the PKS, even if he 
contributes only one PK parameter value for one period to the statistical assessment. 
Descriptive and model based analyses of PK parameters will be based on the PKS.
[…]
Plasma concentration data and parameters of a subject will be included in the statistical 
pharmacokinetic (PK) analyses if they are not flagged for exclusion due to a protocol 
deviation relevant to the evaluation of PK (to be decided no later than in the Report Planning 
Meeting) or due to PK non-evaluability (as revealed during data analysis, based on the 
criteria specified below). Exclusion of a subject’s data will be documented in the CTR.
Relevant protocol deviations may be:

Incorrect trial medication taken, i.e. the subject received at least one dose of trial 
medication the subject was not assigned to

Incorrect dose of trial medication taken

Use of restricted medications
Plasma concentrations and/or parameters of a subject will be considered as non-evaluable, if 
for example

The subject experienced emesis that occurred at or before two times median tmax of the 
respective treatment (Median tmax is to be determined excluding the subjects 
experiencing emesis) 

A predose concentration of BI 474121 is >5% Cmax value of that subject in the 
respective treatment period

Missing samples/concentration data at important phases of PK disposition curve
The descriptive analysis of PK concentrations will be based on the ADS ADPC as described 
at the beginning of Section 7.


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Table 6.3: 1
Subject sets analysed
Subject set
Class of endpoint
TS
PKS
Analyses of PK endpoints 
X
Safety parameters 
X
Demographic/baseline parameters
X
Important protocol deviations
X
Disposition
X
Exposure
X
6.5
POOLING OF CENTRES
This section is not applicable, because the study was performed in only one centre.
6.6
HANDLING OF MISSING DATA AND OUTLIERS
Handling of missing data and outliers will be performed as described in the CTP, Section 7.5.
The only exceptions where imputation might be necessary for safety evaluation are AE dates. 
Missing or incomplete AE dates are imputed according to BI standards (see BI-KMED-BDS-
HTG-0035) (4).
Missing data and outliers of PK data are handled according to BI standards (see BI-KMED-
TMCP-MAN-0012 (5) and BI-KMED-TMCP-MAN-0014 (6).
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
The baseline value is defined as the last measurement before administration of BI 474121 in 
each treatment period.
Section 6.1 of the CTP: Exact times of measurements outside the permitted time windows 
will be documented. The acceptable time windows for screening and the end of trial 
examination are provided in the CTP Flow Chart.


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Study measurements and assessments scheduled to occur ‘before’ trial medication 
administration on Day 1 are to be performed and completed within a 3 h-period prior to the 
administration of 474121.
If not stated otherwise in the flow chart, the acceptable deviation from the scheduled time of 
safety assessments (e.g. vital signs, ECG, and laboratory tests) will be ± 60 min.
Adherence to time windows will be checked via the consistency check listings at the RPM.
Unscheduled measurements of laboratory data and vital signs data will be assumed to be 
repeat measurements of the most recent scheduled measurement (e.g. for follow-up or 
confirmation of a particular value). Therefore, unscheduled measurements will be assigned to 
the planned time point of the previous scheduled measurement. 


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7.
PLANNED ANALYSIS
Safety analysis (refer to Section 7.8) will be performed by 
 and 
will be presented in Sections 15.1 to 15.4 of the CTR and in Appendix 16.2 and 16.1.13.1.
Inferential statistical analyses of PK endpoints (refer to Section 7.4 and Section 7.5.2) will
also be performed by 
and will be presented in Section 15.5 of 
the CTR and in Appendix 16.1.13.3.
Descriptive data analysis of PK endpoints and concentrations will be performed by the 
department 
 at 
 and will be 
presented in Section 15.6 of the CTR.
The format of the listings and tables will follow the BI standards (see BI-KMED-BDS-HTG-
0045 (7)) with the exception of those generated for PK-calculations following BI standards 
for PK/PD analysis (8).
The individual values of all subjects will be listed, sorted by treatment sequence, subject 
number and visit. The listings will be included in Appendix 16.2 of the CTR.
For end-of-text tables, the set of summary statistics for non-PK parameters is: 
N 
number non-missing observations 
Mean
arithmetic mean
SD
standard deviation 
Min
minimum 
Median
median 
Max
maximum
For analyte concentrations, the following descriptive statistics will additionally be calculated:
CV 
arithmetic coefficient of variation
gMean
geometric mean
gCV
geometric coefficient of variation
For PK parameters, the following descriptive statistics will additionally be calculated:
CV 
arithmetic coefficient of variation
gMean
geometric mean
gCV
geometric coefficient of variation
P10 
10th percentile
Q1 
1st quartile
Q3 
3rd quartile
P90 
90th percentile


