A Phase III Randomized, Double-blind, Placebo-controlled Parallel Group Trial to Examine the Efficacy and Safety of Iclepertin Once Daily Over 26 Week Treatment Period in Patients With Schizophrenia (CONNEX-3)
Phase: PHASE3
Conditions: Schizophrenia
Sponsor: Boehringer Ingelheim

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Clinical Trial Protocol
TITLE PAGE
Document Number:
c32699831-04
EudraCT No.
EU Trial No.
2020-003726-23
BI Trial No.
1346-0013
BI Investigational
Medicinal Product(s)
iclepertin
Title
A phase III randomized, double-blind, placebo-controlled parallel 
group trial to examine the efficacy and safety of iclepertin once 
daily over 26 week treatment period in patients with schizophrenia
(CONNEX-3)
Lay Title
Clinical trial of iclepertin effect on cognition and functional capacity 
in schizophrenia.
Clinical Phase
III
Clinical Trial Leader
Coordinating 
Investigator
Version and Date
Version: 4.0
Date: 18 Sep 2023
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2023 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
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CLINICAL TRIAL PROTOCOL SYNOPSIS
Company name
Boehringer Ingelheim 
Protocol date
25 Nov 2020
Revision date
18 Sep 2023
BI trial number
1346-0013
Title of trial
A phase III randomized, double-blind, placebo-controlled parallel 
group trial to examine the efficacy and safety of iclepertin once daily 
over 26-week treatment period in patients with schizophrenia
(CONNEX-3)
Coordinating 
Investigator
Trial site(s)
Multi-centre in approximately 14 countries
Clinical phase
III
Trial rationale
Cognitive impairment, a core feature of schizophrenia, has been shown 
to be a major determinant of poor functional outcome. Currently there 
is no pharmacological treatment available. Inhibition of GLYT1 by 
iclepertin may lead to improvement of cognition by improving
signalling via N-methyl-D-aspartate (NMDA) receptors. Proof of 
clinical concept was demonstrated in the phase II, 12 week trial. This 
registration trial aims to confirm the efficacy, safety and tolerability of 
iclepertin in improving cognition and functioning in patients with 
schizophrenia treated over 6 months (26 weeks).
Trial objective(s)
The primary objective is to assess the efficacy in improving cognitive 
impairment using the Measurement and Treatment Research to Improve 
Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery
(MCCB) in patients with schizophrenia treated for 26 weeks with 
iclepertin 10mg as compared to placebo.
The key secondary objective is to assess the efficacy in daily functioning 
using Schizophrenia Cognition Rating Scale (SCoRS) and Virtual 
Reality Functional Capacity Assessment Tool (VRFCAT) in patients 
with schizophrenia treated for 26-week treatment with iclepertin 10mg 
as compared to placebo.

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The other secondary objectives are to assess the efficacy in improving 
reasoning and problem solving and patients’ experience of cognitive 
impairment associated with their disease. 
Patients will be required to be on stable antipsychotic treatment at the 
time of inclusion.
The primary treatment effect of interest is defined in the primary 
estimand framework as specified in detail in Section 7. All efforts will 
be taken to continue to collect efficacy data at planned visits after 
patients discontinued trial treatment following an intercurrent event. 
For patients who discontinued trial treatment after intercurrent events 
that will be handled by the treatment policy approach, these observed 
off-treatment data will be included in the primary analysis. For patients 
who discontinued trial treatment after other intercurrent events that will 
not be handled by the treatment policy approach, these observed off-
treatment data will be censored and excluded from the primary 
analysis.
In summary, the primary treatment effect of interest is the effect 
obtained at the primary time point if patients had stayed on the 
treatment, i.e. taking the trial medication for the full treatment duration 
while allowing the following intercurrent events: change in 
concomitant medications or background non-pharmacological therapy, 
change in study partner, and treatment interruption or discontinuation 
due to exacerbation, an acute episode, adverse events (AEs) that are 
considered drug related and protocol-defined drug withdrawal.
Trial endpoints
The primary endpoint include:

Change from baseline in overall composite T-score of the 
MCCB after 26 weeks of treatment.
The key secondary efficacy endpoints include: 

Change from baseline in the SCoRS interviewer total score 
after 26 weeks of treatment.

Change from baseline to Week 26 in the adjusted total time T-
score in VRFCAT
The secondary efficacy endpoints include: 

Change from baseline to week 26 in the T-score of number of 
correct responses on Tower of London (ToL).

Change in Patient Reported Experience of Cognitive Impairment 
in Schizophrenia (PRECIS) total score from screening visit 1a to 
Week 24
Trial design
A 26-week, multi-center, multi-national, randomized, double-blind, 
placebo controlled, parallel group trial.

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Total number of patients
randomised
586
Number of patients on 
each treatment
293
Diagnosis
Clinically stable outpatients with established diagnosis of 
Schizophrenia.
Main in- and exclusion 
criteria
Main Inclusion:

Male or female patients who are 18-50 years (inclusive) of age 
at time of consent.

Diagnosis of schizophrenia utilizing Diagnostic and statistical 
manual of mental disorders, fifth edition (DSM-5) with the 
following clinical features:
o
Outpatient, clinically stable and in the residual (non-
acute) phase of their illness.
o
No hospitalization1 or increase in level of psychiatric 
care2 due to worsening of schizophrenia within 12 weeks
prior to randomization. 
o
PANSS score: items P1, P3-P6 ≤ 5 and item P2 and P7 ≤ 
4 at Visit 1, and confirmed at Visit 2.

Patients should have functional impairment in day-to-day 
activities such as difficulties following conversation or 
expressing themselves, difficulties staying focused, difficulties 
remembering instructions, what to say or how to get to places, 
per investigator judgement.

Patients maintained on current antipsychotic treatment 
(minimum 1 and maximum 2 antipsychotics, but clozapine is not 
allowed) for at least 12 weeks and on current dose for at least 35 
days prior to randomization. 

Patients with any other concomitant psychoactive medications 
(except for anticholinergics) need to be maintained on same drug 
for at least 12 weeks and on current dose/ regimen for at least 35 
days prior to randomization. 

Have a study partner, defined as any person who knows the 
patient well, who has been capable of interacting with the patient 
on a regular basis, preferably consistent throughout the study, 
either private or professional.
1 This includes home hospitalization for exacerbation in countries where it applies, 
however NOT hospitalization for social management and/or day programs.
2 This includes home hospitalization, partial (day-time) hospitalization, or ER visits.

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Main Exclusion:

Participant with current DSM-5 diagnosis other than 
Schizophrenia, 
including 
but 
not 
limited 
to 
bipolar, 
schizoaffective, major depressive disorder etc. M.I.N.I. for
psychotic disorders should be used for guidance.

Cognitive impairment due to developmental, neurological (e.g., 
epilepsy, stroke) or other disorders including head trauma, or 
patients with dementia.

Any suicidal behavior in the past 1-year prior to screening and 
during the screening period.

Suicidal ideation of type 5 in the C-SSRS in the past 3 months 
prior to screening and up to and including Visit 2. 

Patients with Suicidal Ideation type 4 in the C-SSRS (i.e. active 
suicidal thought with intent but without specific plan), within 3 
months prior to screening and up to and including Visit 2, can be 
randomized in the study, if assessed and documented by a 
licensed mental health professional that there is no immediate 
risk of suicide.

Haemoglobin (Hb) below lower limit of normal at Visit 1
assessed by the central lab. 
Test product(s)
iclepertin
dose
10 mg q.d.
mode of 
administration
Oral (p.o.)
Comparator product(s)
Matching placebo
dose
Not applicable
mode of
administration
Tablet, p.o.
Duration of treatment
26 weeks
Statistical methods
Restricted maximum likelihood (REML) based approach using a mixed 
effects model with repeated measures (MMRM) will be utilized as the 
main estimator of the primary estimand on the primary endpoint. 
Intercurrent events will be handled as specified in Section 7 and 
missing data as a result from this mixed strategy will be handled via 
MMRM. This MMRM model will include fixed categorical effects of 
treatment at each visit, a stratification factor of screening MCCB 
overall composite T-score (<30, ≥30), and the fixed continuous 
covariate of baseline MCCB overall composite T-score at each visit. 
Subject is treated as random effect, and visit will be treated as repeated 
measure. The primary treatment comparisons will be the contrast 
between iclepertin 10mg QD vs. placebo at Week 26.

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Sensitivity analyses for the primary estimand and analyses based on 
supplementary estimands are planned to assess the robustness of the 
results from the primary estimand analysis and the details are provided 
in Section 7.2.2.
The testing strategy will follow a gatekeeping procedure defining three 
families of endpoints/comparisons. Testing for the families of 
endpoints are illustrated in Section 7.1. 

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FLOW CHART
Trial Periods and 
Procedures
Screening Period 2
Randomized Treatment Period
Safety Follow up Period11
Visit
1
1a
2
3
4
5
6
7
8
9
10
EOT11/ 
1112
eEoT13
F111
F2
Weeks
Screening
0
3
6
9
12
15
18
21
24
26
Within 7 
days of IMP 
discontinuat
ion
EoT/ eEOT 
+14
EoT/ eEoT 
+28
Days from first 
randomized 
treatment
-35 to 0
1
22
43
64
85
106
127
148
169
183
Visit time window 
(days)
-35 to -28
-14 to -7
N/A
±3
±3
±3
±3
±3
±3
±3
±3
±3
+3 days
+7 days
Informed consents1
X
Demographics
X
Medical History
X
Height
X
Physical examination
X
X
X
X
X
X
(X)
Weight
X
X
X
X
X
X
(X)
(X)
Vital signs
X
X
X
X
X
X
(X)
(X)
12-lead ECG
X
X
X
X
X
X
(X)
Drug screen test 
(urine)3
X
(X)
X
X
X
X
X
X
Pregnancy test4
X
X
X
X
X
X
X
X
X
Safety Laboratory 
tests3
X
X
X
X
X
X10
X
X
X
X
PK Sampling5
X
X
X
X
X
X
Biobanking sample 
(optional) 6
X
X
X
Speech sample
(optional)
X
X
X
M.I.N.I.
X
X8
In-/exclusion criteria
X
X
Randomization
X
AiCure training17
X
X
X
AiCure review
X
X
X
X
X
X
X
X
X
X
X
X
Contact IRT
X
X
X
X
X
X
X
X
X
X
X
X
X
Duplication check
X
(re)Dispense & 
administer trial drug at 
site
X9
X
X
X
X
X
X
X
X
IMP Compliance 
check
X
X
X
X
X
X
X
X
X
X
Termination of trial 
drug
X
X
MCCB
X
X
X
X
X
VRFCAT
X
X
X
X
X
PCRS/SCoRS18
X
X
X
X
X
Tower of London
(ToL)
X
X
X
X
CGI-C
X
X
CGI-S
X
X
X
X
X
X
PRECIS
X
X
X
X
SDS (Sheehan)
X
X
X
PGI-C
X
X
PGI-S
X
X
X
X
X
EQ-5D-5L (patient)
X
X
X
X
EQ-5D-5L (study 
partners who are 
caregivers)
X
X
X
SPGI-C
X
X
SPGI-S
X
X
X

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Trial Periods and 
Procedures
Screening Period 2
Randomized Treatment Period
Safety Follow up Period11
Visit
1
1a
2
3
4
5
6
7
8
9
10
EOT11/ 
1112
eEoT13
F111
F2
Weeks
Screening
0
3
6
9
12
15
18
21
24
26
Within 7 
days of IMP 
discontinuat
ion
EoT/ eEOT 
+14
EoT/ eEoT 
+28
Days from first 
randomized 
treatment
-35 to 0
1
22
43
64
85
106
127
148
169
183
Visit time window 
(days)
-35 to -28
-14 to -7
N/A
±3
±3
±3
±3
±3
±3
±3
±3
±3
+3 days
+7 days
SCQ (study partners
who are caregivers)
X
X
X
Adverse events15, 16
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
HCRU
X
X
X
X
X
X
X
X
X
X
X
X
X
Socioeconomic status
X
X
X
Concomitant therapy
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Substance use19
X
X
X
X
E
C-SSRS20
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
SAS/AIMS/BARS
X
X
X
X
X
X
PANSS18
X
X
X
X
X
Patient Participation 
Completion in 
parental trial
X11
X11
X14
Duration in Hr(~)7
6.5
2.5
7.5
1.5
1.5
3.0
5.
0
1.0
3.0
1.0
2.0
8.0
9.0
1.0
2.0
Footnotes:
(X) optional assessments at discretion of investigator
1 For each patient, the main trial and study partner consents must be obtained. Optional consents include 
biobanking and speech analysis.
2 The screening period may take up to 35 days with 2 visits. At the second screening visit, urine drug screen 
may be repeated at discretion of investigators (X) if needed. 
3 Safety lab and/ or drug screen test (urine), may be performed more frequently based on investigator discretion 
or if required locally.
4 Pregnancy tests are required for women of child-bearing potential only and may be performed more frequently 
based on investigator discretion or if required locally. If urine (dipstick) pregnancy test is positive, a serum test 
is required.
5 PK pre-dose/ trough sample collection within 30 minutes before IMP dosing. Note: No IMP dosing is 
applicable to EOT or eEOT vist. PK sample should be taken approximately 24 hours post last dose at the EOT. 
PK sample should be taken as applicable at the eEOT.. For further details please refer to Section 5.3 and 
Appendix 10.1.
6 One sample for DNA biobanking will be taken, preferably at Visit 2. However, collection at a later visit is 
permitted as long as the informed consent for biobanking remains valid. Sample for Plasma and Serum 
banking purposes will be taken at V2 before first IMP intake and again at (e)EOT. 
7 Duration of assessments and visits indicated in this Flow chart are approximate estimates, actual time may 
vary as per site and patient requirements.
8 At visit 2, the MINI does not need to be repeated however the results from visit 1 should be confirmed and 
documented in the source documents.
9 All Baseline assessments must be completed prior to IMP intake at visit 2.
10 Haematology panel A and B only.
11 Patients who finish the 26 weeks of treatment period in this study, can rollover to the extension trial either 
after completing the EOT visit (preferred option) or within 2 weeks of EOT (i.e. at scheduled FU1 including 
vitis window).
12 Visit 11 will be performed only by patients who discontinue early from trial drug but agree to attend further 
visits according to protocol.

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13 In case patient discontinues earlier than 26 weeks, conduct (e)EOT and follow up with the patient as described 
in Section 6.2.5
14 Completion of patient participation who do not consent to extension study and have completed 26 weeks of 
treatment period.
15For adverse events that suggest potential study medication abuse refer to Section 5.2.6.5 and after the patient 
stops taking the study medication, refer to Section 5.2.6.6. for monitoring of withdrawal adverse events.
16For patient not rolling over to extension study, after the individual patient’s end o2.2f the trial the investigator 
should report only any cancers of new histology and exacerbations of existing cancer, trial treatment related 
SAEs and trial treatment related AESIs of which the investigator may become aware of and only via the BI 
SAE form, please see Section 5.2.6.2.1.
17AiCure training may be repeated as often as deemed necessary.
18 Study partner must complete the SCoRS and PANSS interviews at least at Visit 2 and EOT (please refer to 
inclusion criterion #8).
19 Details on alcohol, nicotine and caffeine use will be collected.  
20 Additional collection of the C-SSRS at an unscheduled visit may be done based on the investigator’s 
discretion.  

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TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS .....................................................................2
FLOW CHART........................................................................................................................7
TABLE OF CONTENTS ......................................................................................................10
ABBREVIATIONS................................................................................................................14
1.
INTRODUCTION...............................................................................................18
1.1
MEDICAL BACKGROUND.............................................................................18
1.2
DRUG PROFILE................................................................................................19
1.2.1
Mode of action.....................................................................................................19
1.2.2
Residual Effect Period ........................................................................................19
1.2.3
Data from non-clinical and toxicology studies .................................................19
1.2.4
Clinical Pharmacology........................................................................................20
1.2.5
Data from clinical studies...................................................................................20
1.2.6
Summary..............................................................................................................21
1.3
RATIONALE FOR PERFORMING THE TRIAL.........................................21
1.4
BENEFIT - RISK ASSESSMENT.....................................................................22
1.4.1
Benefits.................................................................................................................22
1.4.2
Risks .....................................................................................................................23
1.4.3
Discussion.............................................................................................................31
2.
TRIAL OBJECTIVES AND ENDPOINTS......................................................33
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS........33
2.1.1
Main objectives....................................................................................................33
2.1.2
Primary endpoint(s)............................................................................................33
2.1.3
Secondary endpoint(s) ........................................................................................34
2.2.2.2
Further safety endpoints ....................................................................................35
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.........................36
3.1
OVERALL TRIAL DESIGN.............................................................................36
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)......................................................................................37
3.3
SELECTION OF TRIAL POPULATION .......................................................37
3.3.1
Main diagnosis for trial entry ............................................................................39
3.3.2
Inclusion criteria .................................................................................................40

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3.3.3
Exclusion criteria ................................................................................................42
3.3.4
Withdrawal of patients from treatment or assessments..................................44
3.3.4.1
Temporary Trial Treatment Discontinuation:.................................................45
3.3.4.2
Permanent Discontinuation of Trial Treatment ..............................................45
3.3.4.3
Withdrawal of consent to trial participation .........................................................46
3.3.4.4
Discontinuation of the trial by the sponsor...........................................................47
4.
TREATMENTS...................................................................................................48
4.1
INVESTIGATIONAL TREATMENTS ...........................................................48
4.1.1
Identity of the Investigational Medicinal Products..........................................48
4.1.2
Selection of doses in the trial and dose modifications......................................49
4.1.3
Method of assigning patients to treatment groups...........................................49
4.1.4
Drug assignment and administration of doses for each patient......................49
4.1.5
Blinding and procedures for unblinding...........................................................50
4.1.5.1
Blinding.................................................................................................................50
4.1.5.2
Unblinding and breaking the code ........................................................................51
4.1.6
Packaging, labelling, and re-supply...................................................................51
4.1.7
Drug accountability.............................................................................................51
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, RESTRICTIONS
...............................................................................................................................52
4.2.1
Other treatments and emergency procedures..................................................52
4.2.2
Restrictions ..........................................................................................................53
4.2.2.1
Restrictions regarding concomitant treatment ......................................................53
4.2.2.2
Restrictions on diet and lifestyle...........................................................................54
4.2.2.3
Contraception requirements..................................................................................54
4.3
TREATMENT COMPLIANCE........................................................................55
5.
ASSESSMENTS..................................................................................................56
5.1
ASSESSMENT OF EFFICACY........................................................................56
5.2
ASSESSMENT OF SAFETY.............................................................................61
5.2.1
Physical examination ..........................................................................................63
5.2.2
Vital signs.............................................................................................................63
5.2.3
Safety laboratory parameters ............................................................................63
5.2.4
Electrocardiogram ..............................................................................................66
5.2.5
Other safety parameters.....................................................................................66
5.2.6
Assessment of adverse events.............................................................................67
5.2.6.1
Definitions of AEs................................................................................................67
5.2.6.2
Adverse event collection and reporting ................................................................70
5.2.6.3
Ocular AEs...........................................................................................................72
5.2.6.4
Haemoglobin and Anaemia................................................................................72
5.2.6.5
AE for assessment of potential abuse liability..................................................73
5.2.6.6
Monitoring of adverse events after stopping of study medication........................73
5.2.6.7
Pregnancy..............................................................................................................73

