Pharmacokinetics, Safety and Tolerability of BI 425809 (Iclepertin) Following Oral Administration in Male and Female Participants With Different Degrees of Renal Impairment (Severe, Moderate and Mild) Compared With Matched Male and Female Participants With Normal Renal Function (an Open-label, Non-randomised, Single-dose, Parallel, Individual-matched Design Trial)
Phase: PHASE1
Conditions: Renal Insufficiency
Sponsor: Boehringer Ingelheim

BI-VQD-11906_40-106_AD-13 (8.0)
Clinical Trial Protocol
TITLE PAGE
Document Number:
c40079435-01
EudraCT No.
2022-002739-74
BI Trial No.
1346-0047
BI Investigational
Medicinal Product
BI 425809 (iclepertin)
Title
Pharmacokinetics, safety and tolerability of BI 425809 
(iclepertin) following oral administration in male and female 
participants with different degrees of renal impairment (severe, 
moderate and mild) compared with matched male and female 
participants with normal renal function (an open-label, non-
randomised, single-dose, parallel, individual-matched design 
trial)
Lay Title
A study to test how iclepertin is taken up in the blood of people 
with and without kidney problems
Clinical Phase
I
Clinical Trial Leader
Phone:
Fax:  
Investigator
Phone: 
Fax: 
Current Version, Date
Version 1.0, 23 November 2022
Original Protocol Date
23 Nov 2022
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This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission

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CLINICAL TRIAL PROTOCOL SYNOPSIS
Company name
Boehringer Ingelheim
Original protocol date
23 November 2022
Revision date
Not applicable
BI trial number
1346-0047
Title of trial
Pharmacokinetics, safety and tolerability of BI 425809 (iclepertin) following oral 
administration in male and female participants with different degrees of renal 
impairment (severe, moderate and mild) compared with matched male and female 
participants with normal renal function (an open-label, non-randomised, single-
dose, parallel, individual-matched design trial)
 Investigator
Trial site
Clinical phase
I
Trial rationale
In this trial, pharmacokinetics, safety, and tolerability of iclepertin single oral dose 
in participants with different degrees of renal impairment compared to individually 
matched participants with normal renal function will be assessed.
Trial objective(s)
To investigate the effect of severe, moderate and mild renal impairment on the 
pharmacokinetics of iclepertin (including its metabolites)
Trial endpoints
Primary endpoints: AUC0-tz and Cmax of iclepertin
Secondary endpoints: AUC0-∞of iclepertin

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Trial design
Open-label, non-randomised, single dose, parallel, individual matched design
Number of participants 
total entered
48*
* additional participants may be included to ensure that the study objectives are 
reached
on treatment
Group 1: 8 participants with severe renal impairment
Group 2: 8 participants with normal renal function matching Group 1**
Group 3: 8 participants with moderate renal impairment
Group 4: 8 participants with normal renal function matching Group 3**
Group 5: 8 participants with mild renal impairment
Group 6: 8 participants with normal renal function matching Group 5**
** each participant with normal renal function may be matched to multiple renal 
impaired participants across different groups and can be matched to only 1 renal 
impaired participant within a group. Thus, the total sample size may be 32 to 48 
participants.
Diagnosis
Participants with renal impairment (severe, moderate and mild) and participants 
with normal renal function (matched controls to the participants with renal 
impairment)
Main inclusion criteria
Male/female participants (at least 25% of each gender), age of at least 18 years 
(inclusive), body mass index (BMI) of 18.5 to 35 kg/m2 (inclusive) with renal 
impairment (severe, moderate and mild) based on assessment of eGFR:
Mild impairment: 60-89 mL/min/1.73m²
Moderate impairment: 30-59 mL/min/1.73m²
Severe impairment: 15-29 mL/min/1.73m²
Participants with normal (≥90 mL/min/1.73m2) renal function, age of at least 18 
years, BMI of 18.5 to 35 kg/m2 (inclusive) – individually matched by age (± 10 
years), gender, weight (± 15%) and race to the participants with renal impairment.
Test product
BI 425809 (iclepertin) film-coated tablet
dose
10 mg
mode of 
administration
Oral with 240 mL of water after an overnight fast of at least 10 h
Duration of treatment
Single dose

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Statistical methods
To assess the effect of renal impairment on the primary and secondary 
pharmacokinetic endpoints of iclepertin, the relative bioavailability will be 
estimated by the ratios of the geometric means of the respective pairwise 
comparison of interest, i.e., for each renal impairment group vs. the respective 
control group. 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 is not specified for any 
comparison of interest. The statistical model will be an analysis of variance 
(ANOVA) on the logarithmic scale including the fixed effect ‘degree of renal
impairment’ and the random effect ‘matched pair’.
Descriptive statistics will be calculated for all endpoints.

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FLOW CHART
Visit
Day
Planned time (relative to 
drug administration) 
[h:min]
Approximate clock time  
of actual day [h:min]
Event and comment
Safety laboratory 8
PK blood 9
PK urine 10
Suicidality assessment 14
12-lead ECG 11
Vital signs (BP, PR) 12
Questioning for AEs and 
concomitant therapy 6
1
-21 to -2
Screening (SCR)1
A
x
x
x
2
-1
-24:00
08:00
Admission to trial site
B 5
x13,15
x
1
-2:00
06:00
x2
x2,7
x2
x2
x2
x2,16
0:00
08:00
Drug administration
▲
0:30
08:30
x
│
0:45
08:45
x
│
1:00
09:00
x
│
x
x
x
1:15
09:15
x
│
1:30
09:30
x
│
1:45
09:45
x
│
2:00
10:00
240 mL fluid intake (snack for participants 
with diabetes)3
x
│
x
x
x
2:30
10:30
x
│
3:00
11:00
x
│
4:00
12:00
240 mL fluid intake, thereafter lunch3
x
┼
x
x
x
6:00
14:00
x
│
8:00
16:00
Snack (voluntary)3
x
┼
x
x
x
10:00
18:00
x
│
11:00
19:00
Dinner3
│
12:00
20:00
x
┼
x 
14:00
22:00
x
│
2
24:00
08:00
B
x
┼
x
x
x
36:00
20:00
x
┼
x
3
48:00
08:00
x
┼
x
4
72:00
08:00
Breakfast (voluntary)3, 
Discharge from trial site
B
x
┼
x
x
x
x
5
96:00
08:00
Ambulatory visit
x
┼
x
6
120:00
08:00
Ambulatory visit
x
▼
x
7
144:00
08:00
Ambulatory visit
x
x
x
3
12 to 19
End of study (EoS) examination4
C
x
x
x
x
r1. Participant must be informed and written informed consent obtained prior to starting any screening procedures. 
Screening procedures include physical examination (including assessment of suicidal ideation and behaviour using the 
C-SSRS questionnaire), check of vital signs, ECG, safety laboratory (including drug screening, alcohol breath test, 
serology, and SARS-CoV-2 PCR test, serum pregnancy test in WOCBP), eGFR, demographics (including 
determination of body height and weight, smoking status and alcohol history), relevant medical history, concomitant 
therapy and review of inclusion/exclusion criteria.
2.
The time is approximate; the procedure is to be performed and completed within the 2 h prior to drug administration.
3.
If several actions are indicated at the same time, the intake of meals will be the last action.
4.
At the end of study (synonym for end of trial), the EoS examination includes physical examination (including 
assessment of suicidal ideation and behaviour using the C-SSRS questionnaire), body weight, vital signs, ECG, safety 
laboratory (including urine pregnancy test in WOCBP), recording of AEs and concomitant therapies.
5.
In addition: urine drug screening, alcohol breath test, SARS-CoV-2 antigen test, as well as serum pregnancy test in 
WOCBP.

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6.
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.
7.
A blank urine sample (x) is to be obtained prior to administration of trial medication. Other urine samples are to be 
collected over the stated post-dose intervals (◄––│––│––►) 0-4, 4-8, 8-12, 12-24, 24-36, 36-48, 48-72, 72-96 and 96-
120 h..
8.
Letters A, B and C define different sets of safety laboratory examinations (for details refer to Section 5.2.3).
9.
For details of PK blood sampling, refer to Section 5.3.2.1.
10. For details of PK urine sampling, refer to Section 5.3.2.2.
11. For details of 12-lead ECG, refer to Section 5.2.4.
12. For details of vital signs evaluation, refer to Section 5.2.2.
13. Including assessment of body temperature (if needed due to the current status of the pandemic).
14. For details of suicidality assessment, refer to Section 5.2.5.1.
15. Including measurement of body weight at this time point.
16. Before administration of study medication at Visit 2, site staff will remind participants to report “any unusual visual 
perception they may experience”, refer to Section 5.2.6.1.5.

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TABLE OF CONTENTS
TITLE PAGE ......................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS ................................................2
FLOW CHART...................................................................................................5
TABLE OF CONTENTS ...................................................................................7
ABBREVIATIONS AND DEFINITIONS..................................................... 11
1.
INTRODUCTION.................................................................................... 14
1.1
MEDICAL BACKGROUND............................................................................14
1.2
DRUG PROFILE...............................................................................................14
1.2.1
Iclepertin (BI 425809)...........................................................................14
1.2.1.1
Non-clinical drug safety and pharmacokinetics.......................14
1.2.1.2
Clinical safety in healthy subjects............................................15
1.2.1.3
Clinical pharmacokinetics in healthy subjects.........................18
1.2.1.4
Pharmacokinetic drug interactions...........................................19
1.2.2
Residual Effect Period..........................................................................19
1.3
RATIONALE FOR PERFORMING THE TRIAL........................................20
1.4
BENEFIT - RISK ASSESSMENT ...................................................................20
1.4.1
Benefits...................................................................................................20
1.4.2
Risks .......................................................................................................20
1.4.3
Discussion...............................................................................................24
2.
TRIAL OBJECTIVES AND ENDPOINTS........................................... 25
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS ......25
2.1.1
Main objectives......................................................................................25
2.1.2
Primary endpoints ................................................................................25
2.1.3
Secondary endpoint ..............................................................................25
2.2.2.3
Safety and tolerability..............................................................26
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.............. 27
3.1
OVERALL TRIAL DESIGN............................................................................27
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUPS........................................................................................28
3.3
SELECTION OF TRIAL POPULATION ......................................................28
3.3.1
Main diagnosis for trial entry..............................................................29

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3.3.2
Inclusion criteria...................................................................................29
3.3.2.1
Inclusion criteria applicable to all participants........................29
3.3.2.2
Inclusion criteria applying only to participants with impaired 
renal function ...........................................................................30
3.3.2.3
Inclusion criteria applying only to participants with normal 
renal function ...........................................................................31
3.3.3
Exclusion criteria ..................................................................................31
3.3.3.1
Exclusion criteria applying to all participants .........................31
3.3.3.2
Exclusion criteria applying only to participants with renal 
impairment...............................................................................32
3.3.3.3
Exclusion criteria applying only to participants with normal 
renal function ...........................................................................33
3.3.4
Withdrawal of subjects from treatment or assessments ...................34
3.3.4.1
Withdrawal from trial treatment ..............................................34
3.3.4.2
Withdrawal of consent to trial participation ............................35
3.3.4.3
Discontinuation of the trial by the sponsor..............................35
3.3.5
Replacement of subjects .......................................................................36
4.
TREATMENTS........................................................................................ 37
4.1
INVESTIGATIONAL TREATMENTS ..........................................................37
4.1.1
Identity of the Investigational Medicinal Products ...........................37
4.1.2
Selection of doses in the trial................................................................37
4.1.3
Method of assigning subjects to treatment groups ............................37
4.1.4
Drug assignment and administration of doses for each subject .......37
4.1.5
Blinding and procedures for unblinding ............................................38
4.1.6
Packaging, labelling, and re-supply ....................................................38
4.1.7
Storage conditions.................................................................................38
4.1.8
Drug accountability ..............................................................................39
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS ...............................................................................................39
4.2.1
Other treatments and emergency procedures....................................39
4.2.2
Restrictions............................................................................................39
4.2.2.1
Restrictions regarding concomitant treatment .........................39
4.2.2.2
Restrictions on diet and life style.............................................40
4.2.2.3
Contraception requirements.....................................................40
4.3
TREATMENT COMPLIANCE.......................................................................40
5.
ASSESSMENTS....................................................................................... 42
5.1
ASSESSMENT OF EFFICACY.......................................................................42
5.2
ASSESSMENT OF SAFETY............................................................................42
5.2.1
Physical examination ............................................................................42
5.2.2
Vital signs...............................................................................................42
5.2.3
Safety laboratory parameters..............................................................42
5.2.4
Electrocardiogram................................................................................45

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5.2.5
Other safety parameters.......................................................................46
5.2.5.1
Suicidality assessment .............................................................46
5.2.6
Assessment of adverse events...............................................................47
5.2.6.1
Definitions of adverse events...................................................47
5.2.6.1.1 Adverse event ............................................................47
5.2.6.1.2 Serious adverse event ................................................47
5.2.6.1.3 AEs considered ‘Always Serious’.............................48
5.2.6.1.4 Adverse events of special interest .............................48
5.2.6.1.5 Ocular AEs ................................................................49
5.2.6.1.6 Intensity (severity) of AEs.........................................49
5.2.6.1.7 Causal relationship of AEs ........................................49
5.2.6.2
Adverse event collection and reporting ...................................50
5.2.6.2.1 AE collection.............................................................50
5.2.6.2.2 AE reporting to the sponsor and timelines ................51
5.2.6.2.3 Pregnancy ..................................................................51
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS..................................................................................51
5.3.1
Assessment of pharmacokinetics .........................................................51
5.3.2
Methods of sample collection...............................................................52
5.3.2.1
Blood sampling for pharmacokinetic analysis.........................52
5.3.2.2
Urine sampling for pharmacokinetic analysis..........................52
5.3.4
Pharmacokinetic - pharmacodynamic relationship...........................53
5.4
ASSESSMENT OF BIOMARKERS................................................................53
5.5
BIOBANKING ...................................................................................................53
5.6
OTHER ASSESSMENTS .................................................................................54
5.7
APPROPRIATENESS OF MEASUREMENTS.............................................54
6.
INVESTIGATIONAL PLAN.................................................................. 55
6.1
VISIT SCHEDULE............................................................................................55
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS ................55
6.2.1
Screening period....................................................................................55
6.2.2
Treatment period ..................................................................................56
6.2.3
Follow-up period and trial completion ...............................................56
7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE......................................................................................... 57
7.1
NULL AND ALTERNATIVE HYPOTHESES ..............................................57
7.2
PLANNED ANALYSES....................................................................................57
7.2.1
General considerations.........................................................................57