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The data format for descriptive statistics of concentrations will be identical to the data format 
of the respective concentrations. The descriptive statistics of PK parameters will be 
calculated using the individual values with the number of decimal places as provided by the 
evaluation program. Then the individual values as well as the descriptive statistics will be 
reported with three significant digits in the CTR.
Tabulations of frequencies for categorical data will include all possible categories available in 
the eCRF and will display the number of observations in a category, as well as the percentage 
(%). Percentages will be rounded to one decimal place and will be based on all subjects in the 
respective subject set whether they have non-missing values or not. The category 'missing' 
will be displayed only if there are actually missing values.
Exclusion of PK parameters
The ADS “ADPP” (PK parameters) contains column variables APEXC and APEXCO 
indicating inclusion/exclusion (APEXC) of a PK parameter and an analysis flag comment 
(APEXCO). All analyses based on the PKS will include parameters if they are not flagged for 
exclusion, that is APEXC is equal to “Included”.
Exclusion of PK concentrations
The ADS “ADPC” (PK concentrations per time-point or per time-interval) contains column 
variables ACEXC and ACEXCO indicating inclusion/exclusion (ACEXC) of a concentration 
and an analysis flag comment (ACEXCO). Exclusion of a concentration depends on the 
analysis flag comment ACEXCO. For example, if ACEXCO is set to ‘ALL CALC’, the value 
will be excluded for all types of analyses based on concentrations. If ACEXCO is set to 
‘DESC STATS’ the value will be excluded from descriptive evaluations per planned time 
point/time interval. If ACEXCO contains the addition ‘TIME VIOLATION’ or ‘TIME 
DEVIATION’ the value can be used for further analyses based on actual times. If ACEXCO
is set to ‘HALF LIFE’, the value will be excluded from half-life calculation (and, as a 
consequence, any calculation that relies on λz) only; the value is included for all other 
analyses.
Further details are given in BI-KMED-TMCP-MAN-0014 “Noncompartmental 
Pharmacokinetic / Pharmacodynamic Analyses of Clinical Studies” (6) and BI-KMED-
TMCP-MAN-0010: “Description of Analytical Transfer Files and PK/PD Data Files” (9).
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Only descriptive statistics are planned for this section of the report, based on the TS.
The data will be summarised in total.


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7.2
CONCOMITANT DISEASES AND MEDICATION
Frequency tables are planned for this section of the report, based on the TS.
Concomitant diseases will be coded using the coding system of the Medical Dictionary for 
Drug Regulatory Activities (MedDRA). Medications will be coded using the World Health 
Organization Drug Dictionary (WHO-DD). The coding version number will be displayed as a 
footnote in the respective output.
The diagnoses and medications will be listed. Subjects without any concomitant diagnoses or 
concomitant therapies should be marked with a “No” in the respective column.
The relevance of the concomitant therapies to the evaluation of PK will be decided no later 
than at the RPM.
7.3
TREATMENT COMPLIANCE
Section 4.3 of the CTP: Compliance will be assured by administration of all trial medication 
in the study centre under supervision of the investigating physician or a designee. The 
measured plasma concentrations of trial medication will provide additional confirmation of 
compliance.
It is not intended to list the compliance separately. Any deviations from complete intake will 
be addressed in the RPM (see Section 6.2) and described in the CTR.
7.4
PRIMARY ENDPOINTS
The effect of itraconazole on the exposure of BI 474121 in plasma is to be determined on the 
basis of the primary pharmacokinetic endpoints AUC0-∞and Cmax (see Section 5.1). 
7.4.1
Primary analysis of the primary endpoints
Section 7.3.1 of the CTP:
The statistical model used for the analysis of the primary endpoints will be an analysis of 
variance (ANOVA) model on the logarithmic scale. That is, the PK endpoints will be log-
transformed (natural logarithm) prior to fitting the ANOVA model. This model will include 
effects accounting for the following sources of variation: subjects and treatment. The effect 
'subjects' will be considered as random, whereas ‘treatment’ will be considered as fixed. The 
model is described by the following equation:
ykm = +k + sm +  ekm