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5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS...................................................................................74
5.3.1
Assessment of pharmacokinetics .......................................................................74
5.4
ASSESSMENT OF BIOMARKER(S) ..............................................................74
5.5
BIOBANKING ....................................................................................................75
5.5.1
Methods and timing of sample collection..........................................................75
5.6
OTHER ASSESSMENTS...................................................................................75
5.6.1
Speech sample collection ....................................................................................75
5.6.2
Medication Adherence and Reminder System.................................................76
5.6.3
Verification of current and past research study status with Verified Clinical 
Trials ....................................................................................................................77
5.7
APPROPRIATENESS OF MEASUREMENTS..............................................77
6.
INVESTIGATIONAL PLAN.............................................................................78
6.1
VISIT SCHEDULE.............................................................................................78
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS .................78
6.2.1
General requirements.........................................................................................78
6.2.2
Screening period..................................................................................................80
6.2.3
Treatment period(s)............................................................................................81
6.2.3.1
Randomization (Visit 2)......................................................................................81
6.2.3.2
Visit 3 to Visit 10 .................................................................................................82
6.2.3.3
End of Treatment (EoT) Visit - For Treatment completers............................83
6.2.4
Follow up of Treatment completers ..................................................................83
6.2.4.1
Trial completers rolling-over to the extension trial.........................................83
6.2.4.2
Treatment completer not rolling over to extension: ........................................84
6.2.5
Early Permanent Treatment Discontinuation and further follow up............84
6.2.5.1
Early Permanent Discontinuation from Treatment ........................................84
6.2.5.2
Safety Follow up: Patients who prematurely discontinue treatment ...................86
7.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE87
7.1
NULL AND ALTERNATIVE HYPOTHESES ...............................................88
7.2
PLANNED ANALYSES.....................................................................................90
7.2.1
General considerations .......................................................................................90
7.2.2
Primary endpoint analyses.................................................................................91
7.2.3
Secondary endpoint analyses .............................................................................93
7.2.5
Safety analyses.....................................................................................................94
7.2.7
Interim Analyses .................................................................................................95
7.3
HANDLING OF MISSING DATA ...................................................................95
7.4
RANDOMISATION ...........................................................................................97
7.5
DETERMINATION OF SAMPLE SIZE .........................................................97

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8.
INFORMED CONSENT, TRIAL RECORDS, DATA PROTECTION, 
PUBLICATION POLICY, AND ADMINISTRATIVE STRUCTURE ......102
8.1
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED CONSENT
.............................................................................................................................102
8.2
DATA QUALITY ASSURANCE ....................................................................103
8.3
RECORDS.........................................................................................................103
8.3.1
Source documents .............................................................................................103
8.3.2
Direct access to source data and documents...................................................104
8.3.3
Storage period of records .................................................................................105
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS ................................105
8.5
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY......105
8.5.1
Collection, storage and future use of biological samples and corresponding data
.............................................................................................................................105
8.6
TRIAL MILESTONES.....................................................................................106
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL .................................106
9.
REFERENCES..................................................................................................108
9.1
PUBLISHED REFERENCES..........................................................................108
9.2
UNPUBLISHED REFERENCES....................................................................113
10.
APPENDICES...................................................................................................114
10.2
DEFINITION OF STUDY PARTNER AND CAREGIVER........................115
10.3
POTENTIAL MODIFICATION OF TRIAL CONDUCT IN CASE OF 
RESTRICTIONS DUE TO COVID-19 OR OTHER EXCEPTIONAL 
CIRCUMSTANCES .........................................................................................116
11.
DESCRIPTION OF GLOBAL AMENDMENT(S) .......................................119
11.1
GLOBAL AMENDMENT 1 ............................................................................119
11.2
GLOBAL AMENDMENT 2 ............................................................................120
11.3
GLOBAL AMENDMENT 3 ............................................................................126

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ABBREVIATIONS
AE
Adverse Event
AESI
Adverse Event of Special Interest
AIMS
Abnormal Involuntary Movement Scale
ALT
Alanine aminotransferase
APP
Application
AST
Aspartate aminotransferase
BARS
Barnes Akathisia Rating Scale
BI 
Boehringer Ingelheim
BP
Blood pressure
BUN
Blood urea nitrogen
CA
Competent authority
CGI-S
Clinical Global Impression of Severity
CGI-C
Clinical Global Impression of Change
CIAS
Cognitive Impairment Associated with Schizophrenia
CK
Creatine Kinase
CNS
Central Nervous System
COVID-19
Corona Virus Disease -19
CRF
Case Report Form
CRO
Contract Research Organisation
CSF
Cerebrospinal Fluid
C-SSRS
Columbia Suicide Severity Rating Scale
CTL
Clinical Trial Leader
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
CRT
Cognitive Remediation Therapy
CYP
Cytochrome P450
DDI
Drug Drug interaction

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DILI
Drug Induced Liver Injury
dL
deciliter
DMC
Data Monitoring Committee
DNA
Deoxyribonucleic Acid
DSM - 5
Diagnostic and Statistical Manual of Mental Disorders 5th Edition
EC
Ethics committee
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
ECT
Electroconvulsive Therapy
(e) EOT
(early) End of Treatment
EPS
Extrapyramidal symptoms
EQ-5D-5L
EuroQol-5Dimensions-5Levels
EQ- 5D-VAS
EuroQol-5Dimensions Visual Analogue Scale
EudraCT
European Clinical Trials Database
FAS
Full Analysis Set
FC
Flow Chart
FDA
Food and Drug Administration
GCP
Good Clinical Practice
eGFR
Estimated glomerular filtration rate
GLYT 1
Glycine Transporter 1
HAP
Human abuse potential
Hb
Haemoglobin
HIV
Human Immunodeficiency Virus
HCRU
Health Care Resource Utilization
IB
Investigator’s Brochure
ICH
International Conference on Harmonization
IRT
Interactive Response Technology
ISF
Investigator Site File
LAI
Long acting injectable (antipsychotics)
MATRICS
Measurement and Treatment Research to Improve Cognition in 
Schizophrenia

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MCCB
MATRICS consensus cognitive battery
MCH
Mean corpuscular haemoglobin
MCHC
Mean corpuscular haemoglobin concentration
MCV
Mean corpuscular volume
MedDRA
Medical Dictionary for Drug Regulatory Activities
M.I.N.I
Mini International Neuropsychiatric Interview
MMRM
Mixed effects Model Repeated Measures
NMDA
N-methyl-D-aspartate
NMDA-R
N-methyl-D-aspartate receptor
NOAEL
No-observed adverse-effect level
NTI
Narrow therapeutic index
OPU
Operative unit
PANSS
Positive and Negative Syndrome Scale
PCP
Phencyclidine
PCRS
Placebo Control Reminder Script
PGI - C
Patient Global Impression of Change
PGI- S
Patient Global Impression of Severity
PI
Principal Investigator
PK
Pharmacokinetics
p.o.
per os (oral)
PoCC
Proof of Clinical Concept
PR
Pulse rate
PRECIS
Patient Reported Experience of Cognitive Impairment in Schizophrenia
q.d.
quaque die (once a day)
REML
Restricted maximum likelihood
REP
Residual effect period, after the last dose of medication with measureable 
drug levels or pharmacodynamic effects still likely to be present
SAE
Serious Adverse Event
SAS
Simpson Angus Scale
SCoRS
Schizophrenia Cognition Rating Scale
SCQ
Schizophrenia Caregiver Questionnaire

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SDS
Sheehan Disability Scale
SoC
Standard of Care
SOC
System Organ Class
SOP
Standard Operating Procedure
SPGI-C
Study Partner Global Impression of Change
SPGI-S
Study Partner Global Impression of Severity
TMS
Transcranial Magnetic Stimulation
ToL
Tower of London
TSAP
Trial Statistical Analysis Plan
TSH
Thyroid stimulating hormone
VRFCAT
Virtual Reality Functional Capacity Assessment Tool
WHO
World health organization
WoCBP
Women of child-bearing Potential

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1.
INTRODUCTION
1.1
MEDICAL BACKGROUND
Schizophrenia is a serious and chronic mental illness leading to poor quality of life and disability. 
It has a lifetime prevalence of approximately 1%, with almost equal distribution worldwide and 
slightly higher incidence in men than women. Schizophrenia is a heterogeneous syndrome
typically defined by three clusters of symptoms: positive symptoms, negative symptoms and 
cognitive impairments.
Cognitive impairments are a core feature of schizophrenia and a major determinant of poor 
functional outcome. Cognitive impairments in schizophrenia are severe [R10-5111], of at least 
one standard deviation below cognitive performance of community controls [R15-3853; R15-
3854], and comparable to moderate to severe traumatic brain injury [R15-3852]. Due to the 
typical onset of schizophrenia in early adulthood, the lack of a cure and long-term impairments 
in day-to-day, social and occupational functioning associated with the disease leads to enormous 
socioeconomic burden [R20-1422, R20-1423].
Schizophrenia is managed with pharmacological and non-pharmacological treatments. 
Antipsychotics are the primary medication for schizophrenia, with major effects on the reduction 
of ‘psychotic’ symptoms and prevention of relapses (maintenance) but demonstrate virtually no 
beneficial effects on cognition in schizophrenia [R15-5596; R15-5580; R18-1825]. 
Antipsychotics also adversely affect some aspects of cognitive function, such as processing 
speed [R15-5595]. Non-pharmacological treatments such as cognitive remediation therapy 
require specialised expertise and are therefore less widely used [R16-2165; R16-1363].
Data from several cross-sectional and longitudinal studies suggest that ameliorating cognitive
deficits can benefit a range of functional measures, which may have significant economic impact 
[R10-5108]. The potential to increase functional recovery is therefore a major unmet medical 
need and drives developing novel treatments for Cognitive Impairment Associated with 
Schizophrenia (CIAS). 
It has been long hypothesized that deficits in glutamatergic signaling plays a key role in 
neuropathology of schizophrenia, particularly negative and cognitive symptoms [R13-4521]. 
Various glutamatergic transmission-enhancing agents have been tested for the treatment of 
negative symptoms and/or cognitive impairments in patients with schizophrenia, and produced 
inconsistent results. Most of these studies were of a small sample size, making interpretation of 
data difficult [R15-5877; R15-5838; R15-5584; R15-5615; R15-5578; R15-5639; R13-4524; R13-
4448; R15-5616].
The majority of large, industry-sponsored studies testing various compounds in CIAS have failed 
to show proof-of concept. The exception was encenicline (nicotinic alpha 7 agonist), showing
improvement of cognition in patients with schizophrenia in Phase II [R16-2465], however these 

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promising results were not confirmed in Phase III. So far, no drug has been approved for the 
treatment of CIAS and iclepertin has the chance to be first medication for CIAS.
1.2
DRUG PROFILE
Iclepertin is a glycine transporter 1 (GLYT1) inhibitor under development for treatment of CIAS.
Iclepertin improved cognition in patients with schizophrenia in Phase II, achieving proof-of-
clinical-concept.
1.2.1
Mode of action
Iclepertin is a potent and selective inhibitor of the Glycine Transporter 1 (GLYT1) and as such, 
increases the concentration of the NMDA receptor co-activator glycine in the synaptic cleft. In 
vivo proof-of-mechanism (i.e. indirect target engagement in the brain) was demonstrated by a 
dose-dependent increase of glycine in Cerebrospinal Fluid (CSF), both in rats (U13-2547) and 
humans (c03724403).
Enhancing glutamatergic neurotransmission is believed to improve brain plasticity (also referred 
to as neuroplasticity) which is essential for learning and memory. Indeed, pre-clinical studies 
with iclepertin have demonstrated pro-cognitive properties in relevant animal models of learning 
and memory and Phase II results showed beneficial effect on cognition that is known to be 
impaired in patients with schizophrenia. It is therefore expected that treatment with iclepertin has
the potential to improve cognition that was impaired by the schizophrenia illness.
1.2.2
Residual Effect Period
The Residual Effect Period (REP) of iclepertin is defined as 12 days after the last dose of trial 
medication. This is the period after the last dose with measurable drug levels and/or 
pharmacodynamic effects still likely to be present.
1.2.3
Data from non-clinical and toxicology studies
In vivo target engagement in brain showed a dose-dependent increase of glycine in rat CSF, with 
a ~50% increase at CSF levels of iclepertin of ~1x GLYT1 IC50 (U13-2547). Exposure leading 
to this level of glycine increase is expected to produce clinical efficacy.
iclepertin has been tested in a comprehensive package of safety pharmacology, genetic 
toxicology, fertility and early embryonic development, embryo-foetal development, and repeat-
dose toxicology studies up to 39 weeks of dosing. Results of these studies support clinical trials 
in adults for chronic administration, including women of childbearing potential (WoCBP).
iclepertin has two major human metabolites, M530 (BI 758790) and M232 (BI 761036). These 
metabolites do not show any relevant activity on GlyT1 and GlyT2, nor against other off-targets 
tested, nor did they show any pharmacological or toxicological activity. 

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iclepertin is primarily metabolized by hepatic CYP3A4 and clinical drug-drug interaction (DDI) 
studies were conducted (see Section 1.2.4).
Human exposure to iclepertin up to the no-observed-adverse-effect level (NOAEL) exposure in 
the most sensitive species (minipig, maximum measured plasma concentration [Cmax] 1430 nM 
and area under the concentration-time curve [AUC0-24 h] 26500 nM·h) is considered safe. The 
10 mg dose to be tested in Phase III is below the no-observed adverse-effect level (NOAEL) with 
multiple exposures at 10 mg in humans 6-7x below the NOAEL. 
1.2.4
Clinical Pharmacology 
iclepertin has a half-life ranging from 37 to 59 h. Steady state is 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 single rising dose study 1346.1 (c02820512) at 25 mg dose the effect of a high calorie, high 
fat meal resulted in an increased exposure with fed/fasted ratio for Cmax 142% and for AUC0-tz
126%.The multiple rising dose study 1346.2 (c03572014) looked at the effect of a light meal, 
and the effect is much less pronounced. In phase II, patients were allowed to take iclepertin "with 
or without" food as no clinically relevant effect on exposure was expected. In Phase III 10mg 
iclepertin will also be administered with or without food as the expected increase of exposure is 
below the exposure already observed in previous trials, e.g. 1346-0009 (c31477880).
As the mechanism of action involves enhancement of brain plasticity (which is higher during day 
than during night), dosing should occur after waking up (i.e. preferably in the morning).
Pharmacokinetic parameters between young and elderly healthy subjects, and between Japanese,
Chinese and Caucasian subjects are comparable.
iclepertin crosses blood-brain barrier and the required 50% glycine increase in the CSF was 
observed after multiple dosing of 10 mg iclepertin. 
iclepertin is a sensitive substrate of CYP3A4, and co-administration of moderate to strong 
CYP3A4 inducers / inhibitors is not permitted, as this reduces / increases plasma concentrations 
of iclepertin. CYP3A4 sensitive drugs with narrow therapeutic index (NTI) are restricted during 
the treatment period. For CYP3A4 sensitive drugs without NTI investigators should assess if 
dose adjustments and/or monitoring of the underlying disease is clinically required for patients 
who are taking such drugs.List of prohibited medication is inserted in the ISF, although the 
impact on common comedication in this target population is minimal.Details can be found in 
Investigator Brochure that is updated and provided to sites at regular intervals.
1.2.5
Data from clinical studies
To date, iclepertin has been well tolerated and has demonstrated a good safety profile. A total of 
323 healthy subjects have received ≥1 dose of iclepertin. In addition, 339 patients with 
schizophrenia and 490 patients with Alzheimer’s disease have been treated with iclepertin for 12 
weeks. The most frequent AEs were related to the Central Nervous System (CNS), with 

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headaches the most common and more frequent in the active groups than in placebo groups. 
Dizziness, somnolence and gastrointestinal disorders, such as nausea and vomiting, were also 
among the AEs reported more frequently on iclepertin than placebo. 
Phase II trials of 12-week treatment duration in patients with schizophrenia and Alzheimer’s 
disease, like trials with other GLYT1 inhibitors such as bitopertin [R15-1266, R18-1054], 
detected an impact of iclepertin on haemoglobin (Hb) levels. There was a slight decrease in Hb
across the active treatment groups, compared to placebo. It should be however noted that 
majority of patients (over 90%) remained in the range of normal values.
There were no other clinically relevant findings in the clinical laboratory evaluation, 12-lead 
electrocardiogram (ECG), assessment of vital signs, or visual tests. No signal was observed for 
suicidal ideation or behaviour.
In the Phase II trial, 1346-0009, in patients with schizophrenia, proof of clinical concept (PoCC)
was demonstrated. Iclepertin improved cognition assessed as the change from baseline in MCCB 
(Measurement and Treatment Research to Improve Cognition in Schizophrenia [MATRICS] 
consensus cognitive battery) overall composite T-score after 12-week treatment (the primary 
endpoint). The largest improvements from baseline versus placebo were observed in the 10 and 
25 mg dose groups; the 25 mg dose did not appear to provide an additional benefit over the 10 
mg dose. Moreover, the 10 mg group showed most consistent efficacy across various analyses.
In the Phase II trial, 1346.23, in patients with mild to moderate AD, results showed no evidence 
for efficacy of iclepertin compared with placebo for the evaluated endpoints.
1.2.6
Summary
In summary, the non-clinical and clinical iclepertin data demonstrated an acceptable profile to 
support clinical trials in males and females, including WoCBP, for oral doses of 10 mg once a 
day, for chronic dosing, in patients with schizophrenia.
For a more detailed description of the iclepertin drug profile please refer to the current
Investigator’s Brochure (IB) (c02155957) which is included in the ISF.
1.3
RATIONALE FOR PERFORMING THE TRIAL
Cognitive impairment, a core feature of schizophrenia [R14-3766], has been shown to be a major 
determinant of poor functional outcome, especially in the areas of interpersonal functioning and 
educational/vocational performance [R15-0570, R15-0567, R18-1769, R18-1770, R18-1768]. 
Patients with schizophrenia perform significantly worse than controls on almost all 
neuropsychological tests [R15-0568]. While many neuropsychiatric disorders are associated with 
some degree of cognitive dysfunction, the impairments seen in schizophrenia tend to be severe, 
leading to functional disability for life. Unfortunately there is no pharmacological treatment 
available.