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7.2.1.1
Analysis sets.............................................................................57
7.2.1.2
Pharmacokinetics.....................................................................57
7.2.2
Primary endpoint analyses...................................................................58
7.2.3
Secondary endpoint analyses ...............................................................59
7.2.5
Safety analyses.......................................................................................59
7.2.6
Interim analyses ....................................................................................60
7.3
HANDLING OF MISSING DATA ..................................................................60
7.3.1
Safety......................................................................................................60
7.3.2
Pharmacokinetics..................................................................................60
7.4
RANDOMISATION ..........................................................................................61
7.5
DETERMINATION OF SAMPLE SIZE ........................................................61
8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY, AND 
ADMINISTRATIVE STRUCTURE...................................................... 62
8.1
TRIAL APPROVAL, SUBJECT INFORMATION, INFORMED 
CONSENT ..........................................................................................................62
8.2
DATA QUALITY ASSURANCE .....................................................................63
8.3
RECORDS..........................................................................................................63
8.3.1
Source documents .................................................................................63
8.3.2
Direct access to source data and documents.......................................64
8.3.3
Storage period of records.....................................................................64
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS .................................65
8.5
STATEMENT OF CONFIDENTIALITY AND SUBJECT PRIVACY.......65
8.5.1
Collection, storage and future use of biological samples and 
corresponding data ...............................................................................65
8.6
TRIAL MILESTONES .....................................................................................65
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL ..................................66
9.
REFERENCES......................................................................................... 68
9.1
PUBLISHED REFERENCES...........................................................................68
9.2
UNPUBLISHED REFERENCES.....................................................................69
10. APPENDICES .......................................................................................... 71
10.1
COLUMBIA-SUICIDE SEVERITY RATING SCALE ................................71
10.2
LISTING RESTRICTED CONCOMITANT MEDICATION......................77
10.2.1 Strong CYP3A4 inhibitors ...................................................................77
10.2.2 Combinations of CYP 3A4 inhibitors .................................................77
10.3
CKD-EPI FORMULA.......................................................................................78
11. DESCRIPTION OF GLOBAL AMENDMENT(S).............................. 79

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ABBREVIATIONS AND DEFINITIONS
%AUCtz-∞
The percentage of AUC0-∞obtained by extrapolation
14C
Radiocarbon
AE
Adverse event
AESI 
Adverse event of special interest
Aet1-t2
Amount of analyte that is eliminated in urine from the time interval t1 to t2
ALCOA
Attributable, legible, contemporaneous, original, and accurate
ANOVA
Analysis of variance
AUC0-∞
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity
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
AUCt1-t2
Area under the concentration-time curve of the analyte in plasma over the 
time interval t1 to t2
AV
Atrioventricular 
BI
Boehringer Ingelheim
Bid
Twice daily (bis in die)
BMI
Body-mass index
BP
Blood pressure
CI
Confidence interval
CIAS
Cognitive impairment associated with schizophrenia
CL
Clearance
 
 
Cmax
Maximum measured concentration of the analyte in plasma
CNS
Central nervous system
COVID-19
SARS-CoV-2 induced disease
CRF
Case report form
CSF
Cerebrospinal fluid
C-SSRS
Columbia suicide severity rating scale
CTP
Clinical trial protocol
CTR
Clinical trial report
CV
Arithmetic coefficient of variation
CYP
Cytochrome P450
DDI
Drug-drug interaction

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DILI
Drug-induced liver injury
ECG
Electrocardiogram
eCRF
Electronic case report form
eDC
Electronic data capture
EoS
End of study
EudraCT
European union drug regulating authorities clinical trials database
 
Fpo
Oral bioavailability
GCP
Good clinical practise
GlyT1
Glycine transporter 1
GMP 
Good manufacturing practice
HbA1c
Glycated haemoglobin
HR
Heart rate
IB
Investigator brochure
IMP
Investigational medicinal product
IPD
Important protocol deviation
IRB
Institutional review board
ISF
Investigator site file
IUD
Intrauterine device
IUS
Intrauterine hormone-releasing system
K2-EDTA
Dipotassium ethylenediaminetetraacetic acid
LC-MS/MS
Liquid chromatography tandem mass spectrometry
MDA
Methylenedioxyamphetamine
MedDRA
Medical Dictionary for Regulatory Activities
MRD
Multiple rising dose
MRTex
Mean residence time of the analyte in the body after extravascular 
administration
NMDA
N-methyl-D-aspartate
NSFS
Negative Symptom Factor Score
PANSS
Positive and Negative Syndrome Scale
PE
Polyethylene
PK
Pharmacokinetics
PKS
Pharmacokinetic parameter analysis set
PP
Polypropylene
PR
Pulse rate
PT
Preferred term
Qd
Once daily (quod diem)

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QT interval
ECG interval from the start of the QRS complex to the end of the T wave
QTc interval
QT interval corrected for heart rate, e.g. using the method of Fridericia 
(QTcF) or Bazett (QTcB)
QWBA
Quantitative whole-body autoradiography
REP
Residual effect period
RI
Renal impairment
SAE
Serious adverse event
SARS-CoV-2
Severe acute respiratory syndrome coronavirus 2
SRD
Single rising dose 
 
TS
Treated Set
TSAP
Trial statistical analysis plan
ULN
Upper limit of normal
VAS
Visual analogue scale
Vss
Volume of distribution
 
WOCPB
Women of childbearing potential

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1.
INTRODUCTION
Iclepertin (BI 425809) is a glycine transporter 1 (GlyT1) inhibitor under development for 
treatment of cognitive impairment associated with schizophrenia (CIAS).
1.1
MEDICAL BACKGROUND
Schizophrenia is a chronic, severe, and disabling brain disorder affecting both men and 
women. The disease is characterised by abnormalities in glutamatergic pathways related to 
N-methyl-D-aspartate (NMDA) receptor hypofunction in cortical and hippocampal brain 
areas [R13-4518, R13-4521]. These abnormalities are hypothesised to lead to negative 
symptoms and cognitive impairment in schizophrenia. Existing treatment options for 
schizophrenia (i.e. first- and second-generation antipsychotics) primarily affect positive 
symptoms but have a limited effect on cognitive and negative symptoms [R15-0595]. 
 
 
 
 
 
 
 
 
 
 
 
 
1.2
DRUG PROFILE
 
 
 
 
 
 

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bioavailability (Fpo). In studies with Caco-2 cell monolayers, the permeability of iclepertin is 
high.
Based on mass balance and metabolite identification studies, the CL of iclepertin occurs 
primarily by metabolism, as only low amounts of unchanged iclepertin are found in excreta. 
Metabolism of iclepertin in mouse, rat, and minipig was determined to be principally 
oxidative. In a quantitative whole-body autoradiography (QWBA) study in the pigmented rat, 
where 14C iclepertin was administered orally, radioactivity extensively distributed into 
tissues, including the CNS. There was no preferential binding of radioactivity to melanin. In 
pregnant rats, orally administered 14C iclepertin, radioactivity was moderately distributed into 
the placenta, embryo and foetus. Higher exposure to 14C iclepertin-related radioactivity was 
observed in the CNS and eye of the foetus relative to the respective maternal organs. In 
lactating rats administered a single oral dose of 14C iclepertin, ~16% of dosed radioactivity 
was excreted into milk.
Metabolite profiling and identification was performed in clinical trial 1346.0016 
[n00277070]. Twenty-one metabolites of iclepertin were identified including two major 
plasma metabolites, 
. Neither 
 
possesses pharmacological activity toward GlyT1, GlyT2 or 102 off-target receptors, and no 
evidence of genotoxicity, effects on embryo-foetal development, or adverse effects has been 
revealed in repeat-dose toxicity studies.
Excretion
In CD-1 mice, Wistar Han rats, and Göttingen minipigs, the major route of excretion of
radioactivity from 14C iclepertin was in faeces. For male and female CD-1 mice, 82 and 77%
of the radioactive dose, respectively, was accounted for in the faeces [n00273967]. For male
and female Wistar Han rats, 91.3 and 86.4% of the radioactive dose, respectively, was
accounted for in the faces [n00237515]. For Göttingen minipigs, 72% of the radioactive dose
(average of male and female) was accounted for in the faeces [n00243611]. In all species
administered a single oral dose of 14C iclepertin, drug-related radioactivity was primarily
excreted as metabolites. In humans, 45.9% of the radioactive dose of iclepertin was excreted
in the faeces and 41.3% of the dose was excreted in the urine [c26534937]. Excretion of
unchanged iclepertin in human was <10% in urine and <1% in faeces.
For details on the non-clinical pharmacology, PK in animals and toxicology of iclepertin
please refer to the current IB [c02155957].
1.2.1.2
Clinical safety in healthy subjects
In total and up to the data lock point for the current IB, 323 healthy participants have received 
≥1 dose of iclepertin, including 265 males (82.0%) and 58 females (18.0%). Safety data 
below were pooled from 12 Phase I clinical trials with healthy participants (trials 
1346.1/.2/.3/.4/.10/ .15/.16/.18/.19/.22/.29/.39); see IB [c02155957] or respective clinical trial 
reports.
Iclepertin was administered in single doses ranging from 0.5 mg to 150 mg qd, or multiple 
doses ranging from 5 mg to 75 mg bid (i.e. a maximum of 150 mg/day) for a maximum of 

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14 days. No deaths or serious adverse events (SAEs) were reported, and no AEs of special 
interest (AESIs) were observed. No ethnic pattern of AEs was observed.
Severe AEs were reported for 3 participants (0.9%): neck pain (trial 1346.3; 10 mg; not drug-
related [c03724403]), nausea (trial 1346.10; 25 mg; drug-related [c03355329]), and vomiting 
(1346.1; 150 mg; drug-related [c02820512]) each in 1 participant. Investigator-defined drug-
related AEs were reported for 37.2% of participants treated with iclepertin versus 26.9% of 
participants on placebo.
Most frequent AEs in iclepertin treatment groups were (on the preferred term (PT) level):

Headache 20.4% vs. 9.6% in the pooled placebo group

Dizziness 10.2% vs. 5.8% in the pooled placebo group

Fatigue 8.4% vs. 5.8% in the pooled placebo group

Nausea 7.4% vs. 1.9% in the pooled placebo group

Nasopharyngitis 5.6% vs. 5.8% in the pooled placebo group

Back pain 5.3% vs. 3.8% in the pooled placebo group

Vomiting 5% vs. 1.9% in the pooled placebo group

Procedural headache 5.0% vs. 0% in the pooled placebo group

Vision blurred 3.4% vs. 0% in the pooled placebo group

Diarrhoea 3.1% vs. 1.9% in the pooled placebo group

Oropharyngeal pain 2.5% vs. 1.9% in the pooled placebo group
AEs leading to discontinuation were reported by 4 participants on iclepertin:

1 participant receiving 5 mg iclepertin qd experienced nausea and vomiting of 
moderate intensity, both not considered drug-related (trial 1346.3, [c03724403])

1 participant receiving 10 mg iclepertin qd experienced procedural headache (CSF 
sampling) of moderate intensity not considered drug-related (trial 1346.3, 
[c03724403])

1 participant receiving 25 mg iclepertin qd experienced diarrhoea of moderate 
intensity not considered drug-related (trial 1346.39, [c30032912])

1 elderly (aged 66 years) female participant receiving 50 mg iclepertin qd experienced 
nausea of moderate and vomiting of mild intensity after the 1st dose, both considered 
drug-related (trial 1346.2, [c03572014])

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In general, there were no clinically relevant findings in the clinical laboratory evaluation, 12-
lead ECG, or vital signs. No suicidal ideation or behaviour was observed.
Clinical pathology findings in repeat-dose studies in mice, rats and minipigs included
changes in red blood cell indices. Findings, generally, included reductions in haemoglobin
(Hb), haematocrit (Hct), mean corpuscular volume (MCV), mean corpuscular haemoglobin
(MCH) and/or mean cell haemoglobin concentration (MCHC) and increases in RBC count,
red cell distribution width (RDW), platelets and/or absolute reticulocytes. In the Phase II
trials in patients with schizophrenia and Alzheimer’s disease, after 12-week treatment with 
iclepertin a dose-dependent decrease in haemoglobin was noted at doses of 10 mg (-2.3%) 
and 25 mg (-3.2%) at last value on treatment as compared to baseline [c31477880].
In trials with healthy volunteers, no notable decrease in haemoglobin or haematocrit was 
noted in the iclepertin treatment groups compared with placebo.
In the single rising dose study (1346.1) using powder as solution formulation, dose-related
increases in Bond-Lader and Bowdle visual analogue scale (VAS) scores were observed
[c02820512]. An increase in VAS scores for drowsiness and AEs of somnolence were
observed with dose-dependency. At high doses (100 to 150 mg), i.e., much higher than the
expected efficacious dose (10 mg tablet formulation), increases in VAS scores related to
perception were observed. Additionally, visual disturbances were noted in the 2 highest dose
groups (1 case of blurred vision in the 100 mg dose group, and all subjects in the 150 mg
group had visual disturbances, including photopsia, blurred vision, and chromatopsia). On
ophthalmologic testing, no abnormality was noted on visual acuity or colour vision, but
abnormalities on the Amsler grid test were noted in 2 subjects (25 and 100 mg). The effects
peaked around tmax. The frequency of ophthalmologic AEs was comparable in iclepertin and
placebo groups in all trials using the tablet formulation.
In the multiple rising dose study (1346.2, [c03572014] multiple doses of 10 mg, 25 mg, 50 
mg and 75 mg were investigated. The following drug-related AEs were reported by healthy 
young participants in Part I of 1346.2, [c03572014]:

10 mg qd: headache (2x), dizziness (1x), head discomfort (1x), nasal dryness (1x)

25 mg qd: blurred vision (2x), headache (2x), abdominal discomfort (2x), abdominal 
pain (2x), nausea (1x), diarrhoea (1x), visual impairment (1x), sleeping disorders (1x)

50 mg qd: headache (2x), dizziness (1x), blurred vision (1x), visual impairment (1x),
blepharospasmus (1x), folliculitis (1x), feeling cold (1x), gait disturbances (1x)

75 mg qd: headache(4x), dizziness (3x), hypoacusis, constipation, vomiting, fatigue 
(1x each)

75 mg bid: insomnia (3x), dizziness (2x), ocular discomfort (2x), reduced visual 
acuity (1x), transiently reduced visual acuity (1x), eye pain (1x), nervousness (1x), 
micturition urgency (1x), feeling drunk (1x), gait disturbances (1x)