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where
ykm = logarithm of response measured on subject m receiving treatment k,
= the overall mean,
k = the kth treatment effect, k = 1, 2,
sm = the effect associated with the mth subject,
m = 1, 2, ..., n
ekm = the random error associated with the mth subject who received
treatment k.
where  ~ (0, 
) i.i.d.,  ~ (0, 
 ) i.i.d. and sm, ekm are independent random 
variables.
Point estimates for the ratios of the geometric means (test/reference) for the primary 
endpoints (see CTP Section 2.1) and their two-sided 90% confidence intervals (CIs) will be 
provided.
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 (Least Squares Means). 
Additionally their two-sided 90% confidence intervals will be calculated based on the 
residual error from the ANOVA and quantiles from the t-distribution. These quantities will 
then be back-transformed to the original scale to provide the point estimate and 90% CIs for 
each endpoint.
The implementation for this analysis will be accomplished by using the CSD macros based 
on PKS. The following SAS code can be used:
PROC MIXED DATA=indata; 
CLASS subject treatment; 
MODEL logpk = treatment / DDFM=KR; 
RANDOM subject; 
LSMEANS treatment / PDIFF CL ALPHA=0.1; 
ESTIMATE 'T-R' treatment -1 1; 
RUN;
 
 


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;
7.5
SECONDARY ENDPOINTS
7.5.1
Key secondary endpoints
This section is not applicable as no key secondary endpoint has been specified in the 
protocol.
7.5.2
Secondary endpoint
The secondary PK parameter AUC0-tz will be assessed using the same methods as described 
for the primary endpoints.
7.7
EXTENT OF EXPOSURE
Descriptive statistics are planned for this section of the report based on the TS. The date and 
time of drug administration will be listed for each subject.


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7.8
SAFETY ANALYSIS
All safety analyses will be performed on the TS. 
The safety data for treated subjects who failed to complete the study (dropouts or 
withdrawals) will be reported as far as their data are available. All withdrawals will be 
documented and the reason for withdrawal recorded.
7.8.1
Adverse Events
AEs will be coded with the most recent version of MedDRA.
Unless otherwise specified, the analyses of AEs will be descriptive in nature. All analyses of 
AEs will be based on the number of subjects with AEs and NOT on the number of AEs. BI 
standards as presented in “Analysis and Presentation of Adverse Event Data from Clinical 
Trials – Display Template” [BI-KMED-BDS-HTG-0041] (10) and [BI-KMED-BDS-HTG-
0066] (11) will be applied. 
The analysis of AEs will be based on the concept of treatment emergent AEs. That means 
that all AEs will be assigned to ‘screening’, ‘on treatment’ or ‘follow-up’ phases as defined in 
Section 6.1. AEs will be analysed based on actual treatments, as defined in Table 6.1: 1.
According to the clinical study protocol, adverse events of special interest (AESI) will be 
analysed:
Section 5.1.5.1.4 of the CTP: 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 (aspartate transaminase) and/or ALT (alanine 
transaminase) ≥3-fold ULN combined with an elevation of total bilirubin 
≥2-fold ULN measured in the same blood sample, or
o
Aminotransferase (ALT, and/or AST) elevations ≥10 fold ULN
According to ICH E3 (12), in addition to Deaths and Serious Adverse Events, ‘other 
significant’ AEs need to be listed in the clinical trial report. These will be any non-serious 
adverse event that led to an action taken with study drug (e.g. discontinuation or dose reduced
or interrupted).
An overall summary of AEs will be presented.
The frequency of subjects with AEs will be summarised by treatment, primary system organ 
class (SOC) and preferred term (PT). Separate tables will be provided for subjects with 


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serious AEs, for subjects with drug-related AEs, for subjects with drug-related serious 
adverse events and for subjects with AESIs. In addition, the frequency of subjects with AEs 
will be summarised by treatment, worst intensity, primary system organ class (SOC) and 
preferred term (PT).
The SOCs and PTs will be sorted by frequency (within SOC). The MedDRA version number 
will be displayed as a footnote in the respective output.
In addition, frequencies of subjects with non-serious AEs that had an incidence of > 5% for at 
least one treatment will be summarised by treatment, primary SOC and PT.
For disclosure of adverse events on EudraCT, additional information not included in a 
standard AE analysis will be performed. The following three entries will be created:

Adverse Events per arm for disclosure on EudraCT

Non-serious Adverse Events for disclosure on EudraCT

Serious Adverse Events for disclosure on EudraCT
7.8.2
Laboratory data
The analyses of laboratory data will be descriptive in nature and will be based on 
BI standards [BI-KMED-BDS-HTG-0042] (13). 
Laboratory data will be analysed qualitatively via comparison of laboratory data to their 
reference ranges. Values outside the reference range as well as values defined as possibly 
clinically significant will be flagged in the data listings.
Clinically relevant findings in laboratory data will be reported as baseline conditions (at 
screening) or as AEs (during the trial) if judged clinically relevant by the investigator, and 
will be analysed as such.
It is the investigator's responsibility to decide whether a lab value is clinically significantly 
abnormal or not (at the RPM at the latest). 
Descriptive statistics of laboratory data including change from baseline will be calculated by 
planned time point based on the worst value of the subject at that planned time point (or 
assigned to that planned time point).
7.8.3
Vital signs
Descriptive statistics over time including change from baseline will be performed for vital 
signs (blood pressure and pulse rate). In the listing the difference from baseline will also be 
displayed.


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For vital signs, descriptive statistics will be calculated by planned time point based on the last 
value of the subject at that planned time point (or assigned to that planned time point).
Clinically relevant findings in vital signs will be reported as AEs.
7.8.4
ECG
ECG recordings will be checked by the investigator for pathological results. Clinically 
relevant abnormal findings for ECG will be listed under 'Relevant Medical History / Baseline 
Conditions' (when they occurred during screening) or will be reported as AEs (when they 
occurred during treatment), and will be analysed as such.
No separate ECG listing will be provided.
7.8.5
Others
Physical examination
Physical examination findings will be reported as relevant medical history/baseline condition
(i.e., a condition already existent before intake of study drug) or as AE and will be
summarised as such. 
No separate listing or analysis of physical examination findings will be prepared.


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8.
TIMEPOINT OF RELEASE OF TREATMENT 
INFORMATION
The treatment information will be loaded into the trial database at trial initiation.


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9.
REFERENCES
1.
CPMP/ICH/363/96: "Statistical Principles for Clinical Trials", ICH Guideline Topic 
E9, Note For Guidance on Statistical Principles for Clinical Trials, current version.
2.
BI-KMED-BDS-TMP-0059: “iPD specification document (sdtm-dv-domain-
specification)”, template, current version, KMED.
3.
001-MCS-40-413: "Identify and Manage Important Protocol Deviations (iPD) ", current 
version, IDEA for CON.
4.
BI-KMED-BDS-HTG-0035: “Handling of Missing and Incomplete AE Dates”, current 
version; KMED.
5.
BI-KMED-TMCP-MAN-0012: “Standards and processes for analyses performed within 
Clinical Pharmacokinetics/Pharmacodynamics”, current version; KMED.
6.
BI-KMED-TMCP-MAN-0014: “Noncompartmental Pharmacokinetic / 
Pharmacodynamic Analyses of Clinical Studies”, current version; KMED.
7.
BI-KMED-BDS-HTG-0045: “Standards for Reporting of Clinical Trials and Project
Summaries”, current version; KMED.
8.
BI-KMED-TMCP-OTH-0003: “Graphs and Tables for Clinical Pharmacokinetics and 
Pharmacodynamic Noncompartmental Analyses”, current version, KMED.
9.
BI-KMED-TMCP-MAN-0010: “Description of Analytical Transfer Files and PK/PD 
Data Files”, current version; KMED.
10. BI-KMED-BDS-HTG-0041: “Analysis and Presentation of Adverse Event Data from 
Clinical Trials – Display Template”, current version; KMED.
11. BI-KMED-BDS-HTG-0066: “Analysis and Presentation of AE data from clinical 
trials”, current version, KMED.
12. CPMP/ICH/137/95: “Structure and Content of Clinical Study Reports”, ICH Guideline 
Topic E3; Note For Guidance on Structure and Content of Clinical Study Reports, 
current version.
13. BI-KMED-BDS-HTG-0042: “Handling, Display and Analysis of Laboratory Data”, 
current version; KMED.


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11.
HISTORY TABLE
Table 11: 1
History table
Version
Date
(DD-MMM-
YY)
Author
Sections 
changed
Brief description of change
1
12-MAY-21
None
This is the final TSAP