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iclepertin is a glycine transporter (GLYT1) inhibitor. Inhibition of GLYT1 increases the 
concentration of the NMDA receptor co-activator glycine in the synaptic cleft thus allowing for 
improved signalling via NMDA receptors, which may lead to improvement of cognitive 
symptoms in patients with schizophrenia.
The efficacy and safety of iclepertin has been investigated in patients with cognitive impairment
due to schizophrenia in a trial of up to 12 weeks of treatment duration. In the Phase II trial 1346-
0009, a total of 339 patients were exposed to iclepertin at doses of 2 mg, 5 mg, 10 mg, and 25 
mg qd. The PoCC was demonstrated for the primary endpoint of change from baseline in MCCB 
overall composite T-score after 12-week treatment.
Regulatory guidance requires proven efficacy and acceptable safety of potential pro-cognitive 
compounds to be demonstrated over at least 6 months. Therefore, the rationale of this registration 
trial is to confirm the efficacy, safety, and tolerability of iclepertin in improving cognition and 
functioning in patients with schizophrenia, when administered for 6 months (26 weeks)in 
combination with standard-of-care therapy for schizophrenia.
In order to be able to address future scientific questions, patients will be asked to voluntarily 
donate biospecimens for banking (please see section 5.5). If the patient agrees, banked samples 
may be used for future biomarker research and drug development projects, e.g. to identify 
patients that are more likely to benefit from a treatment or experience an adverse event (AE), or 
to gain a mechanistic or genetic understanding of drug effects and thereby better match patients 
with therapies. As part of this research program, speech sample collection will be done in order 
to address future scientific questions as described in section 5.6.1.
A separate ocular substudy in selected countries will be conducted. These procedures will be 
described in detail and implemented via local amendments in the country(ies) planned to 
participate in this sub-study.
1.4
BENEFIT - RISK ASSESSMENT
1.4.1
Benefits
Based on non-clinical data, clinical data from other compounds in the same class, healthy 
subjects exposed in Phase I trials, and patients treated in Phase II trials, iclepertin is generally 
considered to be safe and well tolerated.
In addition, all randomized subjects will be on maintenance treatment with antipsychotic and 
other psychotropic medications. New concomitant medications may be prescribed as necessary 
to ensure the welfare of the subject.

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Although this is an experimental drug and an individual benefit cannot be guaranteed, PoCC Phase 
II trial demonstrated efficacy on cognition as assessed using MCCB overall composite T-score in 
patients with schizophrenia.
So far the acquired clinical data suggest that iclepertin improves cognition and this improved 
cognition should lead to functional improvement in day-to-day activities. Patients with functional 
impairment in day-to-day activities such as difficulties following conversation or expressing 
themselves, with difficulties to stay focused, difficulties to remember instructions, what to say or 
how to get to places, could potentially benefit from treatment with iclepertin .
Patients who complete 26 weeks of treatment in this protocol, will be offered the opportunity to 
participate in a long term safety extension study with iclepertin 10 mg.
1.4.2
Risks
The overall safety profile of iclepertin is outlined in the current IB (c02155957).
In the Phase II trial 1346-0009, no dose dependency was observed for the overall number of 
AEs. The frequency of patients with SAEs was low and was comparable across all treatment 
groups. The frequency of patients with AEs leading to discontinuation of trial medication was 
also low. There were no deaths.

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Table 1.4.2:1 Overview over trial related risks 
Possible/ known 
risks of clinical 
relevance for 
this trial
Summary of data, rationale 
for the risk
Mitigation strategy
Investigational Medicinal Product 
The most 
frequent AEs 
were CNS-related 
Headache-
reversible and 
can be clinically 
monitored.
Somnolence 
(drowsiness)
These effects are understood to 
be typically mild to moderate 
and transient.
Refer to the IB (c02155957) 
for more details.
Management of symptoms, 
evaluation, and follow-up as needed 
to ensure subject safety, per 
investigators clinical judgment.
Decrease in Hb
GLYT1 is present on 
erythrocyte precursors in the 
bone marrow and on 
circulating reticulocytes and 
glycine is required for Hb 
synthesis. 
No clear decrease in Hb was 
seen in iclepertin-treated 
subjects compared to placebo 
in phase I. 
In Phase II, the mean 
decrease in Hb was observed 
for 10 mg and 25 mg 
compared to placebo [10 mg: 
-3.3 g/L (-0.33 g/dL); 25 mg: 
-4.5 g/L (-0.45 g/dL); 
placebo: -0.5 g/L (0.05g/dL)]
Patients with haemoglobin (Hb) 
below lower limit of normal at 
Visit 1 assessed by the central lab 
will be excluded from 
participation in this study.
For other GLYT1 inhibitors 
maximum decrease in Hb was 
observed after 4 months of 
treatment, Hb will be checked at 
Visit 9.
Please refer to section 5.2.6.4 -
‘Haemoglobin and anemia’ for 
more details.

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Table 1.4.2:1 Overview over trial related risks (con’t)
Possible/ known 
risks of clinical 
relevance for 
this trial
Summary of data, rationale
for the risk
Mitigation strategy
Ocular AEs
The ocular safety of
iclepertin and its effects on 
ophthalmologic physiology 
in patient with schizophrenia 
were characterised in an 
ocular substudy as part of 
trial 1346-0009, in which a 
subset of patients underwent 
special ocular safety 
assessments. 
No meaningful changes from 
baseline or differences 
between iclepertin treatment 
groups and placebo were 
observed with regards to the 
analysed ocular safety 
variables.
Ocular AEs will be monitored and 
followed up per investigators 
judgment (refer to Section 
5.2.6.3).
Verbatim description for each 
ocular AE is needed
For ocular AEs, the patients must 
be sent to an ophthalmologist for 
detailed evaluation. Report from 
the ophthalmology examination 
will need to be collected.
iclepertin - Drug Interactions
Moderate or 
strong CYP3A4 
inhibitors
Exposure of iclepertin will 
increase in the presence of the 
moderate or strong CYP3A4 
inhibitors
Patients should not be randomized 
if taking any of the drugs listed in 
the ISF or need such drug during 
treatment period (refer section 
4.2.2.1).
Patients requiring Paxlovid (a 
strong CYP3A inhibitor) for the 
treatment of COVID-19 during the 
trial should stop taking iclepertin at 
time point of Paxlovid start, and 
restart iclepertin 1 day after 
Paxlovid cessation.
CYP3A4 
sensitive drugs 
with narrow 
therapeutic index 
(NTI)
Exposure of CYP3A4 sensitive 
drugs with NTI decreases 
during treatment with iclepertin

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Table 1.4.2:1 Overview over trial related risks (con’t)
Possible/ known
risks of clinical 
relevance for 
this trial
Summary of data, rationale 
for the risk
Mitigation strategy
Disease Related Risk
Worsening of 
Schizophrenia or 
relapse
Clinically stable patients with
schizophrenia are randomized 
to this study. Schizophrenia is 
a cycling disease with 
fluctuation of symptom 
severity: acute episodes (e.g., 
relapse) and intervals of 
relative stability (e.g., 
remission) between them. 
Monitoring of symptoms of 
schizophrenia with adjustment of 
maintenance Standard of Care 
(SoC) treatment to control 
symptoms.
Definition of relapse provided to 
monitor in a standardized manner.
Potential 
worsening of 
existing or new 
side effects caused 
by treatment with 
antipsychotics 
(e.g. tardive 
dyskinesia, 
metabolic, 
orthostatic 
hypotension)
No worsening of the AEs due 
to antipsychotic treatment
were seen in the phase II 
study.
AE monitoring 
Extrapyramidal symptoms (EPS)
assessed using Simpson Angus 
Scale (SAS)/ Abnormal Involuntary 
Movement Scale (AIMS)/ Barnes 
Akathisia Rating Scale (BARS)
throughout treatment period
Per investigator judgement 
adjustment of background 
medication is allowed.
Suicidality
Suicidal behavior and suicidal 
ideation are common in this 
population. However, patients 
are in psychiatric treatment 
where continuous assessment 
of suicidal behavior and risk 
is part of the standard of care.
Frequency of suicidal 
ideation/behavior reported for
iclepertin groups was 
numerically similar to that 
reported for the placebo group 
in Phase II trial in patients 
with schizophrenia. 
Prospective assessment of suicidal 
ideation and behavior is included in 
this study using the Columbia 
Suicide Severity Rating Scale (C-
SSRS). In case of a positive report 
of suicidal behavior and/or suicidal 
ideation additional collection of the 
C-SSRS at any frequency and/or 
any medical interventions and 
sufficient follow-up may be done 
based on the investigator’s 
discretion.

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Table 1.4.2:1 Overview over trial related risks (con’t)
Possible/ known 
risks of clinical 
relevance for 
this trial
Summary of data, rationale 
for the risk
Mitigation strategy
Other risks
Potential risk 
while operating 
machinery
General precaution for CNS 
active drugs
It is recommended that subjects 
should exercise caution when 
driving or operating machinery 
after drug administration.
Human abuse 
potential
According to the 2017 FDA 
guidance on “Assessment of 
Abuse Potential of Drugs”, 
assessment of human abuse 
potential (HAP) is required for 
drug products “that contain 
CNS-active new molecular 
entities (NMEs)”.
Based on nonclinical data, 
completed Phase I studies and 
assessment of data from one 
completed Phase II trial in 
CIAS with iclepertin , no 
signal of human abuse 
potential has been observed 
however human abuse liability 
of iclepertin has not been 
formally investigated. 
A list of AEs for assessment of 
potential abuse liability of iclepertin
, will be provided as part of ISF and 
relevant AEs must be reported 
including a verbatim description. 
Investigators will be trained about 
the importance to assess patients for 
abuse and withdrawal related 
adverse events. 
Detailed information will be 
collected and monitored for study 
medication compliance >100% 
Drug-induced 
liver injury 
(DILI)
DILI is a 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 patients´ 
safety.

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Table 1.4.2:1 Overview over trial related risks (con’t)
Possible/ known 
risks of clinical 
relevance for 
this trial
Summary of data, rationale 
for the risk
Mitigation strategy
Other risks
Genotoxicity, 
fertility and 
teratogenicity
iclepertin and its metabolites 
(BI 758790 and BI 761036):
Showed no evidence of 
genotoxicity. 
Demonstrated no effects on 
fertility and no evidence of 
teratogenicity.
Based on this evaluation, 
contraception for male clinical 
trial participants (or their sexual 
partners) is not required.
WoCBP will need to use highly 
effective method of 
contraceptives with failure rate 
<1%

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Table 1.4.2:1 Overview over trial related risks (con’t)
Possible/ known
risks of clinical 
relevance for 
this trial
Summary of data, rationale 
for the risk
Mitigation strategy
Other risks
Corona Virus 
Disease -19 
(COVID- 19) 
pandemic
Overall, the risk for patients 
with schizophrenia 
participating in the iclepertin
CIAS clinical trials is 
considered increased in light 
of COVID-19 pandemic, due 
to the need for the study 
participant to leave his/her 
home, higher prevalence of 
medical comorbidities such as 
diabetes, COPD, and 
cardiovascular disease that 
may increase the risk of 
developing COVID-19 related 
complications. Moreover, 
decreased Hb due to treatment 
with iclepertin may lead to 
anemia and thus increase the 
risk of COVID-19 related 
complications.
In all clinical trials, appropriate risk 
minimization measures will be taken in 
accordance with the public health 
precautions implemented in the 
country where the study will be 
conducted (e.g. minimizing time at the 
clinic, replacement of physical visits 
with remote visits, minimizing the use 
of public transportation to the site etc.). 
Considering the risk, patients with an 
active SARS-CoV-2 infection within 
35 days prior to randomization will be 
excluded from participation in this 
study.
Also, the study drug should be 
discontinued from treatment if the 
patient experiences severe or serious 
symptomatic infection with SARS-
CoV-2.
The investigators will take the totality 
of information related to each single 
patient 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 
patient’s (continued) participation in 
the planned trials. BI as the sponsor, 
where required, will support the 
investigator in their decision finding. It 
is acknowledged that the investigator 
may decide to implement protocol 
deviations where this protects the 
safety, wellbeing and/or is in the best 
interest of the patient.

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Table 1.4.2:1 Overview over trial related risks (con’t)
Possible/ known 
risks of clinical 
relevance for 
this trial
Summary of data, rationale 
for the risk
Mitigation strategy
Placebo risks and risk of stopping the treatment
Placebo Risks
There is currently no 
approved medication
indicated for treatment of 
CIAS. Since an approved, 
effective comparator is not 
available for this study, a 
placebo control group is 
being used in this study 
design.
According to the medication 
assignment planned in this 
trial, patients will be 
assigned to placebo or
iclepertin arm 10 mg in 1:1 
ratio.
Inclusion criteria require that patients 
enrolled in this clinical trial should 
be clinically stable and on stable SoC 
treatment with antipsychotic and 
other psychotropic medications. 
Maintenance antipsychotic treatment 
is needed to prevent relapse of acute 
psychotic episode. Thus, assignment 
to the placebo arm or stopping the 
study drug during the treatment 
period is not associated with a higher 
risk of psychotic relapse.
Psychiatric events, positive and 
negative symptoms, and suicidality 
will be monitored throughout the 
study to ensure that worsening of 
pre-existing conditions or any newly 
occurring events are detected and 
any necessary actions taken 
according to stopping criteria.
Risks of stopping
study drug
In the Phase II study, 
following end-of-treatment, no
increases in adverse events
were observed in patients 
treated with iclepertin in
comparison to those treated
with placebo. Potential adverse 
events after stopping study 
drug have not been formally
investigated thus far and
therefore cannot be fully
excluded.
Monitoring AEs of interest for 
assessment of potential abuse 
liability are described above (refer to 
placebo risks).
In one of the Phase III studies 
(c33087946), after completion of 26 
weeks of treatment, all patients will 
be closely monitored during the 4 
weeks in the safety follow up period 
to assess potential adverse events of 
withdrawal from iclepertin treatment.

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Table 1.4.2:1 Overview over trial related risks (con’t)
Given the patient population and the long treatment period there is a risk of premature treatment 
discontinuation/patient withdrawal. The study has been designed with frequent contacts between 
trial site and patients ensure the motivation and engagement. This will ensure frequent checks 
and reinforce compliance to trial treatment and background medication. For further follow-up 
after premature treatment discontinuation please refer to section 6.2.5.
A Data Monitoring Committee (DMC), independent from the Sponsor, will be established to 
review the safety data at intervals, and to recommend to the Sponsor whether to continue, 
modify, or stop the trial based on safety assessment. The tasks and responsibilities of the DMC 
members will be detailed in the DMC charter.
1.4.3
Discussion
Cognitive impairment associated with schizophrenia (CIAS) remains a tremendous scourge on the 
lives of millions of people across the world. It is the aspect of the illness that most accounts for the 
social isolation and functional disability that plagues most people with schizophrenia for their 
entire lives [R20-0592]. Yet, currently approved antipsychotics do not demonstrate relevant 
efficacy in the treatment of cognitive deficits of schizophrenia. 
Given the acceptable safety profile of iclepertin in clinical, nonclinical and toxicology studies 
performed to date, the sponsor feels the risks to the participating patients are mitigated by the 
careful monitoring that is planned during the study. Although individual benefit may not be 
observed for each patient, this registration trial aims to seek approval of the first pharmacologic 
Possible/ known 
risks of clinical 
relevance for 
this trial
Summary of data, rationale 
for the risk
Mitigation strategy
Trial procedures
General 
discomfort
Blood Draw
The risks of a blood draw 
include fainting and pain, 
bruising, swelling, or rarely 
infection where the needle is 
inserted. 
In rare cases a nerve may be 
damaged, inducing long-
lasting abnormal sensations 
(paraesthesia), impaired 
sensation of touch and 
persistent pain.
Management of discomfort,
evaluation, and follow-up as 
needed to ensure patient safety.

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treatment that improves cognition in patients with schizophrenia, which remains a high unmet 
medical need.
Considering the chronic and severe disease burden of CIAS, main cause of disability in this 
population, the potential therapeutic benefits are assessed to outweigh the currently understood 
potential risks of the treatment.

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2.
TRIAL OBJECTIVES AND ENDPOINTS
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS
2.1.1
Main objectives
The primary objective of this phase III pivotal trial in CIAS is to assess the efficacy in improving 
cognitive impairment using MCCB in patients with schizophrenia treated for 26 weeks with 
iclepertin 10mg as compared with placebo.
The key secondary objective is to assess the efficacy in daily functioning of 26-week treatment 
with iclepertin 10mg as compared with placebo in terms of Schizophrenia Cognition Rating 
Scale (SCoRS) and Virtual Reality Functional Capacity Assessment Tool (VRFCAT). 
The secondary objectives are to assess the efficacy in improving reasoning and problem solving 
and patients’ experience of cognitive impairment associated with their disease. 
Patients will be required to be on stable antipsychotic treatment at the time of inclusion.
The primary treatment effect of interest is defined in the primary estimand framework as 
specified in detail in Section 7. All efforts will be taken to continue to collect efficacy data at 
planned visits after patients discontinued trial treatment following an intercurrent event. For 
patients who discontinued trial treatment after intercurrent events that will be handled by the 
treatment policy approach, these observed off-treatment data will be included in the primary 
analysis. For patients who discontinued trial treatment after other intercurrent events that will not 
be handled by the treatment policy approach, these observed off-treatment data will be censored 
and excluded from the primary analysis.
In summary, the primary treatment effect of interest is the effect obtained at the primary time 
point if patients had stayed on the treatment, i.e. taking the trial medication for the full treatment 
duration while allowing the following intercurrent events: change in concomitant medications or 
background non-pharmacological therapy, change in study partner, and treatment interruption or 
discontinuation due to exacerbation, an acute episode, adverse events (AEs) that are considered 
drug related and protocol-defined drug withdrawal.
2.1.2
Primary endpoint(s)
The primary efficacy endpoint is assessing cognition:

Change from baseline in overall composite T-score of the MCCB after 26 weeks of 
treatment.

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2.1.3
Secondary endpoint(s)
The key secondary efficacy endpoints are:

Change from baseline in the SCoRS interviewer total score after 26 weeks of treatment

Change from baseline to Week 26 in the adjusted total time T-score in VRFCAT
The secondary efficacy endpoints are as follows:

Change from baseline to Week 26 in the T-score of the number of correct responses 
on Tower of London.