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Visual disturbances occurred only in higher dose groups (25 mg, 50 mg, 75 mg). Most cases 
started in the first week of treatment, were of short duration (up to 3 days) and resolved prior 
to the end of dosing. All cases of visual disturbance were of mild intensity. The 2 cases of 
gait disturbances occurred on Day 1 and were accompanied by dizziness on the same day.
All drug-related AEs were of mild or moderate intensity and resolved by end of the trial.
There were no notable changes in lab values, vital signs and ECG parameters after multiple
doses of iclepertin [c03572014].
In trial 1346.22 (DDI study with a cocktail of sensitive CYP substrates) 25 mg iclepertin
were given for 14 days to healthy male participants. The most frequent drug related AEs were
headache (25% of participants) and fatigue (33% of participants). Visual disturbances have 
not been reported in this trial. The evaluation of visual function tests, safety laboratory 
values, vital signs, and ECG recordings revealed no clinically relevant findings [c08949593].
1.2.1.3
Clinical pharmacokinetics in healthy subjects
Initially, pharmacokinetics of iclepertin were investigated after dosing of 0.5 to 150 mg 
iclepertin administered as oral solution in the single rising dose (SRD) part of trial 1346.1
[c02820512]. The drug was rapidly absorbed with median tmax values of approximately 
45 min after drug administration for all dose groups; individual values ranged from about 
30 min to 90 min. The gMean plasma Cmax values ranged from 10.0 nmol/L to 2970 nmol/L 
for the 0.5 mg and 150 mg dose groups. The gMean AUC0-∞values ranged from 
187 nmol∙h/L to 48500 nmol∙h/L for the 0.5 mg and 150 mg dose groups. A linear dose-
exposure relationship was evident for the complete dose range. The gMean values of t1/2 were 
independent of the administered dose and ranged from 32.5 h to 47.0 h.
After administration of iclepertin tablets, maximum plasma concentrations of iclepertin
occurred around 3 to 4.5 h after dosing. The terminal half-life was independent of the 
administered dose and ranged from 37 to 59 h. Food increased drug exposure (fed/fasted ratio 
for Cmax: 142%, for AUC0-tz: 126%). The absolute bioavailability of iclepertin is about 70%. 
The orally administered drug is eliminated via renal and foecal route at comparable amounts.
The amount of iclepertin excreted in urine increased with dose, but the gMean fractional 
renal excretion remained almost the same over all dose groups and was low (around 5%) 
across all doses.
In the multiple rising dose (MRD) trial 1346.2 [c03572014], after qd dosing for 14 days of 10 
to 75 mg iclepertin once or twice daily administered as tablets, steady state was reached after 
6 days of dosing with accumulation ratios for Cmax ranging from 1.96 to 2.63 and for AUC 
from 2.31 to 3.21.
In the current trial, iclepertin 10 mg will be given as a single dose on Day 1 of Visit 2. In the 
trial 1346.2 [c03572014], a half-life of 45.2 h was reported for the 10 mg dose group under 
steady state conditions, maximum plasma concentrations were achieved after 4.5 h 
[c02155957].

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Metabolite profiling and identification was performed using plasma, urine, and faecal 
samples collected from healthy human volunteers receiving a single oral dose of 14C
iclepertin (25 mg) in clinical trial 1346.0016 [n00277070]. In plasma, iclepertin (41.0%) and 
its two major metabolites, 
(34.3%) and 
 (11.9%), accounted for 87.2% 
of total radioactivity (AUC0-168). BI 758790 showed its Cmax of 138 nmol/L at a median tmax
of 10.0 h, 
 appeared later with a median tmax of 192 h and Cmax of 55.6 nmol/L. The 
AUC0-tz showed a comparable plasma exposure for iclepertin and its metabolite 
, 
whereas the AUC0-tz for 
 was about 2-fold higher in comparison. Similar results 
were received for t1/2. The half-lives of iclepertin and 
 were with values of 50.5 h 
and 46.7 h in a similar range, whereas the half-life for 
 was clearly prolonged (243 
h).
1.2.1.4
Pharmacokinetic drug interactions
In vitro studies were conducted to assess the potential for iclepertin or its major metabolites 
to cause clinically relevant DDIs via inhibition or induction of major drug metabolising 
enzymes or inhibition of major drug transporters. Results from in vitro metabolism studies 
indicate that iclepertin is primarily metabolised by hepatic CYP3A. Furthermore, CYP3A 
plays a major role in the in vivo clearance of iclepertin based on clinical DDI studies.
Results from preclinical studies indicate that iclepertin and the metabolite 
 
may cause clinically relevant induction and inhibition of CYP3A. However, in a clinical DDI 
study (1346.22; [c08949593]), inhibition of CYP3A was not observed.
In clinical studies, iclepertin has been characterised to be a substrate of CYP3A4. 
Itraconazole, a recommended inhibitor of CYP3A4, increased the AUC0-∞of iclepertin by 
factor 6 [c03355329]. Rifampin, a recommended inducer of CYP3A4, decreased Cmax and 
AUC of iclepertin by 63% and 90% [c18001523].
In trial 1346.22 [c08949593], the clinical effect of iclepertin on sensitive substrates of 
CYP3A4 (midazolam), CYP2C9 (warfarin), CYP2C19 (omeprazole) and P-glycoprotein 
(digoxin) was investigated. Multiple doses of 25 mg iclepertin did not change the exposure of 
S-warfarin and digoxin but caused a reduction of midazolam by 22% for Cmax and by 29% for 
AUC0-tz indicating for (mild) induction of CYP3A4. Exposure to the other investigated 
substrates seemed to be not relevantly affected. [c08949593]. Currently, a dose of 10 mg qd 
of iclepertin is the proposed therapeutic dose in clinical development.
For a more detailed description of iclepertin please refer to the current IB [c02155957].
1.2.2
Residual Effect Period
The Residual Effect Period (REP) of iclepertin is
 This is the period after the last 
dose during which measurable drug levels and/or pharmacodynamic effects are still likely to 
be present.

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1.3
RATIONALE FOR PERFORMING THE TRIAL
In this trial, PK of iclepertin single oral dose in participants with different degrees of renal 
impairment compared to individually matched participants with normal renal function will be 
assessed.
Iclepertin is being developed for the treatment of CIAS.
This exploratory trial is designed to investigate the effect of mild, moderate, and severe renal 
impairment on the PK, safety and tolerability of iclepertin and its metabolite. The data 
obtained in this trial will provide a basis for the treatment of patients suffering from CIAS 
with renal impairment.
The design of this trial follows the FDA draft guideline for Industry “Guidance for Industry 
Pharmacokinetics in Patients with Impaired Renal Function –Study Design, Data Analysis, 
and Impact on Dosing” [R22-3783] and the EMA “Guideline on the evaluation of the 
pharmacokinetics of medicinal products in patients with decreased renal function” [R22-
3784].
1.4
BENEFIT - RISK ASSESSMENT
1.4.1
Benefits
Participation in this clinical trial is without any (therapeutic) benefit for the participants. 
Their participation, however, is of major importance for the development of iclepertin which 
may help to treat patients suffering from CIAS.
1.4.2
Risks
Participants are exposed to risks of trial procedures and risks related to the exposure to the 
trial medication. An overview of trial-related risks is given in Table 1.4.2: 1.

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Table 1.4.2: 1
Overview of trial-related risks for this trial
Possible or known risks of 
clinical relevance 
Summary of data, rationale 
for the risk
Mitigation strategy
Investigational Medicinal Product: iclepertin
CNS-related effects
CNS depressant effects 
indicated by nonclinical data, 
and also observed in clinical 
studies with other compounds 
in the same pharmacological 
class [R13-4450]R13-4450.
In clinical studies with 
healthy volunteers, headache, 
dizziness and fatigue were the 
most frequently reported AEs 
in iclepertin treatment groups.
For details refer to Section 
1.2.1.11.2.1.1, and the current 
IB [c02155957].
In case of headache, the investigator 
may initiate symptomatic treatment 
if deemed necessary.
Participants will be asked to use 
public transport instead of driving 
cars and not to operate machines 
should they experience CNS-related 
effects that might impair ability to 
drive or operate machines.
In questionable cases neurological 
tests and testing of driving ability 
prior to discharge will be initiated 
by the investigator. In-house stay 
may be prolonged at any time at the
discretion of the investigator.
Alcohol is not permitted from 7 days 
before the drug administration until
the last PK sample.
Psychiatric disorders:
Suicidality
In clinical studies, no signal 
for suicidal ideation or 
behaviour was observed.
Prospective monitoring for suicidal 
ideation behaviour using the C-
SSRS.
The risk after a single administration 
of iclepertin is considered low and 
will be addressed by careful close 
clinical monitoring for AEs and 
increased awareness by the 
investigator for signs and symptoms 
of depression and anxiety as well as 
for signs and symptoms of suicidal 
ideation and behaviour.
Only participants with no relevant 
medical history including 
psychiatric disorders will be 
enrolled.
Any suicidal behaviour in the past 2
years and any suicidal ideation of 
type 4 or 5 on the C-SSRS in the 
past 3 months or at Visit 1 are 
exclusion criteria.
Patient’s withdrawal criteria in case 
of new-onset suicidal behaviour or 
any suicidal ideation of type 4 or 5 
in the C-SSRS.

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Table 1.4.2: 1
Overview of trial-related risks for this trial (cont.)
Gastrointestinal effects
In clinical studies with 
healthy volunteers, nausea, 
vomiting and diarrhoea were 
among the most frequently 
reported AEs in iclepertin 
treatment groups.
For details refer to Section 
1.2.1.11.2.1.1, and the current 
IB [c02155957].
Clinical gastrointestinal symptoms 
will be monitored carefully, and 
symptomatic treatment may be 
initiated by the investigator if 
deemed necessary (e.g. fluid 
replacement in case of diarrhoea).
Ophthalmological effects
In the single rising dose trial 
using powder for oral 
solution formulation (1346.1
[c26534937]), dose-related 
increases in VAS scores and 
visual disturbances (blurred 
vision, photopsia, 
chromatopsia) were observed 
around tmax [c02820512].
For details refer to the current 
IB [c02155957].
Participants will be advised not to 
drive cars or operate machines 
should they experience blurred 
vision.
In questionable cases visual tests 
will be initiated by the investigator. 
In-house stay may be prolonged at 
any time at the discretion of the 
investigator.
In case of ophthalmological AEs, 
evaluation to be made by an 
ophthalmologist (see Section 
5.2.6.1.5).
Haematology changes
Changes in red blood cell 
parameters (reductions in 
haemoglobin, haematocrit, 
etc.) indicated by nonclinical 
data.
In trials with healthy 
volunteers, no notable 
decrease in haemoglobin or 
haematocrit was noted in the 
iclepertin treatment groups 
compared with placebo.
A dose-dependent decrease in 
haemoglobin was noted in the 
longer term 12-week Phase II 
trials with patients at doses 
10 mg (-2.3%) and 25 mg 
(-3.2%) at last value on 
treatment as compared to 
baseline.
For details refer to Section 
1.2.1.1, and the current IB 
[c02155957].
Participants will regularly undergo 
clinical laboratory testing to monitor 
potential iclepertin induced 
alterations.
Administration of iclepertin is 
limited to a single dose of 10 mg 
iclepertin.

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Table 1.4.2: 1
Overview of trial-related risks for this trial (cont.)
Drug-induced liver injury 
(DILI)
Rare but severe event, thus 
under constant surveillance 
by sponsors and regulators.
Timely detection, evaluation, and 
follow-up of laboratory alterations 
in selected liver laboratory 
parameters to ensure participants’ 
safety.
Drug-drug interaction 
between iclepertin and 
other drugs
Co-administration with a 
strong CYP3A inhibitor 
increased the total exposure 
of iclepertin significantly, 
while it was significantly 
decreased in the presence of a 
strong CYP3A4 inducer (for 
details refer to the current 
IB[c02155957]).
Participants will not be allowed to 
use strong and moderate inhibitors 
or inducers of CYP3A4 (see 
Appendix 10.2) within 30 days 
before start of trial treatment.
Trial procedures
Bruising and, in rare 
cases, phlebitis, or nerve 
injury, potentially 
resulting in paraesthesia, 
reduced sensibility, and/or 
pain 
General risk by venipuncture
for blood sampling,
acceptable in the framework 
of trial participation.
Medical expertise of the trial site 
The total volume of blood withdrawn per participant during the entire trial will not exceed the 
volume of a normal blood donation (500 mL). No health-related risk to participants of this 
trial is expected from withdrawal of this volume of blood.
Consideration on male contraception requirements
Contraception for male clinical trial participants with sexual partners who are WOCBP, and 
the collection of pregnancy information from sexual partners of male clinical trial 
participants, are not required in clinical trials with iclepertin.
Considerations on female contraception requirements, pregnancy, and lactation
Iclepertin may be administered to WOCBP with a medically acceptable method of 
contraception (see Section 3.3.2).
Iclepertin should not be used during pregnancy and use should be discontinued upon 
confirmation of pregnancy. Iclepertin must not be administered to women who are, or who 
may be, breastfeeding.

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Considerations on COVID-19
Generally, for participants of this trial, the risk of severe COVID-19 infection is not higher, 
and study participation would not increase the risk of becoming infected with SARS-CoV-2 
beyond the potential risk associated with any need for the study participant to leave their 
home for study related activities. The appropriate risk minimisation measures will be taken in 
accordance with the public health precautions if needed due to the current status of the 
pandemic (e.g. minimising time at the clinic, minimising the use of public transportation to
the site). The investigators will take the totality of information related to each single 
participants and the local COVID-19 situation into consideration when performing the 
individual benefit-risk assessment on a case-by-case basis. Considering all aspects, the 
investigator will decide upon each participant’s (continued) participation in the trial.
Of note, depending on the current status of the COVID-19 pandemic, all participants with 
confirmed SARS CoV-2 infection will be handled in accordance with local guidance and 
SOPs meaning that any confirmed SARS CoV-2 infection during the conduct of the trial will 
lead to discontinuation of the participant.
1.4.3
Discussion
The nature of the target and the mechanism of action of iclepertin is well understood. The
safety profile of iclepertin has been characterized in several clinical trials including the
administration to more than 300 healthy subjects so far. After single dosing, iclepertin up to 
50 mg was safe and well-tolerated, but higher doses showed increased incidences of AEs and 
the occurrence of sedative effects and perceptual alterations. In line with its mode of action, 
drug related AEs after multiple dosing of iclepertin to healthy subjects have a CNS focus and
include headache, fatigue, dizziness, visual disturbances (blurred vision, reduced visual
acuity) and gait disturbances. All these AEs were manageable within the setting of a phase I 
trial, did not jeopardise the subject`s safety and resolved by end of the trial.
In the current trial, adequate safety monitoring including vital signs, ECG, C-SSRS, safety 
laboratory and AE monitoring has been implemented.
Taking into account these safety measures, potential risks to participants with normal renal 
function and those impaired renal function are considered to be low and outweighed by the 
benefit of a successful clinical development of iclepertin in the context of the unmet medical 
need.