Change from screening visit 1a to Week24 in Patient Reported Experience of 
Cognitive Impairment in Schizophrenia (PRECIS) total score 

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2.2.2.2
Further safety endpoints 

Disease under study monitored using:

PANSS total score and change from baseline 

Incidence of relapse 

SAS/BARS/AIMS Scale scores throughout the treatment 

Suicidality as assessed by C-SSRS

Occurrence of protocol specified AESI

Percentage of patients with (S)AEs (including clinically relevant abnormalities of physical 
examination, vital signs, ECG test and laboratory tests)

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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN 
The overall trial design is as follows (see Figure 3.1:1):
Figure 3.1:1
Trial design
This is a 26-week, multi-center, multi-national, randomized, double-blind, placebo controlled,
parallel group trial in patients with schizophrenia. In total, approximately 586 patients with 
schizophrenia on stable antipsychotic treatment who meet the eligibility criteria are planned to be 
randomized in equal ratio into this trial.
Patients are enrolled in the trial once informed consent has been signed. 
Patients who are deemed eligible by the investigator, after screening, will be randomized to the 
26-week treatment period assigned with equal ratio to one of the following arms:
-
iclepertin 10 mg once daily 
-
Placebo once daily 
Randomization of patients will be stratified by MCCB overall composite T-score at screening
(screening MCCB overall composite T-score < 30, ≥30) and participation in the ocular substudy 
(Yes, No) via Interactive Response Technology (IRT) to balance the baseline cognitive level 
among groups.
All patients who finish 26 weeks of treatment with iclepertin or placebo in this study, will be 
offered the opportunity for treatment with iclepertin 10 mg in a long-term safety extension trial.
Eligible patients may enter the extension trial preferably after completing the EOT visit, or 
alternatively within 14 days from EoT (i.e. at FU1 visit including the respective time window).
Extension
R: stratification by 
screening MCCB score
S
R
Iclepertin
10 mg once daily
Day 1
Day -35
Follow-up
Treatment
Iclepertin 10 mg once daily
Placebo
once daily
Screen
Week 26
Day 1 Ext
+28 days
Multi-national
Placebo controlled
Parallel group trial
Double-blind
26-week
Multi-centre
Randomised

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Subjects who do not enroll in the extension study will be followed up for safety for an additional 
period of 4 weeks after last dose of medication. For further details please refer to Section 6.2.
As part of this research program, optional biobanking and speech sample collection will be done 
in order to address future scientific questions as described in Section 5.5 and 5.6.1. 
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)
A parallel group design is appropriate to detect the effects of iclepertin 10 mg compared to 
placebo on cognitive impairment in clinically stable patients with schizophrenia. The primary 
analysis of efficacy is planned after 26 weeks of treatment. Elimination of iclepertin takes 
approximately 12 days, therefore 28 days is considered sufficient to detect any unexpected late 
onset adverse events, to evaluate the pharmacodynamic effect of iclepertin after discontinuation 
and to allow for assessment of reversibility of any unexpected side-effects. Refer to Section 
5.2.6.4 for follow up of Hb related issues. 
Details of the statistical approach and sample size justification are given in Section 7.
There is currently no approved medication indicated for treatment of CIAS and therefore, a placebo 
control group is being used in this study. It should be noted that all patients, including those 
randomized to the placebo group, are permitted to remain on other antipsychotic and psychotropic 
medications, within the eligibility criteria. The risk to the control group is discussed in Section 1.4.
A Data Monitoring Committee (DMC), independent from the Sponsor, will be established to 
review the safety data at regular intervals, and to recommend to the Sponsor whether to continue, 
modify, or stop the trial based on periodic safety monitoring. The tasks and responsibilities of the 
DMC members will be detailed in the DMC charter.
3.3
SELECTION OF TRIAL POPULATION
It is planned that approximately 100 trial centres in multiple countries will be participating in this 
trial and a sufficient number of patients will be screened for the trial to ensure that approximately
586 patients are randomized to trial treatment.
This is a global trial and patients from all ethnic and racial backgrounds may be included.
It is expected that approximately five patients will be randomized at each trial center. If 
enrolment is delayed, additional sites may be recruited. Sites that do not screen patients over a 
prolonged period of time may be closed.
Permission to randomize more than 30 patients per site must be obtained from the Clinical Trial 
Leader (CTL). This will only be allowed after a careful review of the enrolment status of the site.

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Screening of patients for this trial is competitive. Investigators will be notified about screening 
completion and will then not be allowed to screen additional patients for this trial.
A log of all patients 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.
If a patient is entered (randomized) in error (does not meet all inclusion criteria or meets one or 
more exclusion criteria on the day of enrolment), the sponsor should be contacted immediately.
In this study, it was decided that adult patients up to 50 years of age at the time of consent could 
participate, as neuroplasticity (i.e. ability of the brain to change during life by acquiring, storing 
and re-using information) declines with age as well as with duration of the illness and treatment 
with antipsychotics. 
So far, the acquired clinical data suggest that iclepertin improves cognition which should 
translate to functional improvement in day-to-day activities. Therefore patients with functional 
impairments as described in inclusion criterion #4 will be included in this trial.
This trial is investigating iclepertin as a treatment for cognitive impairment due to schizophrenia
and therefore it is hypothesized that iclepertin will improve cognitive impairment caused by the 
disease. Patients who are randomized into the trial must have achieved at least an 8th grade 
education as a surrogate of pre-morbid cognitive capacity.
Retesting
Retesting applies in situations when the issue can be resolved within the screening period of 35 
days, for example patients are testing positive on urine drug screen for cannabis or opioids at 
Visit 1. These patients can be re-tested once (consider long half-life of cannabis) within the 
screening period of 35 days, if there is a reasonable explanation and expectation that the patient 
is not a regular user and will not test positive again on re-test, and at the discretion of the 
investigator. 
In case of retesting, the patient will keep the same subject number. The results of all retests
should be available within the 35 days of screening period. Once retests are available and 
negative for the retested parameter, and in case all other eligibility criteria are met, the patient 
can be randomized on the planned Visit 2 date.

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Rescreening of patients
Rescreening of a patient can be done once, if there is a reasonable explanation and expectation 
that the patient may have become eligible.
Potential reasons for rescreening could be: 

Haemoglobin is too low: Patients with low Hb at screening can be re-screened once 
the cause of low Hb was successfully treated. The reason and its treatment must be 
documented in the source documents.

Active infection with SARS-CoV-2 

Suicidality once the required exclusion period is over 

Clinically significant findings per Investigator’s judgement 

Stability of Schizophrenia symptoms or medications 

Liver enzyme elevation, e.g., ALT/ AST derangements 

Positive urine drug test at screening visit, if longer wash-out period needed 

Anticholinergic dose exceeding allowed limits, etc. 
Background medications should not be adjusted or changed for the purposes of study enrolment 
or to fulfil eligibility. Changes in background medications should occur per standard of care.
Anti-psychotic background therapy must be stable prior to re-screening.
For other potential reasons, please contact the clinical trial leader (CTL).
In case of re-screening, the patient will receive a new subject number. The patient and the study 
partner must sign the current, approved version of the informed consent before any study specific 
procedures are performed. 

If rescreening is done within 12 weeks of screening, all procedures except MCCB, 
SCoRS, VRFCAT and Tower of London must be repeated. 

If the rescreening is done more than 12 weeks after the screening, all procedures as 
shown in the Flow chart for Visit 1 must be repeated. 
For all re-screened patients, the screening period will be again 35 days as per protocol. In case all 
eligibility criteria are met during these repeated screening procedures, the patient can be 
randomized on the newly planned Visit 2 date.
3.3.1
Main diagnosis for trial entry
Clinically stable outpatients with established Schizophrenia (as per Diagnostic and Statistical 
Manual of Mental Disorders, 5th Edition (DSM-5))
Please refer to Section 8.3.1 for the documentation requirements pertaining to the in- and exclusion 
criteria.

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3.3.2
Inclusion criteria
1. Patients must be capable of providing signed and dated written informed consent by date of 
Visit 1 in accordance with ICH Harmonized Tripartite Guideline for Good Clinical Practice
(ICH-GCP) and the local legislation prior to the admission to the trial.
2. Male or female patients who are 18-50 years (inclusive) of age at time of consent.
3. Diagnosis of schizophrenia utilizing DSM-5 with the following clinical features:

Outpatient, clinically stable and in the residual (non-acute) phase of their illness.

No hospitalization3 or increase in level of psychiatric care4 due to worsening of 
schizophrenia within 12 weeks prior to randomization. 

PANSS score: items P1, P3-P6 ≤ 5 and item P2 and P7 ≤ 4 at Visit 1, and confirmed 
at Visit 2.
4. Patients should have functional impairment in day-to-day activities such as difficulties 
following conversation or expressing themselves, difficulties to stay focused, difficulties to
remember instructions, what to say or how to get to places, per investigator judgement.
5. Patients maintained on current antipsychotic treatment (minimum 1 and maximum 2 
antipsychotics, but clozapine is not allowed) for at least 12 weeks and on current dose for at 
least 35 days prior to randomization. 
o
For patients on two antipsychotics, at least one antipsychotic must be within the 
approved label dose range. The second antipsychotic must not exceed the maximum 
daily dose per local label
Note: If the total dose is stable, different dosage forms of the same antipsychotic treatment 
will be considered as one antipsychotic.
6. Patients with any other concomitant psychoactive medications (except for anticholinergics) 
need to be maintained on same drug for at least 12 weeks and on current dose/ regimen for at 
least 35 days prior to randomization. 
o
Maximum daily benzodiazepine load of up to 1 mg lorazepam-equivalent. Table of 
relevant medications and their equivalencies will be provided as a part of ISF
o
For any other psychoactive medications, doses cannot exceed the maximum daily dose 
per local label.
3 This includes home hospitalization for exacerbation in countries where it applies, however NOT hospitalization      
for social management and/or day programs.
4 This includes home hospitalization, partial hospitalization or ER visits

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7. Women of childbearing potential (WOCBP)5 must be ready and able to use highly effective 
methods of birth control per Non-Clinical Safety Studies for the Conduct of Human Clinical 
Trials and Marketing Authorization for Pharmaceuticals (ICH M3 (R2)) that result in a low 
failure rate of less than 1% per year when used consistently and correctly. A list of 
contraception methods meeting these criteria is provided in Section 4.2.2.3. Such methods 
should be used throughout the trial, and for a period of at least 35 days after last trial drug 
intake, and the patient must agree to periodic pregnancy testing during participation in the 
trial.
8. Have a study partner, defined as any person either private or professional who knows the 
patient well, has been capable of interacting with the patient on regular basis, and preferably 
consistent throughout the study. 
o
The study partner must interact with the subject a minimum 1 hour per week and, 
preferably, at least 2 times a week. At least one interaction per week should be in 
person.
o
The study partner must have educational achievement of minimum 8th grade.
o
Professional study partners (e.g. study nurse, social worker etc.) are allowed if not 
involved in administration of any of the protocol assessments.
9. Patients must, in the investigator’s opinion, exhibit reliability and physiologic capability (e.g. 
sufficient hearing, vision etc.), to comply with all protocol procedures, and have attained an 
educational achievement of minimum 8th grade.
10. Patients and his/ her study partner must be fluent in the language of the batteries/ 
questionnaires.
5 A woman is considered of childbearing potential (WOCBP), i.e. fertile, following menarche and until becoming post-
menopausal unless permanently sterile. 
Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy.

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3.3.3
Exclusion criteria
1. Participant with current DSM-5 diagnosis other than Schizophrenia, including but not limited 
to bipolar, schizoaffective, major depressive disorder etc. M.I.N.I. for Psychotic disorders 
should be used for guidance.
2. Cognitive impairment due to developmental, neurological (e.g., stroke) or other disorders
including head trauma, patients with dementia or epilepsy.
3. Severe movement disorders 
o
Leading to cognitive impairment (e.g. Parkinson dementia), or 
o
Interfering with the efficacy assessments, or
o
Due to antipsychotic treatment that cannot be controlled with low dose anticholinergic 
treatment (equal to maximum 1 mg benztropine twice daily). Table of relevant 
medications and their equivalencies will be provided as a part of ISF
4. Any suicidal behavior in the past 1-year prior to screening and during the screening period.
5. Suicidal ideation of type 5 in the C-SSRS (i.e. active suicidal thought with plan and intent) in 
the past 3 months prior to screening and up to and including Visit 2. 

Patients with Suicidal Ideation type 4 in the C-SSRS (i.e. active suicidal thought with 
intent but without specific plan), within 3 months prior to screening and up to and 
including Visit 2, can be randomized in the study, if assessed and documented by a 
licensed mental health professional that there is no immediate risk of suicide.
6. History of moderate or severe substance use disorder (other than caffeine and nicotine), as 
defined in DSM-5 within the last 12 months prior to informed consent.
7. Positive urine drug screen at Visit 1 based on central lab test. For a list of drugs assessed in 
the urine drug screen, please refer to Table 5.2.3:1.
8. Patients who were treated with any of the following within 6 months prior to randomization:
o
Clozapine
o
Stimulants (e.g. methylphenidate, dextroamphetamine, modafinil)
o
Ketamine or esketamine
o
Electroconvulsive therapy (ECT) or Modified ECT
9. Participation in any investigational psychoactive drug trial (both industry/ academic) in last 6 
months, and 30 days or 5 half-lives for no-psychoactive drug trial, prior to randomization.
10. Patients who were previously treated with iclepertin.

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11. Patients who are treated with any of the following within the last 35 days prior to 
randomization: 6

Strong or moderate CYP3A4 inhibitors including grapefruit juice 

Strong or moderate CYP3A4 inducers including St. John’s wort (Hypericum 
perforatum)

Dietary supplements and herbal remedies that may impact cognition, in the 
investigator´s judgement

Antiepileptics (when used for the treatment of epilepsy)7

Tricyclic antidepressants 

Traditional Chinese medicine/ non-Western therapy

Medical devices therapy (e.g. TMS, neurofeedback)
12. Patients who plan to change their current life-style habits including but not limited to alcohol, 
nicotine or caffeine use, or diet, during the treatment period.
13. Patients who have participated in a clinical trial with repeated assessments (i.e. a single 
assessment is not exclusionary) with the MCCB and/ or any other schizophrenia cognitive 
battery within 12 weeks prior to screening.
14. Any formal Cognitive Remediation Therapy (CRT) within 12 weeks prior to screening. 
Initiation of CRT is not allowed during the study.
15. Initiation or change in any type or frequency of psychotherapy (e.g. cognitive behavioral 
therapy, social skills training, vocational/occupational therapy) within 12 weeks prior to 
randomization. Patients with ongoing, stable psychotherapy for more than 12 weeks prior to 
randomization (and intend to maintain the same frequency during the study) may qualify as 
per clinical judgement of the investigator. 
16. Any of the following, in the judgment of the investigator:

Clinically significant finding of the physical examination, vital signs (including blood 
pressure (BP) and pulse rate (PR)), ECG or laboratory value (as measured by the central 
laboratory) that would jeopardize the patient´s safety while participating in the trial or 
their capability to participate in the trial.

Symptomatic/unstable/uncontrolled or clinically relevant concomitant disease or any 
other clinical condition that would jeopardize the patient´s safety while participating in 
the trial or capability to participate in the trial.

Significant or unstable physical condition that may require change in medication or 
hospitalization that would impact cognitive function.
6 List of relevant medication will be provided as a part of ISF.
7 Antiepileptics as monotherapy when used for other indications are acceptable if they fulfil criteria detailed in 
inclusion criteria #6, and should not be started during the treatment period if at all possible.

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
Planned major surgery requiring withdrawal from study medication for more than 2 
weeks during the study period.
Note: Please contact sponsor in case of you have any questions.
17. Haemoglobin (Hb) below lower limit of normal at Visit 1 assessed by the central lab. 
18. History of haemolytic anemia including haemoglobinopathies (for example thalassemia or 
sickle-cell anemia), RBC membrane diseases or known G6PDH (Glucose-6-phosphate 
dehydrogenase) deficiency; or current anemia or patients planning to donate blood.
19. Severe renal impairment defined as an eGFR < 30mL/min/1.73m² assessed by the central lab 
at Visit 1.
20. Indication of liver disease, defined by serum levels of either ALT (SGPT), AST (SGOT), or 
alkaline phosphatase above 3 times upper limit of normal assessed by the central lab at visit 
1.
21. Known history of HIV and/ or known on-going Hepatitis B or C infections. 
22. Patients with known active infection with SARS-CoV-2 within the last 35 days prior to 
randomization.8
23. 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, squamous cell 
carcinoma of the skin or in situ carcinoma of uterine cervix.
24. Women who are pregnant, nursing, or who plan to become pregnant while in the trial.
25. Patient who did not complete the MCCB at Visit 1 and therefore does not have T-score for 
randomization.
26. Patients with an allergy to iclepertin and/or any of the excipients (including lactose). A list of 
iclepertin and placebo ingredients are provided in the Investigator’s Brochure.
3.3.4
Withdrawal of patients from treatment or assessments
Measures to control the withdrawal rate include careful patient selection, appropriate explanation 
of the trial requirements and procedures prior to randomization, as well as the explanation of the 
options for follow-up of patients in case of withdrawal.
Every effort should be made to keep randomized patients in the trial, if possible, or at least to 
collect important trial data.

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Patients may discontinue trial treatment or withdraw consent to trial participation as a whole 
(“withdrawal of consent”). The decision to discontinue trial treatment or withdraw consent for 
further trial participation along with the reason must be documented in the patient files and 
electronic Case Report Form (eCRF). If applicable, consider the requirements for Adverse Event 
collection reporting (Sections 5.2.6.2.1 and 5.2.6.2).
Every effort should be made to keep randomized patients on background medication with 
antipsychotics to prevent relapse.
Every effort should be made to prevent patients from being lost to follow-up. If a patient does not 
come in for a planned visit, please refer to the retention guide for guidance regarding frequency 
and methods to reach out to patient and/or study partner.
3.3.4.1
Temporary Trial Treatment Discontinuation:
Temporary trial treatment discontinuation is permitted. For treatment interruptions of > 10 days, 
the sponsor should be informed.
Reasons of temporary trial treatment discontinuation and exact start and end dates must be 
documented in source documents.
Reasons for temporary drug discontinuation could be due to:

Severe or serious symptomatic infection with SARS-CoV-2. 

Current treatment with Paxlovid.

Other medical condition(s), per investigator judgment.
Patients who prematurely discontinue trial medication are allowed to restart treatment, if 
appropriate, in the opinion of the Investigator.
3.3.4.2
Permanent Discontinuation of Trial Treatment
For all patients the reason for permanent discontinuation from trial treatment (e.g. adverse events) 
must be recorded in the eCRF. Patients who permanently discontinue from the trial after 
randomization will not be replaced. 
Even if the trial treatment is permanently discontinued, the patient should remain in the trial and, 
given the patient’s agreement:

The patient will complete the early end of treatment and safety follow up visits. 

Additionally, the patient will be followed according to the Flow Chart until the planned 
Visit 11 (26 weeks). 
Please refer to Flow Chart and Section 6.2.5 for more information on continued trial 
participation.

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An individual patient is to be withdrawn from trial treatment if:

The patient wants to stop taking the trial treatment permanently.

The patient exhibits suicidality, in the clinical judgement of the investigator or according to 
criteria below:
o
Any suicidal behavior (i.e. actual attempt, interrupted attempt, aborted attempt or 
preparatory acts or behavior)
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) that per certified 
trained mental health professional constitutes a risk of suicidal behaviour

The Hb drops below 100 g/L (10g/dL) OR
Hb decreases by 25% or more from baseline and is below the lower limit of normal.

The patient can no longer be treated with trial medication for serious medical reasons (e.g., 
liver injury, stroke, etc.), per investigator’s clinical judgement. 

The patient needs to take any restricted medication that may impact the patient’s safety to 
continue the treatment, per investigator’s judgement. Please consult with sponsor.

Pregnancy: if a patient becomes pregnant during the trial the study medication will be stopped, 
the patient will be discontinued from the trial and the patient will be followed up until birth or 
otherwise termination of the pregnancy.
o
For further information, including the process for follow-up on the outcome of the 
pregnancy please see Section 5.2.6.7.
If new efficacy/ safety information becomes available, Boehringer Ingelheim will review the
benefit-risk-assessment and, if needed, pause or discontinue the trial treatment for all patients or 
take any other appropriate action to guarantee the safety of the trial patients. 
3.3.4.3
Withdrawal of consent to trial participation
Patients may withdraw their consent to trial participation at any time without the need to justify 
the decision.
Withdrawal of consent to trial participation means permanently stopping the study treatment,
plus no further participation in study visits, study assessments plus no further contact with the 
patient and/or data collection (e.g. through patients representative, medical records, as permitted 
by local regulations).

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If a patient wants to withdraw consent, the investigator should be involved in the discussion with 
the patient and explain the difference between “trial treatment discontinuation” and “withdrawal 
of consent to trial participation”, as well as explain the options for continued follow-up after trial 
treatment discontinuation, please see Section 6.2.5.
3.3.4.4
Discontinuation of the trial by the sponsor
Boehringer Ingelheim reserves the right to discontinue the trial overall or at a particular trial site 
at any time for the following reasons:
1. Failure to meet expected enrolment goals overall or at a particular trial site.
2. New efficacy or safety information invalidating the earlier positive benefit-risk-assessment.
3. Deviations from GCP, the trial protocol, or the contract impairing the appropriate conduct of 
the trial.
Further follow up of patients affected will occur as described in Section 3.3.4.2
The investigator / the trial site will be reimbursed for reasonable expenses incurred in case of 
trial termination (except in case of the third reason).

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4.
TREATMENTS
4.1
INVESTIGATIONAL TREATMENTS
iclepertin tablets have been manufactured by BI Pharma GmbH & Co. KG.
Eligible patients are randomly assigned to one of the double-blind treatment regimens at a ratio 
of 1:1 as follows:

iclepertin 10 mg once daily for 26 weeks

Placebo once daily for 26 weeks
4.1.1
Identity of the Investigational Medicinal Products
Table 4.1.1: 1 Test product 
Substance:
iclepertin
Pharmaceutical formulation:
Tablet
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
10 mg
Posology:
1 tablet once daily
Method and route of administration:
Oral
The characteristics of the reference product are as shown below.
Table 4.1.1: 2 Reference product
Substance:
Placebo matching iclepertin 10 mg 
Pharmaceutical formulation:
Tablet
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
Not applicable
Posology
1 tablet once daily
Method and route of administration:
Oral

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4.1.2
Selection of doses in the trial and dose modifications
The dose was selected based on the following strategy:
1. The effective dose in improving cognition in the PoCC/dose finding trial in patients with 
schizophrenia was 10 mg, as this dose separated best from placebo with regards to the 
primary efficacy endpoint in the phase II trial.
2. iclepertin was well tolerated in patients with schizophrenia up to 25 mg once daily for 12 
weeks.
3. Decrease in Hb was dose dependent but a small decrease of 3.3 g/L in 10mg group and 
4.5 g/L in 25mg was observed. Hb will be monitored.
4. iclepertin was well tolerated in healthy subjects in single doses of up to 150 mg and 
multiple doses of up to 75 mg bid (150 mg per day). 
5. iclepertin showed efficacy at doses which correspond to ~50% glycine increase in CSF 
and CSF levels of the drug in the range of 1x GLYT1 IC50. The dose of 10mg fulfils this 
criteria.
6. In the Proof of Mechanism trial (c03724403) the target mean increase of 50% in CSF 
glycine was observed after multiple dosing of 10 mg iclepertin in healthy volunteers. 
Consequently, the dose of 10 mg once daily of iclepertin will be tested in Phase III pivotal 
studies.
4.1.3
Method of assigning patients to treatment groups
After the assessment of all in- and exclusion criteria, each eligible patient will be randomised to 
treatment groups according to a randomisation plan in a 1:1 ratio at visit 2 via Interactive 
Response Technology (IRT). Note that the medication kit numbers are different from the patient 
number (the latter is generated during screening via the IRT System).
4.1.4
Drug assignment and administration of doses for each patient
Dispensing of medication kits for the double-blind treatment period will begin at Visit 2.
Throughout the treatment period, 2 trial medication kits will be providedat each visit. Medication 
assignment will be provided through IRT. The assigned medication kit numbers must be entered 
in the eCRF, and the corresponding medication kits must be given to the patient. The duration of 
treatment is 26 weeks. At each of the visits, patients will receive supplies for a total of 4 weeks
(21 treatment days plus 7 days reserve).
The first dose of study medication will be taken at the end of Visit 2 under supervision of the 
investigator or delegated site staff, after all Visit 2 assessments have been completed. In case the 
Visit 2 is split into 2 sequential days, the first dose of study medication should be taken on the 
second day of split the visit, after all Visit 2 assessments have been completed.

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Throughout the study, patients should be instructed to take 1 tablet orally with water and with or 
without food after waking up. If a dose is missed by more than 12 hours, that dose should be 
skipped and the next dose should be taken as scheduled.
Patients should be instructed not to take their trial medication AT HOME on each visit day as 
patients will be dosed at the site. Dosing should occur approximately 24 hours after the drug 
administration of the preceeding day.  
The last dose of study medication should be taken on the day before the EoT Visit. In case the 
EoT Visit is split into 2 sequential days, the last dose of study medication should be taken on the 
day before the first day of the split visit.
On longer visit days the dosing may occur in the afternoon. 
A dose reduction of iclepertin is not possible.
4.1.5
Blinding and procedures for unblinding
4.1.5.1
Blinding
Except for independent DMC, patients, investigators, central reviewers, and everyone involved 
in trial conduct or analysis or with any other interest in this double-blind trial will remain blinded 
with regards to the randomised treatment assignments until the database is declared ready for 
analysis according to the sponsor’s SOPs. Further details regarding the timepoint of unblinding 
the database for anlaysis are documented in the TSAP.
The access to the randomisation code will be kept restricted until its release for analysis.
Long-term treatment with GLYT1 inhibitors such as iclepertin may reduce Hb levels in some 
patients. Phase II results from the 1346-0009 trial showed that the majority of patients (over 
90%) have Hb levels that remain in the normal range (c31477880 table 15.3.2.2.). It is also noted 
that decreases in Hb have also been observed in some placebo patients, as there can be 
considerable fluctuation in Hb values. The number of patients with decreased Hb, by at least >2 
g/dl, was the same in placebo group, as in the active treatment arms (c31477880). Therefore,
reductions in Hb may not permit investigators to infer which treatment arm individual patients 
had been allocated to.
Nonetheless, in order to ensure the double-blind nature of the trial, the Hb related parameters
will be blinded to the investigator and sponsor starting at visit 2 until the end of trial. The site 
will receive alerts as detailed in Section 5.2.6.4. The Hb related parameters will be reviewed 
throughout the trial by an independent, third party as well as by the independent DMC. For 
medical management of any patient with an alert on decreased Hb, refer to Section 5.2.6.4.
The responsible bioanalyst of the external bioanalytical laboratory will receive the randomization 
codes prior to last patient completed to allow for the exclusion from the analyses of 
pharmacokinetic (PK) samples taken from placebo patients.

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The trial bioanalyst (TBA) may receive unblinding data from external bioanalytical laboratory 
after the last patient completed the last visit but prior to official unblinding of the trial database 
for preparation of data transfer (e.g. check file structure prior to data upload and SDTM 
transformation and bioanalytical report writing). 
Bioanalytics will not disclose the randomisation code or the results of their measurements until 
the trial is officially unblended.
4.1.5.2
Unblinding and breaking the code
Emergency unblinding will be available to the investigator via IRT. It must only be used in an 
emergency situation when the identity of the trial drug must be known to the investigator in order 
to provide appropriate medical treatment or otherwise assure safety of trial participants. The 
reason for unblinding must be documented in the source documents and/or appropriate CRF 
page.
Due to the requirements to report Suspected Unexpected Serious Adverse Reactions (SUSARs), 
it may be necessary for a representative from BI’s Pharmacovigilance group to access the 
randomisation code for individual patients during trial conduct. The access to the code will only 
be given to authorised Pharmacovigilance representatives for processing in the PV database 
system and not be shared further. 
4.1.6
Packaging, labelling, and re-supply
The investigational medicinal products will be provided by BI or a designated CRO. They will 
be packaged and labelled in accordance with the principles of Good Manufacturing Practice 
(GMP). Re-supply to the sites will be managed via an IRT system, which will also monitor 
expiry dates of supplies available at the sites.
For details of packaging and the description of the label, refer to the ISF.
Drug supplies will be kept in their original packaging and in a secure limited access storage area 
according to the recommended storage conditions on the medication label. A temperature log 
must be maintained for documentation.
If the storage conditions are found to be outside the specified range, the Clinical Research 
Associate (CRA) (as provided in the list of contacts) must be contacted immediately.
4.1.7
Drug accountability
The investigator or designee will receive the investigational drugs delivered by 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 and the 
investigational site,

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
Approval/notification of the regulatory authority, e.g. competent authority,

Availability of the curriculum vitae of the Principal Investigator,

Availability of a signed and dated clinical trial protocol,

Availability of the proof of a medical license for the Principal Investigator,

Availability of FDA Form 1572 (if applicable).
Investigational drugs are not allowed to be used outside the context of this protocol. Patients 
must be instructed to not share or permit others to use their study medication. They must not be 
forwarded to other investigators or clinics. Patients should be instructed to return unused 
investigational drug. In the event that the patient does not return all medication, the investigator 
or designee is required to obtain an explanation from the patient as to why not all medication was 
returned (e.g. if the blister card was discarded by accident, lost medication or medication taken 
by another person, etc.).
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 patient, and the return to the sponsor or warehouse / drug 
distribution centre or alternative disposal of unused products. If applicable, the sponsor or 
warehouse / drug distribution centre will maintain records of the disposal. 
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 patients. The 
investigator or designee will maintain records that document adequately that the patients were 
provided the doses specified by the Clinical Trial Protocol (CTP) and reconcile all 
investigational medicinal products received from the sponsor. At the time of return to the 
appointed CRO, the investigator or designee must verify that all unused or partially used drug 
supplies have been returned by the clinical trial patient and that no remaining supplies are in the 
investigator’s possession.
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, RESTRICTIONS
4.2.1
Other treatments and emergency procedures
Throughout the duration of the trial patients should continue to take their current antipsychotic 
and concomitant psychotropic medications, the dose of which should remain unchanged if at all 
possible. These medications will not be provided as part of the clinical trial supplies, unless 
required by local laws and regulations.
Any change in dose of antipsychotic and concomitant psychotropic medications should be
recorded in the source documentation and on the appropriate pages of the eCRF. Any additional 
treatment that is considered necessary for the patient’s welfare may be given at the discretion of 
the investigator.
Only patients with stable schizophrenia are included in this trial. As such, no rescue medication 
or emergency procedures are foreseen for this trial. In case of worsening of schizophrenia, any 
treatment adjustment deemed necessary per clinical judgment can be given.

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4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
Medications and non-pharmacological interventions that are exclusionary under the eligibility 
criteria (Section 3.3.3) are restricted during the treatment period as well.
In addition, the following concomitant medication and treatment restrictions apply for the 
duration of the treatment period:

Medications that are NOT allowed 8 hours prior to MCCB assessment (i.e. randomization visit,
Visit 6/ week 12 and Visit 11/ week 26/ eEoT) is done:
o
Antihistamines with prominent sedative side effects
o
Anticholinergics
o
Benzodiazepines 
o
Other sedative medication 
o
Short-term use of opioids for pain, cough or diarrhea

Anticholinergics 
o
The total daily dose must not exceed 1 mg benztropine twice daily or equivalence. 
o
If patients are being treated with more than 1 anticholinergic (including OTCs), the total 
daily dose still must not exceed 1 mg benztropine twice daily equivalence (e.g., 
diphenhydramine is an antihistamine with anticholinergic component). 
o
Patients should remain on stable anticholinergic dose, unless absolutely necessary to adjust 
for medical reasons.
o
Screening period can be used to reduce anticholinergic use to maximum 1 mg benztropine
twice daily in total, if clinical situation allows per investigator’s judgement.

Antihistamines
o
Patients taking sedative antihistaminic medication should be on a stable dose not exceeding 
daily recommended dose per label in the country. 

Opioid maintenance therapy or opioid-replacement for opiod dependence (e.g methadone) is 
not allowed during the trial period.

CYP3A4 sensitive drugs with NTI (e.g., fentanyl, cyclosporine) are not allowed during 
treatment with iclepertin. List is included in the ISF.
Permitted therapies include:
1. Non-systemic use (topical, inhalation or nasal administration) of antihistaminics and 
anticholinergics is allowed.

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2. Short-term opioid therapy up to 4 weeks per time, for example with cough syrup or pain 
killer, is allowed (except fentanyl).
3. The CYP3A4 sensitive drugs without NTI have decreased levels of exposure when given 
concomitantly with iclepertin; investigators should assess if dose adjustments and/or 
monitoring of the underlying disease is clinically required for patients who are taking such 
drugs (for a list of CYP3A4 without NTI sensitive drugs please refer to the ISF).
4. Vaccination with COVID-19 vaccines is permitted as per local public health 
recommendations.
4.2.2.2
Restrictions on diet and lifestyle
Diet and lifestyle restrictions listed under the eligibility criteria (Section 3.3.3) are restricted 
during the treatment period as well.
It is not recommended that patient donates blood during the study.
Effects of iclepertin on driving abilities have not been tested so far. It is recommended that subjects 
exercise caution when driving or operating machinery during the treatment period. 
Entering or modifying a smoking-cessation program during the treatment period could negatively 
impact efficacy read-outs and should be avoided if possible.
4.2.2.3
Contraception requirements
WOCBP (for the definition please refer to Section 3.3.2) must use highly effective methods of 
birth control per ICH M3 (R2) that results in a low failure rate of less than 1% per year when 
used consistently and correctly. Such methods should be used throughout the trial, and for a 
period of at least 35 days after last trial drug intake.
Acceptable methods of birth control for this trial include:

Combined (estrogen and progestogen containing) hormonal birth control that prevents 
ovulation (oral, intravaginal, transdermal)

Progestogen-only hormonal birth control that prevents ovulation (oral, injectable, 
implantable)

Intrauterine device or intrauterine hormone-releasing system

Bilateral tubal occlusion or ligation

Vasectomised sexual partner with documented absence of sperm

Complete sexual abstinence when this is in line with the preferred and usual lifestyle 
of the patient (note: periodic abstinence such as calendar, ovulation, symptothermal, 
post-ovulation methods and withdrawal are not acceptable methods of contraception)
Male patients and their female partners:
There are no specific contraceptive requirements for male participants and their female partners.

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4.3
TREATMENT COMPLIANCE
Patients are requested to bring all remaining trial medication including empty package material 
with them when attending visits.
Based on tablet counts, treatment compliance will be calculated as shown in the formula below. 
Compliance will be verified by the CRA authorised by the sponsor.
Treatment compliance (%) =
Number of tablets removed from blister 100
     Number of tablets which should have been taken as 
directed by the investigator
If the number of doses taken is not between 80-100%, site staff will explain to the patient the 
importance of treatment compliance and determine the reason(s) for deviation and document
these in the source and eCRF.
Adverse Events related to the human abuse potential of iclepertin should be reported and 
managed as per the investigator´s judgement. 
In addition to compliance calculation, medication adherence will be monitored via AiCure app. 
Please refer Section 5.6.2 for more details.

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5.
ASSESSMENTS
5.1
ASSESSMENT OF EFFICACY

MATRICS Consensus Cognitive Battery (MCCB) will be used to evaluate the effects of 
iclepertin on cognitive functions. 
MCCB comprises 10 tests, which assess 7 cognitive domains, including speed of processing, 
attention vigilance, working memory, verbal learning, visual learning, reasoning and problem 
solving, and social cognition [R13-2347; R13-2373].
The 10 tests of the MCCB with corresponding cognitive domains are listed in Table 5.1: 1
below:
Table 5.1: 1 MCCB tests and cognitive domains 
Test
Domain
Trail Making Test, Part A (TMT)
Speed of Processing
Brief Assessment of Cognition in Schizophrenia, symbol 
coding subtest (BACS SC)
Speed of Processing
Category Fluency test, animal naming
Speed of Processing
Hopkins Verbal Learning Test –
Revised (HVLT-R), 
immediate recall
Verbal Learning
Wechsler Memory Scale, 3rd ed. Spatial span subtest (WMS-
III SS) 
Working 
Memory 
(nonverbal)
Letter-Number Span test (LNS)
Working 
Memory 
(verbal)
Neuropsychological Assessment Battery, mazes subtest (NAB 
mazes)
Reasoning and Problem 
Solving
Brief Visuospatial Memory Test- Revised (BVMT-R)
Visual Learning
Mayer-Salovey-Caruso Emotional Intelligence Test, managing 
emotions branch (MSCEITTM ME) 
Social Cognition
Continous Performance Test, Identical Pairs version (CPT-IP)
Attention/ Vigilance
Social cognition is distinct from non-social cognition (i.e. neurocognition), thus the MCCB 
neurocognitive composite T-score will be calculated without the Social Cognition domain.
The MCCB overall composite T-score will be used as the primary efficacy endpoint measure 
for this study, while the MCCB neurocognitive composite score will be used as a further
efficacy endpoint. A larger MCCB overall composite T-score indicates better cognition.

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
Schizophrenia Cognition Rating Scale (SCoRS) is a 20-item interview-based assessment 
of cognitive deficits and the degree to which they affect day-to-day functioning. Each item is 
rated on a 4-point scale. Higher ratings reflect a greater degree of impairment. 
The 20 items of the SCoRS specifically assess cognitive functioning, and 19 of these items 
align with the seven MCCB cognitive domains as follows:

Memory: 4 items

Learning: 2 items

Attention: 3 items

Working Memory: 2 items

Problem Solving 3 items

Processing/Motor speed: 2 items

Social Cognition: 3 items
The one additional item of the SCoRS falls within Language, which is not an MCCB domain.
The SCoRS rater integrates information from separate patient and study partner interviews to 
generate a total score. In addition, the patient, study partner and interviewer (rater) will provide 
a global rating score at each post-baseline visit and the interviewer (rater) will provide a change 
score at the eEoT visit.

Placebo Control Reminder Script (PCRS) [R20-4054]: The PCRS is a brief 
psychoeducational tool designed to mitigate placebo responses. A trained rater reads a brief 
passage about factors that have been linked to elevated placebo responses (e.g., 
misunderstandings about the purpose of a placebo treatment condition, unwarranted 
expectancies regarding treatment benefit) and encourages patients to attend to these factors.
The patient and study partner are then asked to describe the content of the script in his/her own 
words. The procedure takes approximately three minutes to complete.

Virtual Reality Functional Capacity Assessment Tool (VRFCAT) will be used as an 
electronic Functional Capacity measure for this study. The VRFCAT is a virtual reality 
shopping trip performed on a tablet. The task has several linked and sequential scenarios, 
including matching a recipe to the content of kitchen cabinets, preparing a shopping list, 
taking the correct bus, shopping efficiently, and catching the correct return bus. These tasks 
are performed in a fixed sequence. There are multiple forms of the VRFCAT and in this 
protocol different versions will be assigned according to the study visit. All data are collected 
through the computer or tablet.
Prior to the performance of the task, a brief tutorial version of the VRFCAT is administered 
with a short recipe. This tutorial needs to be administered to all participants, regardless of 
their statements regarding computer familiarity.
Once the task is launched it operates itself continuously until the end of the procedure. As 
with all electronic assessments, the tester will be required to remain vigilant in order to 

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ensure that the participant is continuously engaged in the task. The task takes approximately 
30 minutes to complete.
The VRFCAT was developed to improve clinical trials by detecting functionally meaningful 
improvements in patients’ everyday lives. Data generated in this trial will support validation 
of this test as a functional outcome measure for future clinical trials.