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2.
TRIAL OBJECTIVES AND ENDPOINTS
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS
2.1.1
Main objectives
The main objective of this trial is to investigate the effect of severe, moderate and mild renal 
impairment on the PK of iclepertin following oral administration.
2.1.2
Primary endpoints
The following PK parameters will be determined for iclepertin:

AUC0-tz (area under the concentration-time curve of iclepertin in plasma over the time 
interval from 0 to the last quantifiable data point)

Cmax (maximum measured concentration of iclepertin in plasma)
2.1.3
Secondary endpoint
The following PK parameter will be determined for iclepertin:

AUC0-∞(area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity)

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2.2.2.3
Safety and tolerability
Safety and tolerability of iclepertin will be assessed based on:  

Adverse events (including clinically relevant findings from the physical examination)

Safety laboratory tests

Assessment of suicidal ideation and behaviour (C-SSRS)

12-lead ECG

Vital signs (blood pressure, pulse rate)

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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN
The trial will be performed as a non-randomised, single dose, open-label, parallel, individual-
matched design in order to investigate the PK of iclepertin (and its metabolites), as well as 
the safety and tolerability of iclepertin in severe, moderate, and mild renal impaired male and 
female participants compared to matched participants with normal renal function.
The treatment will be one 10 mg tablet administered to participants in the fasting state. For 
details, refer to Section 4.1.
The trial will be performed in 6 groups:

Group 1: 8 participants with severe renal impairment (eGFR at screening 
15-29 mL/min/1.73 m2)

Group 2: 8* participants with normal renal function individually matched to 
participants of Group 1 (eGFR at screening ≥90 mL/min/1.73 m2)

Group 3: 8 participants with moderate renal impairment (eGFR at screening 
30-59 mL/min/1.73 m2)

Group 4: 8* participants with normal renal function matching Group 3 (eGFR at 
screening ≥90 mL/min/1.73 m2)

Group 5: 8 participants with mild renal impairment (eGFR at screening 
60-89 mL/min/1.73 m2)

Group 6: 8* participants with normal renal function matching Group 5 (eGFR at 
screening ≥90 mL/min/1.73 m2)
*Each participant with normal renal function may be matched to multiple participants with 
renal impairment across groups and can be matched to only 1 participant within a renal 
impairment group.
Each group will contain at least 25% participants (i.e., 2) of each gender.
Matching criteria of the participants with normal renal function to the participants with renal 
impairment:

Age (± 10 years)

Gender

Race

Weight (± 15%)
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.
Definitions of trial start and end are given in Section 8.6.

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3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUPS
The defined single-dose individual-matched comparison is deemed appropriate to meet the 
objectives of the study.
From preclinical and clinical data (see Section 1.2.1), no clinically relevant increase in 
exposure to iclepertin in participants with impaired renal function is expected.
The single dose of 10 mg of iclepertin selected in this trial is the currently expected 
therapeutic dose and has been considered as safe for the trial populations.
The PK of iclepertin are dose-proportional (up to 150 mg in liquid formulation and 25 mg in 
tablet formulation) and dose-linearity was also shown for 10 mg after multiple doses.
Therefore, a 10 mg single dose has been considered sufficient for the planned PK evaluations
and adequate to meet the objectives of the trial. 
The group size of 8 participants is considered sufficient for the exploratory evaluation of PK. 
The assignment of individually match participants with normal renal function is a useful 
method to control for other factors which may influence the PK of iclepertin in a renal 
impaired population. 
The open-label treatment is not expected to bias results, since the study endpoints are derived 
from measurement of plasma and urine concentrations of the analyte. Furthermore, all 
participants will receive the same dose, and participants will be stratified to the groups 
according to their renal function. 
3.3
SELECTION OF TRIAL POPULATION
It is planned that 24 male and female participants with severe, moderate, or mild renal 
impairment (at least 25% of each gender per group) and up to 24 male and female control 
participants with normal renal function (Groups 2, 4, and 6) will enter the trial. 
The participants with normal renal function will be recruited from the volunteers' pool of the 
trial site. The participants with renal impairment will be recruited in cooperation with 
different nephrological centres who primarily diagnose the underlying medical condition 
leading to chronic renal impairment.
The participants will be assigned to one of the renal function groups (severe, moderate, and 
mild impairment, normal renal function) based on their eGFR according to CKD-EPI (see 
Appendix 10.3). In addition, participants with normal renal function will be assigned to a 
group according to their match to a participant with renal impairment (3.3: 1). 

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Table 3.3: 1
Overview of group stratification
Group
Renal function
eGFR 
(mL/min/1.73 m2)
Number of 
participants
1
Severe impairment
15 – 29
8
2
Normal renal function
≥90
up to 8*
3
Moderate impairment
30 – 59
8
4
Normal renal function
≥90
up to 8*
5
Mild impairment
60 – 89
8
6
Normal renal function
≥90
up to 8*
* Each participant with normal renal function may be matched to multiple participants with renal impairment 
across groups and can be matched to only 1 participant within a renal impairment group
Participants with normal renal function will be matched individually to a participant with 
impaired renal function by gender, race, age (within ±10 years) and weight (within ±15%) to 
1 participant with renal impairment. One participant with normal renal function may be 
matched to multiple participants with renal impairment across different groups and can be 
matched to only 1 participant with renal impairment within a group.
Please refer to Section 4.1.3 regarding the method of assigning participants to treatment 
groups.
A log of all participants 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.
3.3.1
Main diagnosis for trial entry
The trial will be performed in participants with renal impairment (severe, moderate and mild) 
and participants with normal renal function (matched controls to the participants with renal 
impairment).
Please refer to Section 8.3.1 (Source Documents) for the documentation requirements 
pertaining to the in- and exclusion criteria.
3.3.2
Inclusion criteria
3.3.2.1
Inclusion criteria applicable to all participants
Participants will only be included in the trial if they meet the following criteria:
1. Male or female participants 
2. Age of at least 18 years (inclusive)
3. BMI of 18.5 to 35 kg/m2 (inclusive)
4. Signed and dated written informed consent in accordance with ICH-GCP and local 
legislation prior to admission to the trial

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5. Male participants are not required to use contraception
6. WOCBP are allowed to participate provided they use a highly effective 
contraception from at least 30 days before the administration of trial medication until 
30 days after trial completion. 
The following methods of contraception are considered adequate for female 
participants of childbearing potential:
-
Use of combined (oestrogen and progestogen containing) hormonal 
contraception that prevents ovulation (oral, intravaginal or transdermal), plus 
condom
-
Use of progestogen-only hormonal contraception that inhibits ovulation (only 
injectables or implants), plus condom
-
Use of intrauterine device (IUD) or intrauterine hormone-releasing system 
(IUS)
-
Sexually abstinent
-
A vasectomised sexual partner who received medical assessment of the 
surgical success (documented absence of sperm) and provided that partner is the 
sole sexual partner of the trial participant.
Female participants are not considered to be of childbearing potential if they are 
either surgically sterilised (including hysterectomy) or postmenopausal, defined as 
no menses for 1 year without an alternative medical cause (in questionable cases a 
blood sample with levels of FSH above 40 U/L and oestradiol below 30 ng/L is 
confirmatory).
3.3.2.2
Inclusion criteria applying only to participants with impaired renal function
In addition to the inclusion criteria given in Section 3.3.2.1, participants with impaired renal 
function must fulfil the following criteria:
7. Renal impairment based on assessment of eGFR at screening (severe renal 
impairment: 15-29 mL/min/1.73 m2, moderate renal impairment: 
30-59 mL/min/1.73 m2, mild renal impairment: 60-89 mL/min/1.73 m2)
8. Chronic renal impairment > 12 months (documented renal impairment indicated by 
reduced eGFR for more than 12 months until screening)
9. Absence of clinically significant abnormalities, as based on a complete medical 
history including a full physical examination, vital signs (BP, PR), 12-lead ECG, and 
clinical laboratory tests at both screening and check-in, with the exception of 
findings that in the opinion of the investigator are consistent with the participant’s 
renal impairment.
10. Medication and/or treatment regimens must have been stable (i.e., no dose 
adjustments) for at least 4 weeks prior to the screening period and should be kept 
stable until study completion. 
Fluctuating treatment regimens may be considered for inclusion on a case-by-case 

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basis if the underlying disease is under control in the opinion of the investigator and 
must be agreed to by both the investigator and the sponsor’s medical monitor.
3.3.2.3
Inclusion criteria applying only to participants with normal renal function
In addition to the inclusion criteria given in Section 3.3.2.1, participants with normal renal 
function must fulfil the following criteria: 
11. Individually matched to participants with renal impairment according to sex, age, 
and weight, and race
12. eGFR ≥90 mL/min/1.73 m2
13. Absence of clinically significant abnormalities identified by a detailed medical 
history, full physical examination, vital signs and 12-lead ECG at both screening and 
check-in visits
14. Absence of clinically significant abnormalities identified by a laboratory test at 
screening visit
3.3.3
Exclusion criteria
3.3.3.1
Exclusion criteria applying to all participants
Participants will not be allowed to participate, if any of the following general criteria apply:
1. Any evidence of a concomitant disease assessed as clinically relevant by the 
investigator
2. Cholecystectomy or other surgery of the gastrointestinal tract that could interfere 
with the PK of the trial medication (except appendectomy or simple hernia repair)
3. Diseases of the CNS (including but not limited to any kind of seizures or stroke), and 
other relevant neurological or psychiatric disorders (including but not limited to 
major depressive disorder)
4. History of relevant orthostatic hypotension, fainting spells, or blackouts
5. Relevant chronic or acute infections
6. Any documented active or suspected malignancy or history of malignancy within 5 
years prior to screening, except appropriately treated basal cell carcinoma of the skin
7. History of relevant allergy or hypersensitivity (including allergy to the trial 
medication or its excipients) 
8. Use of drugs within 30 days (or 5 of its half-lives, whichever is longer) of planned
administration of trial medication that might reasonably influence the results of the 
trial (including drugs that cause QT/QTc interval prolongation)
9. Intake of an investigational drug in another clinical trial within 60 days (for multiple 
dose studies) / within 30 days (for single dose studies) or 5 half-lives (whichever is 
longer) of planned administration of investigational drug in the current trial, or 

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concurrent participation in another clinical trial in which investigational drug is 
administered
10. Smoker (more than 15 cigarettes or 5 cigars or 5 pipes per day)
11. Inability to refrain from smoking on specified trial days
12. Alcohol abuse (consumption of more than 10 g per day for females and 20 g per day
for males)
13. Drug abuse or positive drug screening
14. Blood donation of more than 100 mL within 30 days of planned administration of 
trial medication or intended blood donation during the trial
15. Intention to perform excessive physical activities within one week prior to the 
administration of trial medication or during the trial
16. Inability to comply with the dietary regimen of the trial site
17. A history of additional risk factors for Torsade de Pointes (such as heart failure, 
hypokalaemia, or family history of Long QT Syndrome)
18. Participant is assessed as unsuitable for inclusion by the investigator, for instance,
because the participant is not considered able to understand and comply with study 
requirements, or has a condition that would not allow safe participation in the study 
19. During COVID-19 pandemic: laboratory test indicative of an ongoing SARS-CoV-2 
infection
20. For female participants: Lactation, pregnancy, positive pregnancy test, or plans to 
become pregnant during the trial or within 30 days after trial completion
21. Any suicidal behaviour in the past 2 years (i.e., actual attempt, interrupted attempt, 
aborted attempt, or preparatory acts or behaviour).
22. Any suicidal ideation of type 4 or 5 on the C-SSRS in the past 3 months or at Visit 1 
and/or Visit 2 predose (i.e., active suicidal thought with method and intent but 
without specific plan; or active suicidal thought with method, intent and plan).
3.3.3.2
Exclusion criteria applying only to participants with renal impairment
In addition to the exclusion criteria listed in Section 3.3.3.1, participants with renal 
impairment fulfilling any of the following criteria will not be included into the trial:
23. A marked prolongation of QT/QTc interval (such as QTc intervals that are repeatedly 
greater than 480 ms in males or repeatedly greater than 500 ms in females) or any 
other relevant ECG finding at screening
24. Acute renal failure or active nephritis
25. Nephrotic syndrome
26. Impaired hepatic function, including relevant increases in liver enzymes indicating 
liver disease

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27. Relevant diseases for which it can be assumed that the absorption of the study drugs 
will not be normal (i.e., relevant malabsorption, chronic diarrhoea)
28. Participant under dialysis or planned to start dialysis during participation in the study
29. History of myocardial infarction, cerebrovascular accident or severe arrhythmia 
within the 6 months prior to the screening visit. 
30. History of vascular surgery or intervention (e.g., coronary artery bypass, 
percutaneous transluminal angioplasty etc.) less than 6 months prior to dosing
31. Congestive heart failure of New York Heart Association grade III or IV, severe 
arrhythmia requiring antiarrhythmic treatment
32. History of clinically significant aortic or pulmonary valve stenosis, or renal artery 
stenosis
33. Any other disease or condition which could influence the physiological metabolic 
turnover (e.g., endocrine diseases, severe infections)
34. Significant uncorrected rhythm or conduction disturbances such as a second-or third-
degree AV block without a cardiac pacemaker, QTc prolongation, or episodes of 
sustained ventricular tachycardia
35. Resting supine systolic BP below 99 or above 179 mmHg and resting supine 
diastolic BP below 50 or above 100 mmHg at screening visit
36. Resting supine HR equal to or below 50 bpm or above 90 bpm, at screening visit
37. Haemoglobin <9 g/dL
38. Serum albumin <30 g/L
39. Platelet count <100 x 109/L
40. Other clinically relevant deviations in clinical chemistry (especially liver enzymes) 
or haematology
41. Participants with diabetes mellitus with a fasting blood glucose >220 mg/dL or 
glycated haemoglobin (HbA1c) >10%
3.3.3.3
Exclusion criteria applying only to participants with normal renal function
In addition to the exclusion criteria listed in Section 3.3.3.1, participants with normal renal 
function fulfilling any of the following criteria will not be included into the trial:
42. Any finding in the medical examination (including BP, PR or ECG) deviating from 
normal and assessed as clinically relevant by the investigator
43. A marked prolongation of QT/QTc interval (such as QTc intervals that are repeatedly 
greater than 450 ms in males or repeatedly greater than 470 ms in females) or any 
other relevant ECG finding at screening
44. Repeated measurement of systolic blood pressure outside the range of 90 to 140 
mmHg (for participants older than 60 years: 90 to 150 mmHg), diastolic blood 