Tower of London (Executive Functions/Reasoning and Problem Solving):
Subjects are shown two images presented on opposite sides of the tablet screen. Each image 
shows a different configuration of 3 colored balls arranged on 3 pegs. The subject is required to 
accurately determine the total number of times the balls in one picture would have to be moved 
in order to make the arrangement of balls identical to that of the other opposing picture, while 
employing the standard rules employed in tower tests (balls are moved one at a time and balls on 
top of other balls must be moved first). Eight alternative forms are available. The outcome 
measure is the number of correct responses. The administration time is about 7 minutes. 

Patient Reported Experience of Cognitive Impairment in Schizophrenia (PRECIS) is a 
patient reported outcome (PRO) under development in accordance with FDA guidelines 
(2009) for recording patients’ subjective experience of CIAS. The questionnaire contains 28
items and generally takes about 5-15 minutes to complete. The PRECIS asks the patient to 
assess their own subjective experience of CIAS over the past week, covering 6 domains 
Memory (6 items), communication (4 items), self-control (3 items), executive function (4 
items), attention (6 items), and sharp thinking (3 items). Two additional items assess the 
overall degree of bother associated with all domains. Questions are answered via a 5-
category Likert scale, with higher scores corresponding to worse patient experience (1=not at 
all/not at all hard, 2=a little bit/a little bit hard, 3=somewhat/somewhat hard, 4=quite a 
bit/quite hard, 5=very much/very hard), e.g. “Overall, in the past week, remembering where I 
put things (for example, my keys, phone, glasses, or other items) was…”. The Total Score is 
derived by calculating the simple average score of the first 26 items. Domain scores can be 
calculated as simple average of the items that fall into the respective domain. If there are 
more than 7 missing items out of the first 26, a total score should not be calculated. For 
number of missing items allowed for each domain scores see Table 5.1:2. Table 5.1:2 lists 
the 28 items of PRECIS, their corresponding domain, and the minimum number of non-
missing items required for each domain.

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Table 5.1: 2 PRECIS items, domains and missing data allowance
Domains
Item descriptions
Item 
numbers
Minimum
number of non-
missing items 
required (per 
domain)
Memory
Remembering what I was supposed to do, Remembering where I put 
things, Remembering what I wanted to say, Remembering what 
someone was saying, Remembering how to get to someplace, 
Remembering what I was about to do
1, 2, 3, 4, 5, 
6
3
Communica-
tion
Coming up with something to say, Interacting with people I don't 
know well, Explaining myself, Finding words to say what I mean
7, 8, 9, 10
3
Self-control
Keeping things from slipping out, Stopping to think before saying or 
doing, Stopping saying or doing wrong
11, 12, 13
3
Executive 
Function
Planning ahead for an event, When someone changed plans, Coming 
up with solutions to problems, Figuring out new ways to do things
14, 15, 16, 
17
4
Attention
My mind drifted off, Got distracted by things going on, Hard to focus 
on something, Thinking about things repetitively, Thoughts were 
racing, Thinking was unclear, cloudy, foggy
18, 19, 20, 
21, 22, 23
3
Sharp 
thinking
Thinking was not as fast as others, When tired, thinking slowed, 
Thoughts were blocked
24, 25, 26
3
NA
Overall bother in the past week
27
NA
Overall bother if thought stay the same
28

Clinical Global impressions – Severity (CGI-S) is a one-item evaluation completed by the 
clinician on the patient’s severity of cognitive impairment. The CGI-S is rated ordinal from 1 
to 4 (none, mild, moderate, severe). Ideally, the same investigator or site staff should assess 
CGI-S at all visits (refer also to section 6.2.1 for additional requirements).

Clinical Global impressions – Change (CGI-C) is a 5-point scale (much better, a little 
better, no change, a little worse, much worse) used to assess the change of the patient´s status 
from start of the treatment and is completed by the clinician.

Study Partner Global Impression of Severity (SPGI-S) is similar to CGI-S but completed 
by the study partner.

Study Partner Global Impressions of Change (SPGI-C) a similar question as the CGI – C 
but completed by the study partner.

Patient Global Impressions-Severity (PGI-S) is a 4-point scale with similar response 
categories as CGI-S, which requires the participant to rate the severity of their own 
symptoms.

Patient Global Impressions-Change (PGI-C) measures a patient's belief about the efficacy 
of treatment. PGI-C is a 5 point scale with similar response categories as CGI-C, depicting a 

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patient's rating of overall improvement since started taking the study medication and is 
completed by the patient.

Health-related quality of life (HRQoL) will be assessed using the EQ-5D-5L instrument at 
the visits indicated on the Flow Chart. EQ-5D-5L is a standardized instrument for use as a 
measure of health outcome. It is a generic measure, rather than disease-specific, and is 
therefore applicable to a wide range of health conditions and treatments. It provides a simple 
descriptive profile from which a single index value for health status is derived, and a visual 
analogue scale (VAS) rating.
EQ-5D-5L is designed for self-completion by patients. The EQ-5D-5L self-report 
questionnaire consists of 2 pages comprising:

The descriptive system (5 dimensions of health: mobility, self-care, usual activities, pain/ 
discomfort, anxiety/ depression). Each dimension comprises 5 levels (no problems, 
slight/moderate/ severe problems, extreme problems, or unable to perform the health
dimension)

The EQ visual analogue scale (VAS) which records the patient’s self-rated health status on 
a vertical graduated (0 – 100) VAS
A patient can self-administer the EQ-5D-5L in a few minutes, and the investigator (or
designated site-personnel) should ensure that the patient has access to a quiet area at the site
where he/she can complete the descriptive system and VAS. In instances where a patient is 
having difficulty deciding upon a response, he/ she should select the option that fits best. 
Investigators (or designated site-personnel) should not scrutinize responses to individual items. 
Instructions to patients will be included in the questionnaire [R12-1920].

Sheehan Disability Scale (SDS)
The Sheehan is a brief self reported tool assessing the functional impact of patients with 
psychiatric disorders. The patient rates on 3 items the extend to which work/school, social life 
and home life or family responsibilities are impaired by his or her symptoms on a 10 point 
analog scale [R20-1844]. Higher scores indicating greater functional impairment. It also 
comprises two additional items assessing days lost and days unproductive, respectively (‘On 
how many days in the last week did your symptoms cause you to miss school or work or leave 
you unable to carry out your normal daily responsibilities?’, ‘On how many days in the last 
week did you feel so impaired on your symptoms, that even though you went to school or 
work, your productivity was reduced?).

Caregiver burden and caregivers’ health-related quality of life: Caregiver burden and 
caregivers’ health-related quality of life will be collected from those study partners that are 
informal (unpaid) caregivers. Assessments will be voluntary, using the EQ-5D-5L and 
Schizophrenia Caregiver Questionnaire (SCQ). 
o
The Schizophrenia Caregiver Questionnaire (SCQ). The SCQ was developed to 
provide a comprehensive assessment of the impact of caregiving for an individual with 
schizophrenia [1,2]. It is a 32-item questionnaire with a recall period of 4 weeks (‘during

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the past 4 weeks’), utilizing a 11-point numerical rating scale from 0 to 10 for all items, 
with higher scores indicated greater impact. Scores of the SCQ are obtained by a sum of 
the recoded item scores, linearly transformed to a 0 to 100 range. The questionnaire 
comprises a ‘Humanistic impact’ supra-domain composed of a global score (17 items) and 
four subdomain scores (‘Physical’ (3 items); ‘Emotional’ (6 items); ‘Social’ (3 items); 
‘Daily life’ (5 items)) and eight other domain scores related to the caregiving role 
(‘Exhaustion with caregiving’ (2 items); ‘Feeling alone’ (1 item); ‘Patient Dependence’ 
(2 items); ‘Worries for the patient’ (3 items); ‘Perception of caregiving’ (2 items); 
‘Financial dependence of the patient’ (1 item); ‘Financial impact of caregiving’ (1 item); 
‘Overall difficulty of caregiving’ (1 item)). Accordingly, 9 multi-item scores and 4 single 
item scores can be derived, and reliability and validity have been confirmed [R20-3808].

Socioeconomic status will assess patient’s working or employment status and housing 
situation (living alone, with family, etc.). A dedicated page to assess socioeconomic status will 
be available in the eCRFs.

HCRU will collect details about hospitalizations, home hospitalizations, ER visits due to 
psychotic symptoms, and other non-study physician visits.
5.2
ASSESSMENT OF SAFETY

Positive and Negative Syndrome Scale (PANSS) will be used to evaluate broad 
psychopathology associated with schizophrenia disease state.
The PANSS has 30 items. Each is rated from 1 to 7 points. The total factor score is the 
summation of the actual points for each item, leading the total score ranging from 30 to 210. 
[R13-5061].
It contains seven positive symptom items, seven negative symptom items and 16 general 
psychopathology symptom items. Fourteen of the PANSS items require input from a study 
partner. A trained rater interviews the patient and the study partner, estimated to take 30-40 
minutes for evaluating the subjects’ disease state.

Extrapyramidal Symptoms (EPS) will be assessed using 3 scales:
o
The Simpson Angus Scale (SAS) is a performance scale that measures drug-induced 
parkinsonism symptoms. The rater asks the patient to perform 10 tasks and rates responses 
on a scale of 0-4 (normal to severe). It consists of one item measuring gait (hypokinesia), 
six items measuring rigidity and three items measuring glabella tap, tremor and salivation, 
respectively. A total score of 0-40 is calculated (or scale score can be calculated by dividing 
the total by 10 to give a score between 0 and 4).

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o
The Abnormal involuntary movement scale (AIMS) records the occurrence of tardive 
dyskinesia (TD) in patients receiving antipsychotic medications. The AIMS test is used to 
detect TD and to follow the severity of a patient's TD over time. These items are also scored 
from 0 (= normal/healthy) to 4 (= severely affected). The scores are summed to give an 
overall score of the involuntary movements. It assesses tardive movement disorders. 
o
The Barnes Akathisia Rating Scale (BARS) is a rating scale that is administered by the 
investigator to assess the severity of drug-induced akathisia. The BARS is the most widely 
used rating scale for akathisia. The BARS is scored as follows: Objective Akathisia, 
Subjective Awareness of Restlessness and Subjective Distress Related to Restlessness are 
rated on a 4-point scale from 0 – 3 and are summed yielding a total score ranging from 0 
to 9. In addition, Global Clinical Assessment of Akathisia is rated from 0-5.

Columbia Suicidality Severity Rating Scale (C-SSRS)
The C-SSRS is a semi-structured, investigator-rated interview, developed by clinical 
experts in cooperation with the FDA, assessing both suicidal behavior and suicidal 
ideation. It does not give a global score but provides some categorical and some severity 
information specifically for behavior and ideation.
The computer-automated C-SSRS interview may be administered using a tablet device.
Subjects who do not have suicidal behavior or ideation will answer a limited number of
questions and will usually complete the assessment in about 3 minutes. Subjects with
significant suicidal ideation or behavior may require up to 10 minutes to answer all 
relevant questions. This assessment should be conducted early in the visit. At the 
conclusion of each assessment, the site will have access to the C-SSRS results. The
results include the findings for suicidal ideation, intensity of ideation, suicidal behavior, 
and lethality / medical damage (for actual suicide attempts only).
The C-SSRS has been widely used in large multinational clinical trials. The C-SSRS will 
be administered first at screening (Visit 1) (using the ‘Baseline / Screening’ version) with 
the aim to exclude subjects with active moderate or severe symptomatology within a 
specified time prior to screening. The lifetime history of suicidal ideation and behavior 
will also be recorded.
After screening (Visit 1) the assessment ‘since last visit’ will be performed at each clinic 
visit (‘Since Last Visit version’). The investigator is to review/ consider the C-SSRS 
results for plausibility and clinical relevance. Doubtful results may be repeated or results 
may be validated by a consulting psychiatrist. If there is a confirmed positive report of 
suicidal behavior or suicidal ideation type 4 or 5 after start of trial, the investigator is to 
immediately interview the subject during the clinic visit (if the investigator did not 
administer the C-SSRS leading to the positive report), and/ or is to consult a psychiatrist 
if considered necessary. 

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For any positive suicidal ideation (type 1 to 5) or suicidal behavior, the rater must document 
additional details in the comment fields in the C-SSRS in Pathway.  
If there is any new suicidality or increase in suicidality, please comment on the clinical 
significance and any additional follow-up actions that may be performed in the eCRF.  
If the positive report is confirmed, appropriate actions for the patient’s safety have to be initiated
and followed up as deemed necessary. The C-SSRS may be repeated at an unscheduled visit at 
the investigator’s discretion.
C-SSRS results will be reported in terms of AEs as described in Section 5.2.6.1.4.
5.2.1
Physical examination
A complete physical examination will be performed at the time points specified in the Flow
Chart. It includes at a minimum general appearance, neck, lungs, cardiovascular system, 
abdomen, extremities, and skin. 
Measurement of height and body weight will be performed at the time points specified in the 
Flow Chart.
The results must be included in the source documents available at the site. 
5.2.2
Vital signs
Vital signs will be evaluated at the time points specified in the Flow Chart, prior to blood 
sampling.
This includes systolic and diastolic blood pressure and pulse rate (electronically or by palpation 
count for 1 minute) in a seated position after 5 minutes of rest. The results must be included in 
the source documents available at the site.
5.2.3
Safety laboratory parameters
Safety laboratory parameters to be assessed are listed in Table 5.2.3: 1. For the sampling time
points please see the Flow Chart.
Patients do not have to be fasted for the blood sampling for the safety laboratory.
All analyses will be performed by a central laboratory, the respective reference ranges will be 
provided in the lab manual in the ISF.
Instructions regarding sample collection, sample handling/ processing and sample shipping are 
provided in the Laboratory Manual in the ISF.

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The central laboratory will send reports to the investigator (except for blinded Hb related 
parameters, for further details refer to Section 4.1.5.1 and Section 5.2.6.4). Laboratory values 
that are out of range should be commented on lab report printouts and evaluated by the 
investigator for clinical significance.
Clinically significant abnormal laboratory results should be reported by the investigators in the 
eCRF either on baseline condition (from Visit 1 test) or on AE page (from subsequent visits test). 
Please refer to Section 5.2.6.
Clinically relevant abnormal laboratory test results will need to be followed per investigators 
judgment, until normalization or stabilization or until an alternative explanation has been found.
Safety lab may be repeated for any or all lab parameters specified in the protocol, at any time 
point during the study, per investigators discretion.
In case the criteria for hepatic injury are fulfilled, a number of additional measures will be 
performed (please see Section 5.2.6.1 and the DILI Checklist provided in the eDC system.)
The amount of blood taken from the patient concerned will be increased due to this additional 
sampling.
The central laboratory will transfer the results of the analysis to the sponsor.
The site should not use a local laboratory to assess the Haematology parameters unless clinically 
justified.

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Table 5.2.3:1 
Safety laboratory tests
Category
Test name
Haematology Panel A
(Refer Section 5.2.6.4)
Haemoglobin (Hb)
Haematocrit (Hct)
MCV, MCH, MCHC
RDW
Red Blood Cell Count/ Erythrocytes
Reticulocyte Count
Reticulocyte index 
Haematology Panel B
White Blood Cells/ Leukocytes
Diff. Automatic (manual if
diff. automatic is abnormal)
- Neutrophils
- Eosinophils
- Basophils
- Monocytes
- Lymphocytes
Platelet Count/ Thrombocytes
Total iron binding capacity (TIBC)
Serum ferritin
Serum iron
Folate
Vitamin B12
Chemistry
AST(GOT)
ALT(GPT)
Alkaline Phosphatase (AP)
Bilirubin Total, fractionated if increased
Creatine Kinase (CK)
CK-MB – only if CK is elevated
C-Reactive Protein
Gamma-Glutamyl Transferase (GGT/γ-
GT)
Lipase
Amylase
Cholesterol, total
Triglycerides
Lactic Dehydrogenase (LDH)
Calcium
Sodium
Potassium 
Glucose
HbA1c
Urea (BUN)
Creatinine
Estimated Glomerular filtration rate 
(eGFR) – using the CKD-EPI 
equation****
Protein, Total 
TSH*
Prolactin*
Pregnancy test
(females only)
Human urine chorionic gonadotropin**
Serum Beta hCG, Qualitative (Only if human urine chorionic gonadotropin is 
positive)
Urinalysis
(quantitative)
Urine creatinine
Urinalysis
(Qualitative)
Urine Nitrite
Urine Protein
Urine Glucose
Urine Ketone
Urobilinogen
Urine Bilirubin
Urine blood
Urine pH
Leukocyte esterase
Urine Drug Screen 
***
(Preliminary and 
confirmatory testing)
Amphetamines
Barbiturates 
Cannabis
Cocaine
Methadone
Opiates
PCP (Phencyclidine)
*The following lab parameters will not be determined at each study visit:

TSH – only at Visit 1

Prolactin – only at Visit 2 and EOT/ eEoT
** To be done at the site with the kit provided by the central lab.

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*** Patients will be considered drug screen positive, if the confirmatory test is positive. Re-test is permitted at visit 
1a (refer to Section 3.3).
****The eGFR will be derived from the serum creatinine value, age, sex and race using the Chronic Kidney Disease 
Epidemiology Collaboration (CKD-EPI) equation [R12-1392]. The race must be collected because the CKD-EPI 
equation uses race as an adjustment factor and therefore it is required for accurate estimation.
5.2.4
Electrocardiogram
The 12-lead ECGs will be performed as scheduled in the Flow Chart. Twelve-lead ECGs (I,
II, III, aVR, aVL, aVF, V1 – V6) will be recorded using equipment provided by a central
ECG vendor. The ECGs will be recorded for at least 10-second duration after the subjects have 
rested for at least 5 minutes in a supine position and prior to lab sampling. Electrode placement 
will be performed according to the method of Einthoven/Goldberger (ankles and wrists). At all 
time points indicated in the Flow Chart, single ECGs will be recorded. ECG recordings at 
planned time points may be repeated for quality reasons like alternating current artefacts, muscle 
movements and electrode dislocation. In this case the repeated ECG recordings will be used if 
quality was better.
The investigator or a designee will evaluate whether the ECG is normal or abnormal and whether 
it is clinically significant, if abnormal. The electronic version of the ECG is regarded as source 
data. Dated and signed printouts will be stored in the patient’s medical file if there is no validated 
and certified e-medical record for ECG data.
Additional ECGs may be collected by the investigator for safety reasons. Clinically relevant 
findings noticed at Visit 1 should be reported as baseline condition.
Clinically relevant abnormal findings noticed afterVisit 1 will be reported as
AEs and followed up and/or treated locally until normal or stable condition.
All ECGs will be transmitted electronically to the central ECG vendor for centralized and 
independent evaluation. and the vendor will provide a report to the site. Abnormalities detected 
during this centralized ECG evaluation will not necessarily qualify as an AE. Decisions on 
eligibility for the trial are the responsibility of the investigator. Abnormalities detected in central 
evaluation must be reviewed by the investigator and if considered clinically significant reported 
as baseline condition if identified at Visit 1 or as adverse event if identified at or after Visit 2. All 
clinically relevant abnormal findings will be managed as medically appropriate, per investigators 
clinical judgment
5.2.5
Other safety parameters
Assessment of disease state:

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PANSS will be used to evaluate the disease severity. Refer to Section 5.2. In addition 
investigator may use CGI-S and his/her clinical judgment for assessing schizophrenia worsening/ 
relapse.
Schizophrenia worsening (i.e., deterioration of chronic residual symptoms): Fluctuation in 
the severity of symptoms is common and should be managed and reported as per the clinical 
judgment of the investigator. Adjustment of background medication is allowed when necessary. 
In such cases, schizophrenia worsening must be reported as adverse event per the clinical 
judgment of the investigator.
Schizophrenia Relapse (acute episode): If severity of schizophrenia symptoms fulfils the 
criteria of relapse (acute episode), investigator must report relapse as adverse event. 
Definition of relapse for this program is: Increased level of care (such as hospitalization, home 
hospitalization, emergency room (ER) visit due to psychotic symptoms) due to worsening of 
psychotic symptoms / increased PANSS per investigators judgment. 
5.2.6
Assessment of adverse events
5.2.6.1
Definitions of AEs 
5.2.6.1.1
Adverse event
An AE is defined as any untoward medical occurrence in a patient or clinical investigation 
subject administered a medicinal product and which does not necessarily have to have a causal 
relationship with this treatment.
An AE can therefore be any unfavourable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of a medicinal product, whether 
or not considered related to the medicinal product.
The following should also be recorded as an AE in the CRF and BI SAE form (if applicable):
Worsening of the underlying disease or of other pre-existing conditions 
Changes in vital signs, ECG, physical examination and laboratory test results, if they are 
judged clinically relevant by the investigator.
If such abnormalities already exist prior to trial inclusion, they will be considered as baseline 
conditions and should be collected in the eCRF only.
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,

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-
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 on 
appropriate medical judgement which may jeopardise the patient and may require 
medical or surgical intervention to prevent one of the other outcomes listed in the above 
definitions. Examples of such events are intensive treatment in an emergency room or at 
home for allergic bronchospasm, blood dyscrasias or convulsions that do not result in 
hospitalisation or development of dependency or abuse. 
For Japan only: the following events will be handled as “deemed serious for any other reason”. 
AEs which possibly lead to disability will be reported as SAEs.
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. 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 and exacerbations of existing cancer must be classified as a serious 
event regardless of the time since discontinuation of the drug and must be reported as described 
in Section 5.2.6.2, subsections “AE Collection” and “AE reporting to sponsor and timelines”.
5.2.6.1.4
Suicidal Risk assessed by the C-SSRS 
All reports of suicidal behaviour and all C-SSRS reports of suicidal ideation type 4 or 5 must be 
reported as SAEs by the investigator.
For each instance of suicidal ideation type 1, 2 or 3 after start of the trial, the investigator is to 
decide based on clinical judgement whether it represents an AE as defined in the protocol. If this 
is considered as AE, then it must be reported as SAE, using SAE form and eCRF AE page, as 
this is listed on the “BI always serious adverse event list”.
For ‘Self-injurious behaviour, no suicidal intent’ standard AE/SAE reporting rules are to be 
applied. 

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5.2.6.1.5
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:
Hepatic injury
A hepatic injury is defined by the following alterations of hepatic laboratory parameters: 

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 draw sample, or

aminotransferase (ALT, and/or AST) elevations ≥10 fold ULN.
These lab findings constitute a hepatic injury alert and the patients showing these lab 
abnormalities need to be followed up according to the “DILI checklist”.
In case of clinical symptoms of hepatic injury (icterus, unexplained encephalopathy, unexplained 
coagulopathy, right upper quadrant abdominal pain, etc.) without lab results (ALT, AST, total 
bilirubin) available, the investigator should make sure these parameters are analysed, if necessary 
in an unscheduled blood test. Should the results meet the criteria of hepatic injury alert, the 
procedures described in the DILI checklist should be followed.
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.
5.2.6.1.7
Causal relationship of AEs
Medical judgement should be used to determine whether there is a reasonable possibility of a 
causal relationship between the adverse event and the given study 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.

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
The event is known to be caused by or attributed to the drug class.

A plausible time to onset of the event relative to the time of drug exposure.

Evidence that the event is reproducible when the drug is re-introduced.

No medically sound alternative aetiologies that could explain the event (e.g. pre-existing
or concomitant diseases, or co-medications).

The event is typically drug-related and infrequent in the general population not exposed 
to drugs (e.g. Stevens-Johnson syndrome).

An indication of dose-response (i.e. greater effect size if the dose is increased, smaller 
effect size if dose is reduced).
Arguments that may suggest that there is no reasonable possibility of a causal relationship could 
be:

No plausible time to onset of the event relative to the time of drug exposure is evident 
(e.g. pre-treatment cases, diagnosis of cancer or chronic disease within days / weeks of 
drug administration; an allergic reaction weeks after discontinuation of the drug 
concerned).

Continuation of the event despite the withdrawal of the medication, taking into account 
the pharmacological properties of the compound (e.g. after 5 half-lives).
Of note, this criterion may not be applicable to events whose time course is prolonged 
despite removing the original trigger.

Additional arguments amongst those stated before, like alternative explanation (e.g. 
situations where other drugs or underlying diseases appear to provide a more likely 
explanation for the observed event than the drug concerned).

Disappearance of the event even though the trial drug treatment continues or remains 
unchanged.
5.2.6.2
Adverse event collection and reporting
5.2.6.2.1
AE Collection
The investigator shall maintain and keep detailed records of all AEs in the patient files.
The following must be collected and documented on the appropriate CRF(s) by the investigator:

For patients who roll-over to the extension trial:
o
From signing informed consent onwards until first dose of trial medication in the
extension trial: all AEs (serious and non-serious) and all AESIs. Updates to concomitant 
therapy should also be included until first dose of trial medication in the extension trial.
Note: Updates for SAEs and/ or AESIs ongoing at the time of rollover to the extenstion 
trial, must be also updated in parent trial, in addition to the extension trial, as long as the 
data base of parent trial is not locked. On SAE form, updates for events reportable on 
SAE form with onset in parent trial are only reported into the parent trial.

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
For patients who do not roll-over to the extension trial:
o
From signing the informed consent onwards until the 28 days (F2 visit) after the end of 
treatment visit: all AEs (serious and non-serious) and all AESIs.
o
After the individual patient’s end of trial: The investigator does not need to actively 
monitor the patient 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.

For patients who permanently discontinue trial medication prematurely:
o
From signing the informed consent onwards until the 28 days (Follow-up 2 visit) after 
the early end of treatment visit: all AEs (serious and non-serious) and all AESIs.
o
From Follow-up 2 visit up to the individual patients’ planned end of Trial (i.e. 26 
weeks/visit 11): Until the individual patient’s planned end of trial, the investigator must 
report 

Treatment related SAEs / AESIs

Following regardless of causal relationship
-
Anaemia
-
SAEs from C-SSRS assessments
-
Any occurrence of cancer
-
Deaths/ fatal AEs
o
After the individual patient’s planned end of trial (i.e. 26 weeks/ completion of visit 
11): The investigator does not need to actively monitor the patient 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 immediately (within 24 hours) to the sponsor’s 
unique entry point (country specific reporting process will be provided in the ISF). The same 
timeline applies if follow-up information becomes available. In specific occasions, the 
investigator could inform the sponsor upfront via telephone. This does not replace the 
requirement to complete and 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 individual patient’s end of trial must be 
followed up until they have resolved, have been assessed as “chronic” or “stable”, or no further 
information can be obtained.

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5.2.6.3
Ocular AEs
Before administration of study medication at Visit 2, site staff will remind patients to report
“any unusual visual perception they may experience”. 
During the study, if a patient reports a change in perception or any ocular AE, site staff must 
record the patient’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.
5.2.6.4
Haemoglobin and Anaemia
To reduce bias on efficacy assessments, starting at visit 2 until the end of trial, Haematology 
Panel A parameters (refer table 5.2.3:1) will be blinded to the site and to the sponsor.
Sites will be alerted if the following occurs:

Alert 1: Hb decrease > 20 g/L (2 g/dL) compared to baseline value

Alert 2: The Hb value is below the normal reference range

Alert 3: Hb value fulfils the criteria to withdraw the treatment (refer to Section 3.3.4)
An independent third party will review both haematology panels parameters throughout the 
trial. In addition, the independent DMC will review unblinded safety data on a regular basis 
throughout the study.
Scenarios and Actions:
Alert 1:

Patients may continue on the study medication.

Both haematology panels should be performed at the next visit (or earlier, per 
investigator’s judgement). Both haematology panels should be repeated at subsequent 
visits until alerts are no longer triggered or once the end of trial has been reached.
Alert 2:

Patients may continue on the study medication.

Both haematology panels should be performed at the next visit (or earlier, per 
investigator’s judgement). Both haematology panels should be repeated at subsequent 
visits until alerts are no longer triggered or once the end of trial has been reached.

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
The investigator should further evaluate the patient status and report the AE “Anaemia”
based on investigators clinical judgment. Once Alert 2 is no longer trigged, the 
investigator may evaluate whether or not the AE “Anaemia” is resolved.
For Alert 1 and/or 2, patients can be rolled over to the extension study. Details on monitoring of 
ongoing adverse event “Anaemia” in the extension study will be provided in 1346-0014 study 
protocol (c33088336).
Alert 3:

Stop study medication. Refer to Section 3.3.4.2.

Report as an AE “Anaemia”

Both haematology panels should be performed at the next visit (or earlier, per 
investigator’s judgement). Both haematology panels should be repeated at subsequent 
visits until alerts are no longer triggered or once the end of trial has been reached.

Patient should be referred to a specialist for further management.

Patients are not eligible for the extension trial.

These patients will undergo follow up per Section 5.2.6.2.1 AE collection and Section
6.2.5. 
Note: The Investigator may consider further management once any Alert is triggered.
5.2.6.5
AE for assessment of potential abuse liability
To assess whether iclepertin has abuse potential, investigators are required to provide a detailed 
description of specific types of AEs. Detailed information should be recorded in the source 
documents and eCRF and if applicable, on the SAE form. A list of AEs for assessment of 
potential abuse liability will be provided as part of ISF. 
5.2.6.6
Monitoring of adverse events after stopping of study medication
Patients who are not rolling over to the extension trial should be closely monitored during the 
safety follow up period to assess AEs after stopping of study medication.
5.2.6.7
Pregnancy
In rare cases, pregnancy might occur in a clinical trial. Once a patient has been enrolled in the 
clinical trial and has taken trial medication, the investigator must report any drug exposure 
during pregnancy in a trial participant immediately (within 24 hours) by means of Part A of the 
Pregnancy Monitoring Form to the sponsor’s unique entry point.
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 

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for Clinical Studies (Part B). The ISF will contain the Pregnancy Monitoring Form for Clinical 
Studies (Part A and B).
As pregnancy itself is not to be reported as an AE, in the absence of an accompanying SAE 
and/or AESI, only the Pregnancy Monitoring Form for Clinical 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.
If a patient becomes pregnant, please also refer to section 3.3.4.2.
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS
5.3.1
Assessment of pharmacokinetics
Trough samples will be collected as specified in Flow Chart before dosing the patient. 
 
5.4
ASSESSMENT OF BIOMARKER(S)
Not applicable

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5.5
BIOBANKING
Participation in biobanking is voluntary and not a prerequisite for participation in the trial. 
Biobanking will only occur after a separate biobanking informed consent has been given in 
accordance with local ethical and regulatory requirements.
Banked samples may be used for future biomarker research and drug development projects, e.g. 
to identify patients that are more likely to benefit from a treatment or experience an adverse 
event (AE), or to gain a mechanistic or genetic understanding of drug effects and thereby better 
match patients with therapies.
5.5.1
Methods and timing of sample collection
Detailed instructions on sampling, preparation, processing, shipment and storage are provided in 
the laboratory manual. For sampling timepoints see Flow Chart.
Blood will be drawn for DNA, Plasma and Serum banking purposes.
Any analyses on DNA or plasma/serum samples will not be reported in main CTR.
Samples will be collected only in countries where all applicable local regulatory and ethics 
approvals have been obtained for biobanking.
5.6
OTHER ASSESSMENTS
5.6.1
Speech sample collection 
Speech analysis has emerged as new potential marker of abnormal mental conditions as for 
instance cognititive imparement in disorders like Schizophrenia. Speech analysis includes 
various evaluations of language as e.g. semantic coherence or syntactic complexity.
For use in future exploratory investigations, voluntary speech samples will be collected after 
separate optional speech sampling informed consent has been given in accordance with local 
ethical and regulatory requirements in participating countries. Participation in the speech 
sampling is not a prerequisite for participation in the trial.
Speech samples, along with related information on communication and mental state, will be 
collected with a tool on the tablet computer. The tool leads the participant through a set of speech 
elicitation tasks designed to assess motor and cognitive function as well as affect. Acoustic and 
language-level features will be extracted from the speech data and will be used to examine 
changes in speech and language features for each participant over time. These data may be 
combined with data from other trials of psychiatric indications to explore possible association 
between speech parameters and clinical parameters. 

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Speech collection will occur at the time points indicated in the Flow Chart. Instructions for 
recording are provided in a speech analysis procedures manual, filed in the ISF
Note: speech sample collection may not be available in all countries at initiation and therefore 
will be implemented as soon as it is available and approved by regulatory authorities and ethic 
committees in respective countries. 
Speech analyses will be analysed independently by a vendor and reported in a separate report.
5.6.2
Medication Adherence and Reminder System
Because non-compliance with medication is a significant challenge in Schizophrenia trials, this 
study will use a medication adherence monitoring platform for all participants in the study. All 
patients must consent to use the AiCure app at screening. If a randomized patient on treatment 
refuses to continue to use the app, the patient will be allowed to continue in the trial. The 
Platform is provided on the AiCure smartphone application and uses artificial intelligence to 
confirm medication ingestion. Built-in reminders and a communication system allow real-time 
intervention in case of missed doses. Use of the platform is foreseen for all subjects in the study 
to reinforce the proper dosing schedule and improve data integrity.
Registration in the AiCure platform
In most countries, the platform may be downloaded as an app on the participant’s personal 
smartphone. If a participant does not own a smartphone or prefers not to use his/ her personal 
smartphone, one of the backup provisioned devices should be provided. In some countries, all 
participants will use a provisioned device. 
Participants should be registered in the platform during screening visit and begin confirming 
appropriate compliance to their background antipsychotic treatment/s to ensure stability prior to 
randomization. At visit 2, participants will begin using the platform to monitor study drug intake 
and continue to log their background antipsychotic use. 
Ongoing use and monitoring of medication adherence 

Participants should use the application to record each intake of study medication throughout 
the trial, both at home between visits and during the visits when study drug is taken at the 
site. 

Site personnel should regularly check the dashboard to ensure consistent medication 
adherence throughout the study. In cases of missed doses or pending data, site personnel 
should follow up with the participant as soon as possible to assess the reason for non-
adherence and reinforce the importance of complying with the study drug dosing schedule. If 
the participant reports that a dose was taken but not logged in the app, site personnel should 
reclassify this dose to “site reported” using the dashboard. 

Participants who are consistently non-compliant with study medication should be discussed 
with the sponsor.

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Monitoring of background antipsychotic treatment
Participants using a daily oral antipsychotic should be registered in the platform during screening 
to confirm stability of their background antipsychotic prior to randomization. Participants will be 
asked to confirm that they have taken their background antipsychotic treatment. 
Data Privacy and Security in the AiCure platform 
The AiCure platform is compliant with all applicable privacy and data security laws; data is 
captured, processed, and analyzed in a compliant manner as outlined in each local informed 
consent form
5.6.3
Verification of current and past research study status with Verified Clinical 
Trials
Duplicate enrollment and protocol violations are risk factors for poor quality data and safety 
concerns. These issues may result in increased placebo rates and failed clinical trials. Each 
subject, in this study, must have their current study status checked by utilizing the Verified 
Clinical Trials system. This is a mandatory process for countries that have not opted-out by 
a local amendment.
Following proper informed consent and after issuing a study subject number, each subject will be 
checked in the Verified Clinical Trials database, as indicated in the Flow Chart. Partial identifiers 
will be utilized. This will include checking a valid form of picture ID when available. The first 3 
letters of the first and last name will be entered along with the middle initial, DOB, Sex, and last 
5 digits of that ID. If the research subject is a Verification Success they may proceed in the 
study. Verification Failures will not be permitted to screen without sponsor approval. 
The duplicate patient check will be performed only after approval is received in accordance with 
local regulations.
5.7
APPROPRIATENESS OF MEASUREMENTS
All measurements performed during this trial are acceptable measurements and commonly
used in monitoring safety aspects or assessing treatment response in patients with CIAS.
The scheduled measurements are appropriate to see drug induced changes in physical
examination, vital signs, ECG and standard laboratory values. The primary and secondary
efficacy endpoints and safety endpoints are standard and accepted for evaluation of safety
and tolerability of an oral drug, and they are widely used in these kind of studies. The period of
26 weeks of treatment with iclepertin is deemed appropriate to see a change in cognitive
function in schizophrenic patients.
Therefore, the appropriateness of all measurements applied in this trial is given.

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6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
Study procedures have to be completed according to the Flow Chart. All patients should adhere 
to the visit schedule as specified in the Flow Chart including time windows for rescheduling. 
Preferably the visits should be conducted in the morning.
If any visit has to be rescheduled, subsequent visits should follow the original visit schedule 
calculated from randomization (Visit 2). The trial medication kits contain sufficient medication 
to allow for these time windows.
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
6.2.1
General requirements
The following requirements for the conduct of the assessments need to be followed:

The MCCB should be done as the first efficacy assessment preferably in the morning
(depending on the sleep cycle of the patient), followed by VRFCAT, ToL and SCoRS.

All other assessments can be completed per the convenience of patient and site at all 
respective visits.

It is very important to have the MCCB done at approximately the same time of day for 
each individual patient throughout the trial. The MCCB assessments at Visit 6 and (e)EoT 
Visit must be started at approximately the same time of the day as MCCB assessment at 
Visit 2 (+/- 60 minutes). In case this cannot be adhered to, then the visit should be 
rescheduled within the allowed visit window.

Assessment of each rating scale should preferentially be done by the same rater for a given 
patient throughout the study period. However, for MCCB and VRFCAT, the consistency 
of time of day is more important than the consistency of the rater.

The global impression anchor scales (CGI-S/CGI-C and/or PGI-S/PGI-C and/or SPGI-
S/SPGI-C) should be assessed after SCoRS at the respective visits when they are scheduled. 
Similarly, patients should complete PGI-S/PGI-C after PRECIS is completed at the 
respective visits when these measurements are scheduled.If qualified, the SCoRS rater 
should preferably perform the CGI-S/CGI-C.

The CGI rater should base their assessment after review of information about the patient at 
that visit for CGI-S or since start of treatment for CGI-C including the SCoRS interview.

To prevent bias on SCoRS rating, raters of SCoRS should remain blinded to the patient’s 
performance on both MCCB and VRFCAT and MUST be different from the person 
adminstring MCCB and VRFCAT.

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
During the MCCB assessments and throughout the visit, patients are allowed to take short 
breaks as needed, in the judgement of the rater/investigator.