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pressure outside the range of 50 to 90 mmHg, or pulse rate outside the range of 50 to 
90 bpm
45. Any laboratory value outside the reference range that the investigator considers to be 
of clinical relevance
46. Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, 
immunological or hormonal disorders
For restrictions of the trial, refer to Section 4.2.2.
3.3.4
Withdrawal of subjects from treatment or assessments
Participants may withdraw or may be removed from trial treatment or may withdraw consent 
to trial participation as a whole (‘withdrawal of consent’) with very different implications; 
please see Sections 3.3.4.1 and 3.3.4.2 below.
If a participant is removed from or withdraws from the trial prior to the administration of trial 
medication, the data of this participant will not be entered in the case report form (CRF) and 
will not be reported in the clinical trial report (CTR).
If a participant is removed from or withdraws from the trial after the administration of trial 
medication, this will be documented and the reason for discontinuation must be recorded in 
the CRF; in addition, trial data will be included in the CRF and will be reported in the CTR. 
Following removal or withdrawal, a complete end-of-trial examination should be performed.
If the discontinuation or withdrawal occurs before the end of the REP (see Section 1.2.2, the 
discontinued participant 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 participant.
3.3.4.1
Withdrawal from trial treatment
An individual participant will be withdrawn from trial treatment if:
1. The participant wants to withdraw from trial treatment. The participant will be asked 
to explain the reasons but has the right to refuse to answer
2. The participant has repeatedly shown to be non-compliant with important trial 
procedures and, in the opinion of both, the investigator and sponsor representative,
the safety of the participant cannot be guaranteed as he / she is not willing or able to 
adhere to the trial requirements in the future.
3. The participant needs to take concomitant medication that interferes with the 
investigational medicinal product or other trial treatment
4. The participant can no longer receive trial treatment for medical reasons (such as 
pregnancy, surgery, AEs, or diseases)
5. The participant 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

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6. The participant exhibits suicidality, in the clinical judgment of the investigator or 
according to the following criteria:
o
any suicidal behaviour (i.e. actual attempt, interrupted attempt, aborted attempt, or 
preparatory acts or behaviour)
o
any suicidal ideation of type 4 or 5 in the C-SSRS (i.e. active suicidal thought 
with intent but without specific plan, or active suicidal thought with plan and 
intent)
In addition to these criteria, the investigator may discontinue participant at any time based on 
his or her clinical judgment.
If it is known that a participant becomes pregnant during the trial, she is to be removed from 
the trial. The participant is to be followed until she has given birth or until the end of the 
pregnancy. The participant’s data are to be collected until the end of the trial (last visit of last 
participant) and reported in the CTR. For reporting of pregnancy and associated events, refer 
to Section 5.2.6.2.3.
If new efficacy or safety information becomes available, Boehringer Ingelheim will review 
the benefit-risk-assessment and, if needed, pause or discontinue the trial treatment for all 
participants or take any other appropriate action to guarantee the safety of the trial 
participants.
3.3.4.2
Withdrawal of consent to trial participation
Participants may withdraw their consent to trial participation at any time without the need to 
justify the decision. If a participant wants to withdraw consent, the investigator should be 
involved in the discussion with the participant and explain the options for continued follow-
up after trial discontinuation.
3.3.4.3
Discontinuation of the trial by the sponsor
Boehringer Ingelheim reserves the right to discontinue the trial at any time for any of the 
following reasons (if reasons 4 and/or 5 are met, the trial should be discontinued 
immediately):
1. Failure to meet expected enrolment goals overall or at a particular trial site
2. The sponsor decides to discontinue the further development of the investigational 
products
3. Deviation from GCP, or the CTP, or the contract with BI impairing the appropriate 
conduct of the trial
4. New toxicological findings, SAEs, or any safety information invalidating the earlier 
positive benefit-risk-assessment (see Section 3.3.4.1)
5. More than 50% of the participants show drug-related and clinically relevant AEs of 
moderate intensity, or if more than two participants have drug-related severe non-
serious AEs, or if at least one drug-related SAE is reported

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The investigator / trial site will be reimbursed for reasonable expenses incurred in case of 
trial termination (except if item 3 applies).
3.3.5
Replacement of subjects
In case more than 2 participants in a group do not complete the trial (including participants
non-evaluable for PK), additional participants may be enrolled and treated in this respective 
trial group, i.e. ‘replaced‘, if considered necessary to reach the objective of the trial.
Participants who withdraw or are withdrawn from treatment or assessments because of a
drug-related adverse event will not be replaced. The Clinical Trial Leader together with the 
Trial Pharmacokineticist and the Trial Statistician are to decide, if and how many participants
will be replaced. The total number of replacements may not exceed 1/3 of the total number of 
evaluable participants anticipated to complete the trial. A replacement participant will be 
assigned a unique trial participant number. In case of enrolment of additional participants, the 
trial site should ensure the requirements for distribution of gender (‘at least 25% of each 
gender per group’) are still met within the comprising group of further on treated and 
additionally enrolled participants.

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4.
TREATMENTS
4.1
INVESTIGATIONAL TREATMENTS
4.1.1
Identity of the Investigational Medicinal Products
The characteristics of the test product are given below:
Substance:
BI 425809 (iclepertin)
Pharmaceutical formulation: Film-coated tablet
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
10 mg
Posology:
1-0-0
Mode of administration:
Oral
4.1.2
Selection of doses in the trial
The dose of 10 mg of iclepertin selected for this trial is the therapeutic dose that is used in 
clinical drug development (see Section 1.2).
4.1.3
Method of assigning subjects to treatment groups
There is only one treatment investigated in this trial.
The participants with renal impairment and the matching participants with normal renal 
function will be assigned to treatment groups according to their renal impairment based on 
their eGFR and as control group as outlined in Table 3.3:1.
Once a participant number has been assigned, it cannot be reassigned to any other 
participants.
All participant within one group may be treated in one cohort, i.e. all participant 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. For discussion 
of trial-associated risks and safety measures, see Section 1.4).
4.1.4
Drug assignment and administration of doses for each subject
This is a non-randomised, open-label, parallel, individual matched-group design trial. All 
participants will receive the same active treatment. The treatments to be evaluated are 
summarised in Table 4.1.4: 1 below. 

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Table 4.1.4: 1
Dosage and treatment schedule
Treatment
Substance
Formulation
Unit strength
Dosage
Total dose
T (Test)
iclepertin
Film coated 
Tablet
10 mg
1 tablet (10 mg) single dose for 1 day
10 mg
Administration of trial medication will be performed after participants have fasted overnight; 
fasting is to start no later than 10 h before the scheduled dosing. The investigator (or 
authorised designee) will administer the trial medication as an oral dose together with about 
240 mL of water to participants who are in a sitting/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.
Participants will be kept under close medical surveillance until 48 h after drug administration. 
During the first 4 h after drug administration, participants are not allowed to lie down (i.e. no 
declination of the upper body of more than 45 degrees from upright posture), except for 
assessments and examinations.
4.1.5
Blinding and procedures for unblinding
This non-randomised open-label Phase I trial will be handled in an open fashion throughout. 
There will be only one treatment, so the treatment assignment will be available to all involved 
parties.
4.1.6
Packaging, labelling, and re-supply
The investigational medicinal products will be provided by BI. They will be packaged and 
labelled in accordance with the principles of Good Manufacturing Practice (GMP). 
For details of packing and the description of the label, refer to the ISF.
The telephone number of the sponsor and the name, address and telephone number of the trial 
site are provided in the participant information form. The EudraCT number is indicated on 
the title page of this protocol as well as on the participant information and informed consent
forms. 
No re-supply is planned.
4.1.7
Storage conditions
Drug supplies will be kept in their original packaging and in a secure limited access storage 
area in accordance with the recommended (labelled) storage conditions. If necessary, a 
temperature log must be maintained to make certain that the drug supplies are stored at the 
correct temperature. If the storage conditions are found to be outside the specified range, the 
Clinical Research Associate (as provided in the list of contacts) is to be contacted
immediately.

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4.1.8
Drug accountability
The investigator or designee will receive the investigational drugs delivered from the sponsor
when the following requirements are fulfilled:

Approval of the clinical trial protocol by the IRB / ethics committee

Availability of a signed and dated clinical trial contract between the sponsor or 
delegate and the investigational site

Approval/notification of the regulatory authority, e.g. competent authority

Availability of the curriculum vitae of the Principal Investigator

Availability of a signed and dated clinical trial protocol
Only authorised personnel documented in the form 'Trial Staff List' may dispense 
investigational drugs to trial participants. Investigational drugs are not allowed to be used 
outside of this protocol.
The investigator or designee must maintain records of the product’s delivery to the trial site, 
the inventory at the site, the use by each participant, 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 
participants. The investigator or designee will maintain records that document adequately that 
the participants were provided the doses specified by the CTP and reconcile all 
investigational medicinal products received from the sponsor. At the time of disposal of 
remaining trial medication, the investigator or designee must verify that no remaining 
supplies are in the investigator’s possession.
All unused medication will be disposed of locally by the trial site upon written authorisation 
of the Clinical Trial Leader. Receipt, usage and disposal of trial medication must be 
documented on the appropriate forms. Account must be given for any discrepancies.
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS
4.2.1
Other treatments and emergency procedures
There are no special emergency procedures to be followed. No additional treatment is 
planned. However, if adverse events require treatment, the investigator can authorise 
symptomatic therapy. In those cases, participants 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.
4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
In principle, no concomitant therapy is allowed for participants with normal renal function, 
except for hormonal contraceptives or ovary hormone replacement. 

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In participants with renal impairment, contraceptives as well as concomitant medication for 
treatment of the renal or other concomitant diseases are allowed.
Strong CYP3A inhibitors are restricted medication in all trial participants due to potential 
DDIs (see Appendix 10.2). See also Section 3.3.3 for excluded medication. If necessary, 
short-term use of ibuprofen or acetylsalicylic acid is acceptable for symptomatic treatment of 
AEs.
All concomitant or rescue therapies will be recorded (including time of intake on trial days) 
on the appropriate pages of the CRF.
4.2.2.2
Restrictions on diet and life style
While admitted to the trial site, the participants will be instructed not to consume any foods 
or drinks other than those provided by the staff. Standardised meals will be served at the 
times indicated in the Flow Chart. No food is allowed for at least 4 h after drug intake. Only 
participants with diabetes will receive a snack at 2 h post dose, if necessary.
From 1 h before drug intake until lunch, fluid intake is restricted to the water administered 
with the drug, and an additional 240 mL of water at 2 h and 4 h post-dose (mandatory for all 
participants). From lunch until 24 h post-dose, total fluid intake is restricted to 3000 mL.
Alcoholic beverages, grapefruits, Seville oranges (sour or bitter oranges) and their juices, and 
dietary supplements are not permitted from 7 days before administration of trial medication
until after the last PK sample of each trial period is collected.
Products containing St. John's wort (Hypericum perforatum) are not permitted from 30 days 
before the administration of trial medication until after the last PK sample 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 trial medication until the end of 
in-house confinement at the trial site.
Smoking is not allowed during from 10 h before until 8 h after administration of trial 
medication.
Excessive physical activity (such as competitive sport) should be avoided from 7 days before 
administration of trial medication until the end of trial examination.
4.2.2.3
Contraception requirements
If WOCBP are included in the trial, adequate contraception is to be maintained throughout 
the course of the trial (see Section 3.3.2 for the definition of adequate measures).
4.3
TREATMENT COMPLIANCE
Compliance will be assured by administration of all trial medication in the trial centre under 
supervision of the investigating physician or a designee. The measured plasma concentrations 
and/or urinary excretion of trial medication will provide additional confirmation of 
compliance.

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Participants who are non-compliant (for instance, who do not appear for scheduled visits or 
violate trial restrictions) may be removed from the trial and the CRF will be completed 
accordingly (for further procedures, please see Section 3.3.4.1).

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5.
ASSESSMENTS
5.1
ASSESSMENT OF EFFICACY
Not applicable.
5.2
ASSESSMENT OF SAFETY
5.2.1
Physical examination
At screening, the medical examination will include demographics, height and body weight, 
smoking and alcohol history (alcohol history not mandatory to be entered into CRF or to be 
reported), relevant medical history and concomitant therapy, C-SSRS, 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, a physical examination including determination of body weight, recording of AEs and 
concomitant therapies, and C-SSRS scale.
5.2.2
Vital signs
Systolic and diastolic blood pressures (BP) as well as pulse rate (PR) or heart rate (heart rate 
is considered to be equal to pulse rate) will be measured by a blood pressure monitor 
(
,
) at the times 
indicated in the Flow Chart, after participants have rested for at least 5 min in a supine 
position. All recordings should be made using the same type of BP recording instrument on 
the same arm, if possible.
Body temperature will be monitored as part of vital signs assessment if still needed due to the 
current status of the pandemic. Body temperature will not be entered into the eCRF.
5.2.3
Safety laboratory parameters
For the assessment of laboratory parameters, blood and urine samples will be collected by the 
trial site at the times indicated in the Flow Chart after the participants have fasted for at least 
10 h. For retests, at the discretion of the investigator or designee, overnight fasting is not 
required. 
The parameters to be assessed are listed in Tables 5.2.3: 1 and 5.2.3: 2. Reference ranges will 
be provided in the ISF. 
Manual differential white blood cell count or urine sediment examinations will only be 
performed if there is an abnormality in the automatic blood cell count or in the urinalysis, 
respectively. 

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Table 5.2.3: 1
Routine laboratory tests
Functional lab group
BI test name [comment/abbreviation]
A
B
C
Haematology
Haematocrit
Haemoglobin
Red Blood Cell Count/Erythrocytes 
White Blood Cells/Leucocytes 
Platelet Count/Thrombocytes (quant)
HbA1c (in diabetic participants only)
X
X
X
X
X
X
X
X
X
X
X
--
X
X
X
X
X
--
Automatic WBC 
differential, relative 
Neutrophils/Leukocytes; Eosinophils/Leukocytes; 
Basophils/ Leukocytes; Monocytes/Leukocytes; 
Lymphocytes/Leukocytes 
X
X
X
Automatic WBC 
differential, absolute 
Neutrophil, absol.; Eosinophils, absol.; Basophils, absol.; 
Monocytes, absol.; Lymphocytes, absol.
X
X
X
Manual differential 
WBC (if automatic
differential WBC is 
abnormal)
Neut. Poly (segs)/Leukocytes; Neut. Poly (segs), absol.; 
Neutrophils Bands/Leukocytes; Neutrophils Bands, absol.; 
Eosinophils/Leukocytes; Eosinophils, absol.; 
Basophils/ Leukocytes; Basophils, absol.; 
Monocytes/Leukocytes; Monocytes, absol.; 
Lymphocytes/Leukocytes; Lymphocytes, absol.
Coagulation
Activated Partial Thromboplastin Time 
Prothrombin time
Prothrombin time – INR (International Normalisation Ratio)
Fibrinogen
X
X
X 
X
--
--
--
--
X
X
X
--
Enzymes
AST (Aspartate aminotransferase) /GOT, SGOT 
ALT (Alanine aminotransferase) /GPT, SGPT
Alkaline Phosphatase
Gamma-Glutamyl Transferase 
Glutamate Dehydrogenase (GLDH)
Creatine Kinase (CK)
Creatine Kinase Isoenzyme MB (only if CK is elevated)
Lactic Dehydrogenase
Lipase
Amylase
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hormones
Thyroid Stimulating Hormone
Free T3 - Triiodothyronine  
Free T4 – Thyroxine
FSH (if applicable)
Oestradiol (if applicable)
X
X
X
X
X
--
--
--
--
--
--
--
--
--
--

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Table 5.2.3: 1
Routine laboratory tests (cont.)
Functional lab group
BI test name [comment/abbreviation]
A
B
C
Substrates
Glucose (Plasma)
Creatinine 
GFR/ CKD-EPI
Bilirubin, Total 
Bilirubin, Direct
Protein, Total
Albumin
C-Reactive Protein (Quant)  
Uric Acid 
Cholesterol, total 
Triglyceride
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Electrolytes
Sodium
Potassium
Chloride
Calcium
Phosphate (as Phosphorus, Inorganic)
Magnesium
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urinalysis (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
X
X
X
X
X
X
X
X
X
Urine sediment 
(microscopic 
examination if 
erythrocytes, 
leukocytes or nitrite 
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 on Day -1, 2 and 4 (for time points refer to Flow Chart)
C: parameters to be determined at Visit 3 (end of trial examination)
The tests listed in Table 5.2.3: 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 pregnancy tests and drug screening, it is planned to perform these tests 
during screening only. Pregnancy testing in WOCBP will be performed at screening, prior to 
treatment, and as part of the end of trial examination. Drug screening will be performed at 
screening and prior to treatment.

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Table 5.2.3: 2
Exclusionary laboratory tests
Functional lab group
Test name 
Drug screening (urine)
Amphetamine/MDA
Barbiturates
Benzodiazepine
Cannabis
Cocaine 
Methadone
Methamphetamines
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)
Pregnancy test (serum at 
screening and Day -1 and urine at 
EoS)
Beta human chorionic gonadotropin (beta-HCG)
COVID-19 (nasopharyngeal 
swab)
SARS CoV-2 PCR test (screening) and antigen test on Day -1
To encourage compliance with alcoholic restrictions, a breath alcohol test (
 
will be performed prior to each treatment period, and may be repeated at 
any time during the trial at the discretion of an investigator or designee. The results will not 
be included in the CTR.
The laboratory tests listed in Tables 5.2.3: 1 and 5.2.3: 2 will be performed at
with the exception of drug screening, urine pregnancy tests. The
urinalysis (Stix) will be performed with the Combur Test. These tests will be performed at the 
trial site using Drug-Screen Multi 10TC Urine (distributed by 
) and meditrol 
hCG, urine test stripe (distributed by 
, respectively, or 
comparable test systems.
Laboratory data will be transmitted electronically from the laboratory to the trial site.
It is the responsibility of the Investigator to evaluate the laboratory reports. Clinically 
relevant abnormal findings as judged by the Investigator are to be reported as AEs (please 
refer to Section 5.2.6). 
In case the criteria for hepatic injury are fulfilled, a number of additional measures will be 
performed (please see Section 5.2.6.1.4). 
5.2.4
Electrocardiogram
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. 

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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 participants are at 
complete rest.
All ECGs will be recorded for a 10 sec duration after participants have rested for at least 5 
min in a supine position. ECG assessment will always precede all other trial 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. 
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 (if identified at the 
screening visit) if assessed to be clinically relevant by the investigator. Any ECG 
abnormalities will be carefully monitored and, if necessary, the participant 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. 
5.2.5
Other safety parameters
5.2.5.1
Suicidality assessment
Prospective monitoring will be conducted throughout this trial using C-SSRS.
The C-SSRS is a semi-structured, investigator-rated interview, developed by clinical experts 
in cooperation with the FDA, assessing both suicidal behaviour and suicidal ideation. It does
not give a global score but provides some categorical and some severity information
specifically for behaviour and ideation.
The C-SSRS has been widely used in large multinational clinical trials. The C-SSRS will be
administered at the screening visit (using the ‘screening/baseline’ version) with the aim to
exclude participant’s suicidal ideation type 4 to 5 within the preceding 3 months or at Visit 1
or any suicidal behaviour in the past 2 years. The lifetime history of suicidal ideation and
behaviour will also be recorded.
After Visit 1, the assessment ‘since last visit’ will be performed at each clinic visit (‘since last
visit’ version).
Appendix 10.1 provides details how the C-SSRS will be assessed.
C-SSRS results will be reported in terms of AEs as described in Section 5.2.6.2.

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5.2.6
Assessment of adverse events
5.2.6.1
Definitions of adverse events
5.2.6.1.1
Adverse event
An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a medicinal product and which does not necessarily have 
to have a causal relationship with this treatment.
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether considered related or not.
The following should also be recorded as an AE in the CRF and BI SAE form (if applicable):

Worsening of the underlying disease or of other pre-existing conditions 

Changes in vital signs, ECG, physical examination, and laboratory test results, if they 
are judged clinically relevant by the investigator
If such abnormalities already pre-exist prior to trial inclusion, they will be considered as 
baseline conditions and should be collected in the eCRF only.
SAE reporting in case of suicidal risk assessed by the C-SSRS
All C-SSRS reports of suicidal ideation type 4 and 5 and all reports of suicidal behaviour 
must be reported as separate SAEs by the investigator.
For ‘self-injurious behaviour, no suicidal intent’ (type 11) standard AE/SAE reporting rules 
are to be applied.
For each negative report (Suicidal ideation type 1, 2, or 3) after the start of the trial, the 
investigator is to decide based on clinical judgement whether it represents an AE as defined 
in the CTP, and if it is considered an AE then it must be reported accordingly.
5.2.6.1.2
Serious adverse event
A serious adverse event (SAE) is defined as any AE which fulfils at least one of the 
following criteria:
Results in death 
Is life-threatening, which refers to an event in which the patient was at risk of death at 
the time of the event; it does not refer to an event that hypothetically might have 
caused death if more severe 
Requires inpatient hospitalisation, or prolongation of existing hospitalisation
Results in persistent or significant disability or incapacity 
Is a congenital anomaly/birth defect 
Is deemed serious for any other reason if it is an important medical event when based 
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 

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the above definitions. Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalisation or development of dependency or 
abuse
5.2.6.1.3
AEs considered ‘Always Serious’
In accordance with the European Medicines Agency initiative on Important Medical Events, 
Boehringer Ingelheim has set up a list of AEs, which, by their nature, can always be 
considered to be ‘serious’ even though they may not have met the criteria of an SAE as 
defined above.
The latest list of ‘Always Serious AEs’ can be found in the eDC system, an electronic data 
capture system which allows the entry of trial data at the trial site. A copy of the latest list of 
‘Always Serious AEs’ will be provided upon request. These events should always be reported 
as SAEs as described in Section 5.2.6.2.
Cancers of new histology must be classified as a serious event regardless of the time since 
discontinuation of the trial medication and must be reported as described in 5.2.6.2, 
subsections ‘AE Collection’ and ‘AE reporting to sponsor and timelines’.
5.2.6.1.4
Adverse events of special interest
The term adverse events of special interest (AESI) relates to any specific AE that has been 
identified at the project level as being of particular concern for prospective safety monitoring 
and safety assessment within this trial, e.g. the potential for AEs based on knowledge from 
other compounds in the same class. AESIs need to be reported to the sponsor’s 
Pharmacovigilance Department within the same timeframe that applies to SAEs, please see 
Section 5.2.6.2.2.
The following are considered as AESIs:

Potential severe DILI
A potential severe Drug Induced Liver Injury (DILI) that requires follow-up is 
defined by the following alterations of hepatic laboratory parameters: 
o
An elevation of AST (aspartate aminotransferase) and/or ALT (alanine 
aminotransferase) ≥3-fold ULN combined with an elevation of total bilirubin 
≥2-fold ULN measured in the same blood sample, or in samples drawn within 
30 days of each other, or
o
Aminotransferase (ALT, and/or AST) elevations ≥10-fold ULN
These lab findings constitute a hepatic injury alert and the participants 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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5.2.6.1.5
Ocular AEs
Before administration of study medication at Visit 2, site staff will remind participants to 
report “any unusual visual perception they may experience”.
During the study, if a participant reports a change in perception or any ocular AE, site staff 
must record the participant’s verbatim description in the source documents and report it in the 
same way in the eCRF (and SAE form, if applicable).
A local ophthalmology assessment will be required for all ocular adverse events. The 
ophthalmologist will act as a consultant to the investigator and may offer advice on the 
proper management and treatment for the reaction as per standard of care.
5.2.6.1.6
Intensity (severity) of AEs
The intensity (severity) of the AE should be judged based on the following:
Mild:
Awareness of sign(s) or symptom(s) that is/are easily tolerated
Moderate:
Sufficient discomfort to cause interference with usual activity
Severe:
Incapacitating or causing inability to work or to perform usual activities
Infections classified as ‘severe’ are considered as AESIs, see Section 5.2.6.1.4.
5.2.6.1.7
Causal relationship of AEs
Medical judgment should be used to determine whether there is a reasonable possibility of a 
causal relationship between the AE and the given trial treatment, considering all relevant 
factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge, 
confounding factors such as concomitant medication, concomitant diseases and relevant 
history.
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:

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
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

There is an alternative explanation (e.g. situations where other drugs or underlying 
diseases appear to provide a more likely explanation for the observed event than the 
drug concerned

Disappearance of the event even though the trial drug treatment continues or remains 
unchanged
5.2.6.2
Adverse event collection and reporting
5.2.6.2.1
AE collection
Upon enrolment into a trial, the participant’s baseline condition is assessed (for instance, by 
documentation of medical history/concomitant diagnoses), and relevant changes from 
baseline are noted subsequently. 
Participants will be required to report spontaneously any AEs. In addition, each participant
will be regularly assessed by the medical staff throughout the clinical trial and whenever the 
investigator deems necessary. As a minimum, participants 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 participant’s end of 
trial (the End of Study (EoS) visit): 
o All AEs (serious and non-serious) and all AESIs 
o The only exception to this rule are AEs (serious and non-serious) and AESIs in 
Phase I trials in healthy volunteers, when participants discontinue from the 
trial due to screening failures prior to administration of any trial medication. In 
these cases, the participants’ data must be collected at trial site but will not be 
entered in the CRF and will not be reported in the CTR.

After the individual participant’s end of trial: 

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o The investigator does not need to actively monitor the participant for new AEs 
but should only report any occurrence of cancer and trial treatment related 
SAEs and trial treatment related AESIs of which the investigator may become 
aware of by any means of communication, e.g. phone call. Those AEs should 
be reported on the BI SAE form (see Section 5.2.6.2.2), but not on the CRF.
5.2.6.2.2
AE reporting to the sponsor and timelines
The Investigator must report SAEs, AESIs, and non-serious AEs which are relevant for the 
reported SAE or AESI, on the BI SAE form to the sponsor’s unique entry point within 
24 hours of becoming aware of the event, the country specific reporting process will be 
provided in the ISF. The same timeline applies if follow-up information becomes available. 
On specific occasions, the Investigator could inform the sponsor upfront via telephone. This 
does not replace the requirement to complete and send the BI SAE form. 
With receipt of any further information to these events, a follow-up SAE form has to be 
provided. For follow-up information, the same rules and timeline apply as for initial 
information. All (S)AEs, including those persisting after the individual participant’s end of 
trial, must be followed up until they have resolved, have been sufficiently characterised (e.g. 
as ‘chronic’ or ‘stable’), or no further information can be obtained.
5.2.6.2.3
Pregnancy
In rare cases, pregnancy might occur in a clinical trial. Once a participant has been enrolled in 
the clinical trial and has taken trial medication, the investigator must report any drug 
exposure during pregnancy in a trial participant immediately (within 24 hours) by means of 
Part A of the Pregnancy Monitoring Form to the sponsor’s unique entry point.
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 Studies (Part B). The ISF will contain the Pregnancy Monitoring Form for Studies
(Part A and Part B).
As pregnancy itself is not to be reported as an AE, in the absence of an accompanying SAE 
and/or AESI, only the Pregnancy Monitoring Form for Studies and not the SAE form is to be 
completed. If there is an SAE and/or AESI associated with the pregnancy, an SAE form must 
be completed in addition.
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS
5.3.1
Assessment of pharmacokinetics
For the assessment of pharmacokinetics, blood and urine samples will be collected at the time 
points / time intervals indicated in the Flow Chart. The actual sampling times will be 
recorded and used for determination of pharmacokinetic parameters. 

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5.3.2
Methods of sample collection
5.3.2.1
Blood sampling for pharmacokinetic analysis
For quantification of iclepertin, 
concentrations in plasma, 2.7 mL 
of blood 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 venipuncture with a metal needle.
The EDTA-anticoagulated blood samples should be centrifuged immediately for 
approximately 10 min at approximately 2000 x g to 4000 x g and 4 to 8 °C. If an immediate 
centrifugation is not feasible blood samples must be stored on ice until centrifugation. Interim 
storage on ice should not be longer than 30 min. Two plasma aliquots will be obtained and 
stored in polypropylene tubes. The aliquots should contain 0.5 mL of plasma. Before 
pipetting plasma into the PP tubes 10 µL (matches 2%) ortho-phosphoric acid (42.5%) must 
be added into the tubes. To obtain ortho-phosphoric acid (42.5%) solution, 1 ml ortho-
phosphoric acid (85%) will be added to 1 ml deionized water. The resulting ortho-phosphoric 
acid (42.5%) solution can be stored at approximately 4 to 8 °C. The process from blood 
collection until transfer of plasma aliquots into the freezer should be completed in less than 
60 min, with interim storage of blood samples and aliquots in ice water or on ice. 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 -80°C +/- 10°C 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 -80°C or below until analysis.
At a minimum, the sample tube labels should list BI trial number, subject number, visit, and 
planned sampling time. 
5.3.2.2
Urine sampling for pharmacokinetic analysis
A blank urine sample will be collected before administration of trial medication (ref. Flow 
Chart) and two 0.5 mL aliquots will be retained to check for analytical interference by 
concomitant or rescue medication.
All urine voided during the sampling intervals indicated in the Flow Chart will be collected in
3 L polyethylene (PE) containers and stored at room temperature or at 4 to 8 °C. Participants 
are told to empty their bladders at the end of each sampling interval. 
Due to the known adsorption of the drug (its metabolites) to the container wall, 0.5% of a 
10% Tween 20 solution will be added to each material prior to the start of urine sampling that 
urine contact first (3 L PE collection container, collections cup, or whatever). For example, 
15 ml of 10% Tween 20 solution to be added to a 3 L urine collection container. The weight 
of the empty container will be determined, 0.5% of 10% Tween 20 will be added, and the 
weight of the container at the end of each sampling interval will be determined. Two 0.5 mL 
aliquots will be stored in PP tubes for bioanalytical measurements. If more than one 
collection container is used in a sampling interval, the contents of all containers have to be 
mixed before aliquots are prepared. Mixing should be done by transferring the entire content

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of all collection containers into a single PE/PP or glass container, and stirring the mixed 
fractions for about 1 min (manually or using a stir bar or other stirring device made of PE, 
PP, Teflon, or glass). Generally, the collection container should be shaken upon addition of 
every urine fraction to ensure proper distribution of Tween and urine.
At a minimum, the sample tube labels should list BI trial number, subject number, visit, and 
planned collection time. 
Until transfer on dry ice to the analytical laboratory, the urine samples will be stored at
approximately -20°C +/- 5°C at the trial site. The second aliquot will be transferred after the 
bioanalyst has acknowledged safe arrival of the first aliquot. At the analytical laboratory, the 
urine samples will be stored at approximately -20°C or below until analysis.
After analysis, the urine samples may be used for further methodological investigations (e.g. 
for stability testing, assessment of metabolites) or to address Health Authority questions 
regarding the results/methodology. However, only data related to the analyte and/or its 
metabolite(s) will be generated by these additional investigations. The trial samples will be 
discarded after completion of the additional investigations but not later than 5 years after the 
CTR has been archived.
5.3.4
Pharmacokinetic - pharmacodynamic relationship
No analysis of the relationship between pharmacokinetic and pharmacodynamic parameters is 
planned for this trial.
5.4
ASSESSMENT OF BIOMARKERS 
Not applicable.
5.5
BIOBANKING
Not applicable.

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5.6
OTHER ASSESSMENTS
Not applicable. 
5.7
APPROPRIATENESS OF MEASUREMENTS
All measurements performed during this trial are standard measurements and will be 
performed in order to monitor participants’ safety and to determine pharmacokinetic 
parameters in an appropriate way. The scheduled measurements will allow monitoring of 
changes in vital signs, standard laboratory values, suicidality behaviour, and ECG parameters 
that might occur as a result of administration of trial medication. The safety assessments are 
standard, are accepted for evaluation of safety and tolerability of an orally administered drug, 
and are widely used in clinical trials. The PK parameters and measurements outlined in 
Section 5.3 are generally used assessments of drug exposure.

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6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
Exact times of measurements outside the permitted time windows will be documented. The 
acceptable time windows for screening and the end of trial examination are provided in the 
Flow Chart.
Study measurements and assessments scheduled to occur ‘before’ trial medication 
administration on Day 1 are to be performed and completed within a 2 h-period prior to the 
trial drug administration.
If not stated otherwise in the Flow Chart, the acceptable deviation from the scheduled time 
for vital signs, ECG, and laboratory tests will be ± 30 min during the inhouse period, and 
± 2 h for ambulatory visits.
If scheduled in the Flow Chart at the same time as a meal, blood sampling, vital signs, and 
12-lead ECG recordings have to be done first. Furthermore, if several measurements 
including venipuncture are scheduled for the same time, venipuncture should be the last of 
the procedures due to its inconvenience to the participant and possible influence on 
physiological parameters.
For planned blood sampling times and urine collection intervals, 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 PK parameters.
To allow for a streamlined operational conduct of trials at trial site, the following flexibility 
as regards time-windows for PK sampling times will be allowed: 

Predose: within 3 h prior to drug administration

Postdose:
-
From dosing until 2 h: ± 2 min; 
-
>2 h until 4 h: ± 5 min; 
-
>4 h until 72 h: ± 15 min; 
-
>72:00: ± 60 min
If a participant misses an appointment, it will be rescheduled if possible. The relevance of 
measurements outside the permitted time windows will be assessed no later than at the Report 
Planning Meeting.
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
6.2.1
Screening period
After having been informed about the trial, all participants will provide written informed 
consent in accordance with GCP and local legislation prior to enrolment in the trial.
For information regarding laboratory tests (including drug and virus screening), ECG, vital 
signs, suicidality assessment, and physical examination, refer to Sections 5.2.1 to 5.2.5.

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6.2.2
Treatment period
On Day -1 of the treatment period, trial participants will be admitted to the trial site. They 
will be kept under close medical surveillance for at least 48 h following drug administration. 
The participants will then be allowed to leave the trial site after formal assessment and 
confirmation of their fitness. On all other trial days, participants will come to the trial site for 
ambulatory visits.
For details on time points and procedures for collection of plasma and urine samples for PK 
analysis, refer to Flow Chart and Section 5.3.2.
The safety measurements performed during the treatment period are specified in Section 5.2
of this protocol and in the Flow Chart. AEs and concomitant therapy will be assessed 
continuously from obtaining participant’s written informed consent until the end of trial
examination.
For details on times of all other trial procedures, refer to the Flow Chart.
6.2.3
Follow-up period and trial completion
For AE assessment, laboratory tests, recording of ECG and vital signs, suicidality assessment, 
and physical examination during the follow-up period, see Section 5.2.
Participants who discontinue the trial prematurely should undergo the EoS Visit.
If needed in the opinion of the investigator, additional visits may be scheduled after the EoS
Visit for continued safety monitoring.
All abnormal values (including laboratory parameters) that are assessed as clinically relevant 
by the investigator will be monitored using the appropriate tests until a return to a medically 
acceptable level is achieved. (S)AEs persisting after a participant’s EoS 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
NULL AND ALTERNATIVE HYPOTHESES
To assess the effect of renal impairment on the PK of iclepertin, the relative bioavailability 
will be estimated by the ratios of the geometric means of the respective pairwise comparison 
of interest for the primary and secondary endpoints, i.e., for each renal impairment group vs. 
the respective control group. Additionally, their 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.
7.2
PLANNED ANALYSES
7.2.1
General considerations
7.2.1.1
Analysis sets
Statistical analyses will be based on the following analysis sets:

Treated set (TS): The treated set includes all participants who were treated with at 
least one dose of trial drug. The treated set will be used for safety analyses.
Pharmacokinetic parameter analysis set (PKS): This set includes all participants in the 
treated set (TS) who provide at least one PK endpoint that was defined as primary or 
secondary and that was not excluded due to a protocol deviation relevant to the 
evaluation of PK or due to PK non-evaluability (as specified in Section 7.2.1.2). Thus, 
a participant will be included in the PKS, even if he/she contributes only one PK 
parameter value to the statistical assessment. Descriptive and model-based analyses of 
PK parameters will be based on the PKS.
Descriptions of additional analysis sets may be provided in the TSAP.
Adherence to the protocol will be assessed by the trial team. Important protocol deviation 
(IPD) categories will be suggested in the IPD specification file. IPDs will be identified no 
later than in the Report Planning Meeting, and the IPD categories will be updated as needed.
7.2.1.2
Pharmacokinetics
The PK parameters listed in Section 2.1 and 2.2.2 for drug iclepertin, 
 
will be calculated according to the relevant BI internal procedures. 
Plasma and urine concentration data and parameters of a participant will be included in the 
statistical 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 participant’s data will be documented in the CTR.
Important protocol deviations may be

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
Incorrect dose of trial medication taken

Use of restricted medications
Plasma and urine concentrations and/or parameters of a participant will be considered as non-
evaluable, if for example

The participant experienced emesis that occurred at or before two times median tmax of 
the respective treatment (Median tmax is to be determined excluding the participants 
experiencing emesis), 

A predose concentration is >5% Cmax value of that participant

Missing samples/concentration data at important phases of PK disposition curve
Plasma/urine concentration data and parameters of a participant which are flagged for 
exclusion will be reported with its individual values but will not be included in the statistical 
analyses. 
Only concentration values within the validated concentration range and actual sampling times 
will be used for the calculation of pharmacokinetic parameters. Concentrations used in the 
pharmacokinetic calculations will be in the same format provided in the bioanalytical report, 
(that is, to the same number of decimal places provided in the bioanalytical report). 
7.2.2
Primary endpoint analyses
Primary analyses
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 
the effects accounting for ‘degree of renal impairment’ as a fixed effect as well as ’matched
pair’ as a random effect. The model is described by the following equation:
yik = + si + k + eik, where
yik = logarithm of response measured for the degree of renal impairment k, matched 
pair i, 
= the overall mean,
si = the effect associated with the ith matched pair (each renal impaired participant
with his/her own matched participant with normal renal function), i = 1, 2, ..., 8
k = the effect associated with the kth degree of renal impairment, k = 1 for normal 
renal function (control) and k=2, 3, 4 for mild, moderate, severe renal impaired
respectively,
eik = the random error associated with the kth degree of renal impairment for matched 
pair i.

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where s ~ N(0, σ
) i.i.d., e ~ N(0, σ
 ) i.i.d. and si, eik are independent random variables
(note that the indices ‘B’ and ‘W’ correspond to ‘between’ and ’within’ matched pair variability, 
respectively). The model described above will be fitted separately for the three renal impaired 
groups, i.e., one model for the participants with mild renal impairment and their matched 
controls, one model for the participants with moderate renal impairment and their matched 
controls and one model for the participants with mild renal impairment and their matched 
controls.
For the evaluation of each primary endpoint, the difference between the expected mean for 
log response of renal impaired group k (k=2, 3, 4) – log response of normal control group 
(k=1) will be estimated will be estimated by the difference in the corresponding adjusted 
means (Least Squares Means). Additionally their two-sided 90% CIs 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.
Further exploratory analyses
In addition to the model based approach all parameters will be calculated and analysed 
descriptively.
7.2.3
Secondary endpoint analyses
The secondary endpoint (refer to Section 2.1.3) will be calculated according to the relevant 
BI internal procedures and will be assessed statistically using the same methods as described 
for the primary endpoints.
7.2.5
Safety analyses 
Safety will be analysed based on the assessments described in Section 2.2.2.2. All treated 
participants (TS, refer to Section 7.2) will be included in the safety analysis. Safety analyses 
will be descriptive in nature and based on BI standards. No hypothesis testing is planned.
Groups will be compared in a descriptive way. Tabulations of frequencies/proportions will be 
used to evaluate categorical (qualitative) data, and tabulations of descriptive statistics will be 
used to analyse continuous (quantitative) data.
Measurements (such as vital signs, or laboratory parameters) or AEs will be assigned to 
treatments (see Section 4.1) based on the actual treatment at the time of the measurement or 
on the recorded time of AE onset (concept of treatment emergent AEs). Therefore, 
measurements performed or AEs recorded prior to first intake of trial medication will be 
assigned to the screening period, those between first trial medication intake and end of REP 
(see Section 1.2.2) will be assigned to the treatment period. Events occurring after the REP 
but prior to EoS examination date will be assigned to ’follow-up’. These assignments 

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including the corresponding time intervals will be defined in detail in the TSAP. Note that 
AEs occurring after the last per protocol contact but entered before database lock of the trial
will be reported to Pharmacovigilance only and will not be captured in the trial database.
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). Frequency, severity, and causal relationship of AEs will be tabulated by 
treatment, system organ class, and preferred term. SAEs, AESIs (see Section 5.2.6.1), and 
other significant AEs (according to ICH E3) will be listed separately. 
C-SSRS results will be reported in terms of AEs as described in Section 5.2.6.2 and will be 
summarized as such. Results of the C-SSRS will be provided as listing.
Previous and concomitant therapies will be presented per group without consideration of time 
intervals and treatment periods.
In general, unless otherwise specified in the TSAP, the last non-missing measurement prior to 
study treatment will be used as baseline for safety variables.
Laboratory data will be compared to their reference ranges. Values outside the reference 
range as well as possibly clinically significant values will be highlighted in the listings. 
Additionally, differences from baseline will be evaluated.
Vital signs or other safety-relevant data will be assessed with regard to possible on-treatment 
changes from baseline.
Relevant ECG findings will be reported as AEs.
7.2.6
Interim analyses
No interim analysis is planned.
A preliminary, exploratory analyses of all available or specific data (e.g. safety, PK) may be 
performed prior to final database lock to inform other activities during the development of 
iclepertin. In case of preliminary assessment of PK data, the PK parameters will be calculated 
according to the relevant BI internal procedure. In contrast to the final PK calculations, the 
preliminary analysis will be based on planned sampling times rather than on actual times, 
regardless of whether actual times were within the time windows. Therefore, minor 
deviations may occur between preliminary and final results. The possible preliminary PK 
analysis will provide individual and gMean concentration profiles and summary statistics of 
PK parameters per group. No inferential statistical preliminary analysis is planned.
7.3
HANDLING OF MISSING DATA
7.3.1
Safety
It is not planned to impute missing values for safety parameters.
7.3.2
Pharmacokinetics
Handling of missing PK data will be performed according to the relevant BI internal 
procedures.

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PK parameters that cannot be reasonably calculated based on the available drug 
concentration-time data will not be imputed.
7.4
RANDOMISATION
The trial will not be randomised, thus this section is not applicable.
7.5
DETERMINATION OF SAMPLE SIZE
It is planned to include a maximum of 48 participants in the trial: 8 participants with mild 
renal impairment, 8 participants with moderate renal impairment, 8 participants with 
severerenal impairment and up to 24 matched control participants with normal renal function 
will be treated. Note, one participant with normal renal function may match a participant in 
only one, two or in all three groups with renal impaired participants. The matching criteria 
are described in Section 3.1.
The planned sample size is not based on a power calculation but is considered as sufficient to 
detect major differences between the different groups of participants with renal impairment 
and the respective control group with participants with normal renal function .

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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 directive 
2001/20/EC and other relevant regulations. Investigators and site staff must adhere to these 
principles. Deviation from the protocol, the principles of ICH GCP or applicable regulations 
will be treated as ‘protocol deviation’.
Standard medical care (prophylactic, diagnostic, and therapeutic procedures) remains the 
responsibility of the participant’s treating physician.
The investigator will inform the sponsor immediately of any urgent safety measures taken to 
protect the trial participants against any immediate hazard, as well as of any serious breaches 
of the protocol or of ICH GCP.
The Boehringer Ingelheim transparency and publication policy can be found on the following 
web page: trials.boehringer-ingelheim.com. The rights of the investigator and of the sponsor 
with regard to publication of the results of this trial are described in the investigator contract. 
As a general rule, no trial results should be published prior to finalisation of the CTR.
The terms and conditions of the insurance coverage are made available to the investigator and 
the participants 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 participant’s participation in the trial, written informed consent must be obtained 
from each participant 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 participant-information form retained by the investigator 
as part of the trial records. A signed copy of the informed consent and any additional 
participant information must be given to each participant.
The participant must be given sufficient time to consider participation in the trial. The 
investigator or delegate obtains written consent of the participant’s own free will with the 
informed consent form after confirming that the participant understands the contents. The 
investigator or 
 delegate must sign (or place a seal on) and date the informed consent form. 
If a trial collaborator has given a supplementary explanation, the trial collaborator also signs 
(or places a seal on) and dates the informed consent.
Re-consenting may become necessary when new relevant information becomes available and 
should be conducted according to the sponsor’s instructions.

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

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For the CRF, data must be derived from source documents, for example:

Subject identification: gender, 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 subject
meets all inclusion criteria and does not meet any exclusion criteria. The absence of 
records (either medical records, verbal documented feedback of the subject or testing 
conducted specific for a protocol) to support inclusion/exclusion criteria does not 
make the subject eligible for the clinical trial.
8.3.2
Direct access to source data and documents
The investigator/institution will allow site trial-related monitoring, audits, IRB / IEC review 
and regulatory inspections. Direct access must be provided to the CRF and all source 
documents/data, including progress notes, copies of laboratory and medical test results, which 
must be available at all times for review by the Clinical Research Associate, auditor and 
regulatory inspector (e.g. FDA). They may review all CRFs and informed consents. The 
accuracy of the data will be verified by direct comparison with the source documents 
described in Section 8.3.1. The sponsor will also monitor compliance with the protocol and 
GCP.
8.3.3
Storage period of records
Trial site:
The trial site(s) must retain the source and essential documents (including ISF) according to 
contract or the local requirements valid at the time of the end of the trial (whatever is longer).
Sponsor:
The sponsor must retain the essential documents according to the sponsor’s SOPs.

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8.4
EXPEDITED REPORTING OF ADVERSE EVENTS
BI is responsible to fulfil their legal and regulatory reporting obligation in accordance with 
regulatory requirements.
8.5
STATEMENT OF CONFIDENTIALITY AND SUBJECT PRIVACY
Data protection and data security measures are implemented for the collection, storage and 
processing of subject data in accordance with the principles 7 and 12 of the WHO GCP 
handbook.
Individual subject data obtained as a result of this trial is considered confidential and 
disclosure to third parties is prohibited with the following exceptions: 
Personalised treatment data may be given to the subject’s personal physician or to other 
appropriate medical personnel responsible for the subject’s welfare. Data generated at the site 
as a result of the trial need to be available for inspection on request by the participating 
physicians, the sponsor’s representatives, by the IRB / IEC and the regulatory authorities.
8.5.1
Collection, storage and future use of biological samples and corresponding 
data
Measures are in place to comply with the applicable rules for the collection, storage and 
future use of biological samples and clinical data, in particular

Sample and data usage have to be in accordance with the informed consent

The BI-internal facilities storing biological samples from clinical trial participants as 
well as the external storage facility are qualified for the storage of biological samples 
collected in clinical trials.

An appropriate sample and data management system, incl. audit trail for clinical data 
and samples to identify and destroy such samples according to ICF is in place

A fit for the purpose documentation (e.g. biomarker proposal, analysis plan and 
report) ensures compliant usage

A fit for purpose approach will be used for assay/equipment validation depending on 
the intended use of the biomarker data

Samples and/or data may be transferred to third parties and other countries as 
specified in the ICF
8.6
TRIAL MILESTONES
The start of the trial is defined as the date when the first subject in the whole trial signs 
informed consent.
The end of the trial is defined as the date of the last visit of the last subject in the whole trial 
(‘Last Subject Completed’).
Early termination of the trial is defined as the premature termination of the trial due to any 
reason before the end of the trial as specified in this protocol.

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Temporary halt of the trial is defined as any unplanned interruption of the trial by the sponsor 
with the intention to resume it.
Suspension of the trial is defined as an interruption of the trial based on a Health Authority 
request.
The IEC / competent authority in each participating EU member state will be notified about 
the trial milestones according to the laws of each member state. 
A final report of the clinical trial data will be written only after all participants 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 participant
(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
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 (CT Leader), responsible for coordinating all 
required trial activities, in order to 

Manage the trial in accordance with applicable regulations and internal SOPs

Direct the clinical trial team in the preparation, conduct, and reporting of the trial

Ensure appropriate training and information of local Clinical Trial Managers
(CT Managers), Clinical Research Associates (CRAs), and investigators of 
participating trial sites
The trial medication will be provided by the 
Safety laboratory tests will be performed by the local laboratory of the trial site (
Analyses of iclepertin, 
concentrations in plasma and urine 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.

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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
R13-4447
Lane HY, Chang YC, Liu Y, Chiu CC, Tsai GE. Sarcosine or D-serine 
addon treatment for acute exacerbation of schizophrenia: A randomized, 
double-blind, placebo-controlled study. Arch Gen Psychiatry 2005. 
62:1196-1204.
R13-4450
Liem-Moolenaar, Peeters P, Kamerling C, et al. Early stage development 
of the glycine re-uptake inhibitor SCH 900435: central nervous system 
effects compared with placebo in healthy men: Br J Clin Pharmacol 2013; 
75(6):1455-1467.
R13-4451
Ouellet D, Sutherland S, Wang T, Griffini P, Murthy V. First-time-
inhuman study with GSK1018921, a selective GlyT1 inhibitor: 
Relationship between exposure and dizziness. Clin Pharmacol Ther 2011; 
90(4):597-604.
R13-4508
Martin-Facklam M, Patat A, Hofmann C, et al. Safety, tolerability and 
pharmacokinetics of RG1678, a novel glycine reuptake inhibitor, after
multiple doses in healthy volunteers. Schizophrenia Res 2012. 136(Suppl. 
1):S267.
R13-4518
Hu NW, Ondrejcak T, Rowan MJ. Glutamate receptors in preclinical 
research on Alzheimer's disease: Update on recent advances. Pharmacol 
Biochem Behav 2012. 100:855-862.
R13-4521
Lin CH, Lane HY, Tsai GE. Glutamate signaling in the pathophysiology 
and therapy of schizophrenia. Pharmacol Biochem Behav 2012. 100:665-
677.
R13-4524
Tsai G, Lane HY, Yang P, Chong MY, Lange N. Glycine transporter I
inhibitor, N-methylglycine (sarcosine), added to antipsychotics for the
treatment of schizophrenia. Biol Psychiatry 2004. 55(5):452-456.
R15-0595
Dunlop J, Brandon NJ. Schizophrenia drug discovery and development in 
an evolving era: are new drug targets fulfilling expectations? J 
Psychopharmacol 2015;29(2):230-238.
R15-1266
Umbricht D, Alberati D, Martin-Facklam M, et al. Effect of bitopertin, a 
glycine reuptake inhibitor, on negative symptoms of schizophrenia: a 
randomized, double-blind, proof-of-concept study. JAMA Psychiatry 
2014; 71(6):637-646.
R18-1054
Bugarski-Kirola D, Blaettler T, Arango C, et al. Bitopertin in negative 
symptoms of schizophrenia - results from the phase III FlashLyte and 
DayLyte studies. Biol Psychiatry 2017; 82(1):8-16.

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R22-3783
European Medicines Agency. Committee for Medicinal Products for 
Human use (CHMP): guideline on the evaluation of the pharmacokinetics 
of medicinal products in patients with decreased renal function (17 
December 2015, EMA/CHMP/83874/2014). 2015
R22-3784
Food and Drug Administration. Guidance for industry: pharmacokinetics 
in patients with impaired renal function - study design, data analysis, and 
impact on dosing: draft guidance (this guidance document is being 
distributed for comment purposes only.) (September 2020, clinical 
pharmacology, revision 2). 2020
R13-4387
Kidney Disease: Improving Global Outcomes (KDIGO) Blood Pressure 
Work Group. KDIGO 2012 clinical practice guideline for the evaluation 
and management of chronic kidney disease. Kidney Int Suppl; 2013
R12-1392
Levey AS, Stevens LA, Schmid CH, Zhang Y, Castro AF, Feldman HI, 
Kusek JW, Eggers P, Lente F van, Greene T, Coresh J, Chronic Kidney 
Disease Epidemiology Collaboration (CKD-EPI). A new equation to 
estimate glomerular filtration rate. Ann Intern Med; 2009
9.2
UNPUBLISHED REFERENCES
c02155957
Investigator`s Brochure BI 425809 Alzheimers Disease Cognitive 
Impairment Associated with Schizophrenia (CIAS). Current version.
c02820512
Safety, tolerability, and pharmacokinetics of single rising oral doses of BI 
425809 in healthy male subjects (partially randomised, single-blind, 
placebo-controlled) and investigation of relative bioavailability and food 
effect of BI 425809 (open-label, randomised, three-way crossover).1346.1.
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.
c03572014
Safety, tolerability, and pharmacokinetics of multiple rising doses of BI 
425809 tablets given orally once or twice daily for 12 days to young and 
elderly healthy male and female volunteers (randomised, double-blind, 
placebo-controlled within dose groups Phase I study) (Part 1) and 
comparison of pharmacokinetics of a single oral dose of BI 425809 after 
oral administration in the morning versus oral administration in the evening 
in young healthy male and female volunteers (randomised, two-sequence, 
open, two period, two-way cross over) (Part 2). 1346.2.
c03724403
Non-randomised, open label, sequential-group study to assess the 
pharmacokinetics and pharmacodynamic effect of different multiple oral 
doses of BI 425809 in healthy male volunteers. 1346.3

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c08949593
A study to investigate the effects of multiple doses of BI 425809 on the 
single dose pharmacokinetics of cytochrome P450 substrates (midazolam, 
warfarin and omeprazole) and a P-glycoprotein substrate (digoxin) 
administered orally in an open-label, one-sequence trial in healthy male 
subjects. 1346.22.
c18001523
Effects of rifampicin on the pharmacokinetics of BI 425809 following oral 
administration in healthy male subjects (an open-label, two-period, fixed 
sequence trial). 1346.18.
c26534937
Metabolism and pharmacokinetics of BI 425809 after administration of BI 
425809 (C-14) as oral solution in healthy male volunteers. 1346.16.
c30032912
A study to investigator the effects of memantine on the pharmacokinetics of
BI 425809 and vice versa in healthy male and female subjects 
(nonrandomised, single-arm, open-label, three-period, one fixed sequence
crossover study). 1346.39.
c31477880
A phase II randomized, double-blinded, placebo-controlled parallel group 
trial to examine the efficacy and safety of 4 oral doses of BI 425809 once 
daily over 12 week treatment period in patients with Schizophrenia. 1346.9.
n00237515
Excretion in urine, faeces and bile and pharmacokinetics of radioactivity in
plasma after oral and intravenous administration of [14C]BI 425809 to rats.
A083/14JS.
n00277070
BI 425809 metabolite profiling and tentative metabolite identification in 
human 1346-0016. 29 September 2021.
n00243611
Absorption, disposition and excretion of [14C]BI 425809 in male and 
female minipigs. BI 425809. 07-Jul-2015

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10.
APPENDICES
10.1
COLUMBIA-SUICIDE SEVERITY RATING SCALE

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10.2
LISTING RESTRICTED CONCOMITANT MEDICATION
10.2.1
Strong CYP3A4 inhibitors

boceprevir

ceritinib

clarithromycin

cobicistat

conivaptan

diltiazem

idelalisib 

indinavir

itraconazole

ketoconazole oral administration

LCL161

mifepristone

mibefradil

nefazodone

nelfinafir

posaconazole

ribociclib

ritonavir

saquinavir

telaprevir

telithromycin

troleandomycin

VIEKIRA PAK2

voriconazole
10.2.2
Combinations of CYP 3A4 inhibitors

danoprevir/ritonavir

elvitegravir/ritonavir

indinavir/ritonavir

lopinavir/ritonavir

paritaprevir/ritonavir/ombitasvir/dasbuvir

saquinavir/ritonavir

tipranavir/ritonavir

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10.3
CKD-EPI FORMULA
eGFR (mL/min/1.73m2) = 141 x min(SCr/κ, 1)α x max(SCr /κ, 1)-1.209 x 0.993Age
x 1.018 [if female] x 1.159 [if Black] 
SCr (standardized serum creatinine) = mg/dL 
κ = 0.7 (females) or 0.9 (males) 
α = -0.329 (females) or -0.411 (males) 
min = indicates the minimum of SCr/κ or 1 
max = indicates the maximum of SCr/κ or 1 
age = years 
See references [R12-1392, R13-4387].

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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
This is the original protocol.

 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c40079435
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clincial-trial-protocol-version-01
Pharmacokinetics, safety and tolerability of BI 425809 (iclepertin) following oral
administration in male and female participants with different degrees of renal
impairment (severe, moderate and mild) compared with matched male and female
participants with normal renal function (an open-label, non-randomised, single-dose,
parallel, individual-matched design trial)
Author-Clinical Trial Leader
23 Nov 2022 14:26 CET
Verification-Paper Signature
Completion
23 Nov 2022 15:16 CET
Approval-Clinical Program 
23 Nov 2022 23:42 CET
Author-Trial Statistician
24 Nov 2022 08:11 CET

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(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
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Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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