In case of patient experiences acute episode of schizophrenia (relapse), all efficacy 
assessments MUST be rescheduled (even if outside the visit window) until patient 
stabilizes, per investigators judgment. All safety assessments including PANSS, C-SSRS
should be conducted, if possible. 

It is the responsibility of the Principal Investigator at the site to ensure that all site staff 
members are properly trained on all trial procedures and training documentation is filed in 
the ISF. 
o
In addition, the site staff members who are administering the scales must be 
trained and certified.

Vital signs and ECG should always be measured before any blood samples are taken. For 
further details on how to collect ECG, please refer to Section 5.2.4, for details on vital signs 
measurement, please refer to Section 5.2.2.

Any abnormal condition of clinical significance identified, during physical examination, 
vital signs, 12 lead ECG, laboratory assessment or any other medical assessment should be 
recorded as a baseline condition (if noted at screening)/ adverse event (if noted during 
treatment or follow up period), as applicable.

Safety lab and/ or drug screen test (urine), may be performed more frequently based on 
investigator discretion or if required locally.

Patients do not have to come fasted for any trial visits.
Study partner requirements:

The study partner should remain constant throughout the trial period, however in 
exceptional circumstances, a change of study partner will be allowed.

Input from study partners will be required on the assessments indicated in the Flow 
Chart. 

In-person ratings are preferred whenever possible. However, if the study partner is not 
available for in-person ratings, telephone interview is acceptable. The telephone 
interview with the study partner must be conducted within the visits window indicated in 
the Flow Chart for which study partner input on SCoRS, PANSS and SPGI-S/C is
required.
For study partners who also fulfil the criteria of a caregivers:

Study partners who are also caregivers will be asked to complete the EQ-5D-5L and 
SCQ. Please refer to Appendix 10.2 for definition of study partner vs. caregiver.

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
For caregiver assessments, in person visit is preferred. However, if not possible, the 
caregiver may come on another day to fill-in the EQ-5D-5L and SCQ questionnaires –
this should be as close to the visit as possible, preferably within the study visit window.
COVID-19 specific instructions:

During the COVID-19 pandemic, there might be situations when patients already in the 
study might not be able to come to the site for the scheduled visit. This might be due to 
restrictions set by authorities or by the investigator site/institution, because the patient is 
quarantined, or because of any patient specific situation that the investigator judges as 
being not safe for the patient to come to the site. For details on potential modifications of 
the trial conduct related to the COVID-19 pandemic, please refer to Appendix 10.3.
6.2.2
Screening period
Screening Period (Visit 1 and Visit 1a, as applicable)

A signed trial informed consent form must be obtained from the patient before either the 
patient or the study partner performs any study related procedure. A signed informed 
consent form must be obtained from the study partner before performing any study 
related procedure by the study partner. If visit 1 procedures are performed on multiple 
days, each individual assessment or procedure must not be conducted over 2 different 
days (for example, the entire MCCB must be performed on one day). All visit 1 
procedures must be completed before completing visit 1a.The patient is recorded on the 
enrolment log and registered in the IRT system as a screened patient.

Duplication check: the patient IRT number and identifiers will be recorded on the 
vendor portal to confirm that the patient is not participating in another clinical trial.
Screening can only continue after Verified Clinical Trials provides confirmation. The 
investigator will receive email confirmation from the duplication check vendor that the 
patient is currently not participating in another trial in their database. Once email is 
received the site can continue screening. 

Please refer to the general requirements in section 6.2.1.

Drug of abuse testing: During screening, the investigator should highlight to patients the 
importance of not taking drugs of abuse during the study, and that the urine drug screen 
will be repeated periodically throughout the trial. Patients should also be informed that 
they cannot participate in the trial if they have a positive urine drug screen (see further 
the relevant exclusion criterion in Section 3.3.3).

The MCCB scoring sheets must be sent to the vendor (
) as soon as possible. The 
Screening MCCB T-score is required for randomization via the IRT at visit 2.

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
Eligibility Assessement:
o
Once all screening procedures are complete (including laboratory results are 
received), all data collected should be reviewed against the eligibility criteria.
o
If the patient is eligible, the patient should be contacted to schedule next visit 
(Visit 2).
o
If the patient is not eligible (i.e. if they are considered a screen failure), they must 
be registered as a screen failure in IRT.

Rescreening: Patients who fail screening may repeat the screening period once after 
discussion between investigator and sponsor. Please see Section 3.3 for further details 
regarding re-screening.
6.2.3
Treatment period(s)

The randomized treatment period is from Visit 2 to EoT or (e)EoT Visit.

Please refer to the general requirements in Section 6.2.1.

Please refer to Appendix 10.3 for guidance in case of any exceptional circumstances.
Sites should consult with sponsor before making any modifications.

At Visit 2, and during the treatment period, patients should be reminded to take the trial 
drug as instructed, see Section 4.1.4.

At Visit 2, and as needed throughout the treatment period, patients should be reminded 
about the importance of not taking drugs of abuse during the trial, and that the urine drug 
screen will be repeated periodically throughout the trial.
6.2.3.1
Randomization (Visit 2)

It should be ensured that all Visit 1 and Visit 1a procedures have been successfully
completed.

MCCB is to be done before any other efficacy assessments.

Study procedures for Visit 2 can be split into 2 sequential days, in which case: 
o
The MCCB and VRFCAT must be performed on the first day.
o
The remaining assesments can be done per the convienence of the patient and site, 
either on day 1/ day 2.
o
To reduce burden on study partner, it is recommended to perform PANSS and 
SCoRS on the same day.
o
In case of a split visit, the second day will be day of first study drug intake.

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
Biobanking sample, for patients who have signed the optional Biobanking consent form, 
should be collected before the intake of the first dose of study medication (refer to
Section 5.5.1).

The MCCB overall T-score from the visit 1 (screening) is required for
randomization at visit 2. 
o
In case that screening MCCB T-score is not available at visit 2, site may postpone 
this visit by maximum of 2 weeks.

Patient eligibility must be confirmed before the patient is randomized in the IRT. Intake 
of the study medication must be done after the patient has completed all of the other visit 
2 assessments.

First intake of trial drug will be done on site using the AiCure medication adherence 
monitoring app and under supervision by trial staff.

The first two medication kits will be dispensed and will contain sufficient trial drug for 
28 days (21 treatment days plus 7 days reserve). For further information refer to Section 
4.1.4.

At each clinic visit, patients should be reminded not to take study medication AT HOME 
on the morning of the visit. At each visit, patient will take medication AT THE CLINIC 
using AiCure under supervision by trial staff.
6.2.3.2
Visit 3 to Visit 10

Pre-dose PK blood samples will be collected during the treatment period as per the  Flow 
Chart. Patients should not take trial medication before coming to the clinic on visit days.
Refer to Section 5.3 and Appendix 10.1 for more details.

Patients should be instructed to bring all trial medication (used and unused kits/
packaging including blisters) with them to these clinic visits.

Sufficient trial drug for 28 days (21 treatment days plus 7 days reserve), as assigned by 
IRT, will be dispensed at each visit.

Visit 6 can be split into 2 sequential days, in which case: 
o
MCCB and VRFCAT should be performed on the first day; 
o
The remaining assesments can be done per the convienence of the patient and site, 
either on day 1/ day 2.
o
To reduce burden on study partner, it is recommended to perform PANSS and 
SCoRS on the same day.

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
At Visit 10, patients will be instructed to take the last dose of study medication on the day
before the EoT Visit. In case the EoT Visit is split into 2 sequential days, the last dose of
study medication should be taken on the day before the first day of the split visit.
6.2.3.3
End of Treatment (EoT) Visit - For Treatment completers

Trough PK samples will be collected at the EoT Visit (approximately 24 hours after the 
last dose) for all patients who have not permanently stopped taking the study medication.

The final MCCB assessment at the EoT Visit must be performed after the patient 
completes the 26 week treatment period.

The EoT Visit can be split into 2 sequential days, in which case: 
o
The MCCB and VRFCAT must be performed on the first day.
o
The remaining assesments can be done per the convienence of the patient and site, 
either on first day or the second day of the EOT visit.
o
To reduce burden on study partner, it is recommended to perform PANSS and 
SCoRS on the same day.

Termination of trial medication eCRF pages will be completed.
6.2.4
Follow up of Treatment completers
6.2.4.1
Trial completers rolling-over to the extension trial
Patients who complete the 26 weeks treatment in 1346-0013 and are willing to participate in 
the open label extension trial with iclepertin 10mg (c33088336):

The patient completing the 26 week treatment period will be considered as treatment and 
trial completer. If the patient rolls over into the extension trial at the EOT visit (preferred 
option), the Follow up period visits (14 and 28 days follow up visit) do not have to be 
completed. Termination of trial medication and trial completion eCRF pages will be 
completed with same visit date.

The patient will start participation in the open label extension trial with iclepertin 10mg 
(c33088336).
o
This extension study is conducted under a separate trial protocol and patients will 
need to provide consent to participate in the extension trial. 
o
These patients may enter the extension trial (Visit 1) either (preferably) on the day 
of EOT or at the latest 2 weeks after the EOT visit (i.e. Follow up 1 timepoint 
including the applicable time windows). 
o
If patient decides to roll over between day 1- 7 after EOT, no safety laboratory 
assessment needs to be done unless medically required. 

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o
If patient decides to roll over between day 8 – 14 after EOT, the assessments 
according to Follow up visit 2 shall be completed instead of Follow-up visit 1.
o
If patients decide, at the latest 2 weeks after the EOT visit, not to roll-over to 
extension, please follow the instructions in Section 6.2.4.2.
o
Further details will be provided in the 1346-0014 protocol (c33088336).
6.2.4.2
Treatment completer not rolling over to extension:

Patients who completed 26 weeks treatment but are unwilling to participate in the open 
label extension trial with iclepertin 10mg (c33088336), safety follow up visits (14 and 28 
days follow up visit) will be completed as planned.

After completing 28 days of follow up, the patient will be considered a trial completer. 
Trial completion eCRF pages will be completed.

Patients should continue to take their background therapy for schizophrenia, as prescribed 
by the investigator or treating physician.
6.2.5
Early Permanent Treatment Discontinuation and further follow up
Every effort should be made to collect data in all randomised patients. This includes randomised 
patients who never took the study medications and patients who permanently discontinued study 
drug.
6.2.5.1
Early Permanent Discontinuation from Treatment

If a patient permanently discontinues the study medication, an eEOT visit must
preferably be performed within 7 days after the last dose of study medication. It is 
extremely important that patient should be encouraged to complete at least the MCCB, 
SCoRS and VRFCAT assessments. The termination of trial medication eCRF page must 
be completed with the reason for discontinuation of treatment.

The eEoT Visit can be split into 2 sequential days, in which case: 
o
The MCCB and VRFCAT should be performed on the first day; 
o
PRECIS should not take place immediately after MCCB, to avoid bias
o
The remaining assesments can be done per the convienence of the patient and site, 
either on first day or the second day of the eEOT visit.
o
To reduce burden on study partner, it is recommended to perform PANSS and 
SCoRS on the same day.

After the eEOT visit, patients should complete the safety follow-up visits and continue 
with scheduled trial visits and assessments until the planned end of the trial for that 
patient unless they withdraw consent to participate in the study
o
Refer to the Retention Pan Guide in your ISF for further information. 

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
If it is not possible to attend all visits, a phone contact should occur at the scheduled visit 
time points. It is vital to explain to these patients the importance of continued trial 
participation.

When discussing options for continued trial participation, sites must present the first 
option to the patient and discuss this option thoroughly before presenting the next option 
for follow-up.

Patients should be encouraged to choose the most rigorous follow-up regimen they 
are willing and able to comply with. The investigators should inform these patients 
that they will be allowed to change this regimen later if needed. 

Patients may choose to re-start trial medication intake at any time during their 
planned treatment period as long as there is no safety concern in the opinion of the 
investigator. 
Table 6.2.5.1: 1
Follow-up of patients who prematurely discontinue the study treatment*
Early D/C Option 1
Continue to conduct regularly scheduled study visits as per protocol
and prioritize the collection of the efficacy endpoints, at least for the 
primary, key secondary and secondary efficacy endpoints 
In case patient does not 
agree to option 1, then 
present 
Early D/C Option 2
Focus on key efficacy endpoints MCCB, SCoRS, VRFCAT (the 
minimum at least MCCB) and safety** assessments per Flow Chart.
In case patient does not 
agree to option 2, then 
present 
Early D/C Option 3
Collect safety** data: 

at scheduled study visit time points or

as agreed with the patient or

at least at planned EOT or EOT +28 days, whichever is longer 
* Dispense and administer IMP, IMP compliance check, AiCure related activities, PK Sampling, 
biobanking sampling do not need to be performed in patients who have permanently stopped taking 
the study drug.
** Safety data may be collected from the patient, or a person designated by the patient (e.g., family, 
spouse, partner, legal representative, or physician etc…) or through review of patient’s medical 
information from alternative sources (e.g., doctor’s notes, hospital records, etc.). Refer section 
5.2.6.2.1 AE Collection: For patients who permanently discontinue trial medication prematurely.

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6.2.5.2
Safety Follow up: Patients who prematurely discontinue treatment

Follow up Visits will be conducted 14 and 28 days after the early EoT visit.

In case the Follow-up visits are completed earlier than the planned timepoints by mistake, 
then a repeated follow-up visit on or after 28 days post early EOT needs to be performed.

AEs that are ongoing at the last Follow-up Visit should be followed up until they are
resolved, have been assessed as “chronic” or “stable”, or no further information can be
obtained or deemed reasonably followed up by the investigator. Refer Section 5.2.6.2.1
AE Collection: For patients who permanently discontinue trial medication prematurely.

Refer to ISF for follow up post 28 days (Follow-up 2 visit) up to the planned end of Trial 
Period (i.e. 26 weeks).

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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
The primary efficacy objective is to assess the absolute difference in adjusted mean change from 
baseline to Week 26 in MCCB overall composite T-score (cognition) for once daily oral 
treatment with iclepertin 10mg QD as compared with placebo in patients with CIAS. The key 
secondary efficacy objectives are to assess the absolute difference in adjusted mean change from 
baseline to Week 26 in SCoRS interviewer total score and adjusted total time T-score in 
VRFCAT between iclepertin 10mg QD and placebo. Intercurrent events will be addressed using 
a strategy that differs depending upon the nature of the intercurrent event.
The treatment effect for the following treatment policy is of interest: patients remain on 
randomized treatment for the duration of the trial unless an exacerbation or acute episode or an 
event considered to be drug-related interrupts or discontinues treatment. Changes in background 
medication or non-pharmacological intervention are allowed. 
Estimation will assume that the policy is followed by all randomized patients. All measurements 
obtained for patients while on this policy are therefore relevant for the estimation of the primary 
estimand, while measurements obtained after a deviation from this policy are not relevant for the 
estimation of the primary estimand. 
The following intercurrent events are considered to form part of the treatment policy being 
assessed and hence subsequent measurements are included in the primary analysis of the 
endpoint: 

Change in background medication (e.g. antipsychotics, etc)

Change in non-pharmacological therapy (e.g. cognitive therapy, any kind of psychotherapy, 
nicotine withdrawal therapy, diet, etc)

Exacerbation or acute episode which results in interruption or early termination of treatment

Investigator assessed drug-related adverse events which lead to early termination of study 
medication

Protocol-defined drug withdrawal due to treatment, e.g. haemoglobin decrease, concomitant 
medications with CYP3A4 substrates

Change in study partner in the assessment of functional capacity, e.g. SCoRS
All other intercurrent events are considered to represent breaks from the treatment policy and 
therefore confound estimation of the treatment effect of interest. Such intercurrent events would 
include, for example, early termination of treatment due to reasons unrelated to treatment (e.g. 
consent withdrawal, incarceration, somatic illness like stroke, cardiovascular events, etc, 
hospitalization due to somatic illness). Measurements after these intercurrent events are excluded 
from the primary analyses.

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7.1
NULL AND ALTERNATIVE HYPOTHESES
The hypothesis testing strategy is a gatekeeping procedure [R20-0199] with strong control of
family-wise type I error rate at one-sided 0.025 as depicted in Figure 7.1: 1. The first family
consists of the superiority hypothesis test (H1) of the primary endpoint. The second family
consists of the superiority hypothesis tests (H2 for SCoRS and H3 for VRFCAT) of the two
key secondary endpoints. The third family consists of the superiority hypothesis tests (H4 for
Tower of London and H5 for PRECIS) of the two secondary endpoints. The overall family-wise 
type I error rate is controlled at one-sided alpha of 0.025. Let α1, α2 and α3 denote the controlled
one-sided alpha rate allocated at the beginning of Family 1, Family 2 and Family 3 and α = α1
= 0.025. The observed one-sided p-values from each hypothesis test in each family are
denoted as p1, p2, p3, p4, and p5.
Figure 7.1: 1
Gatekeeping procedure of the hypothesis testing strategy
a) First family: Superiority test of the primary endpoint, change from baseline to Week 26 in 
MCCB overall composite T-score
(1) H0,1: 
The adjusted mean change from baseline to Week 26 in MCCB overall composite 
T-score in iclepertin 10mg QD is worse than or equal to that in placebo;
versus 
HA,1: The adjusted mean change from baseline to Week 26 in MCCB overall composite 
T-score in iclepertin 10mg QD is better than that in placebo.

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The primary objective of this pivotal phase III trial will be achieved if H0,1 is rejected at the one-
sided alpha of 0.025 level and this trial is considered a success. Family 1 serves as a parallel 
gatekeeper for Family 2. If H0,1 is not rejected at one-sided alpha of 0.025 level, then α2 = 0 and 
no formal hypothesis tests in the second and third families will be conducted.
After H0,1 is rejected, the full family-wise type I error rate of one-sided 0.025 will be passed
on to the hypothesis tests in the second family (i.e. α2 = 0.025 one-sided) for which a
truncated Hochberg approach [R97-0605] will be used with a truncation parameter γ. Based
on our simulation results, we choose γ = 0.2 for this trial.
b) Second family: Superiority tests of the two key secondary endpoints
(2)
H0,2: 
The adjusted mean change from baseline to Week 26 in SCoRS interviewer total 
score in iclepertin 10mg QD is worse than or equal to that in placebo;
versus 
HA,2: The adjusted mean change from baseline to Week 26 in SCoRS interviewer total 
score in iclepertin 10mg QD is better than that in placebo.
(3)
H0,3: 
The adjusted mean change from baseline to Week 26 in adjusted total time T-
score in VRFCAT in iclepertin 10mg QD is worse than or equal to that in placebo;
versus 
HA,3: The adjusted mean change from baseline to Week 26 in adjusted total time T-
score in VRFCAT in iclepertin 10mg QD is better than that in placebo.
If both p2 and p3 are < α2*(1+)/2 (one-sided), then both hypothesis tests are statistically 
significant and the one-sided type I error of 0.025 will be passed on to the third family, i.e. α3 = 
0.025.
If the maximum of p2 and p3 is ≥ α2*(1+)/2 (one-sided), then the smaller of the two p-values 
will be tested at one-sided alpha of α2/2 and the corresponding hypothesis test is statistically 
significant if the remaining p-value is < α2/2 (one-sided). In this case as only one of the two key 
secondary efficacy endpoints is statistically significant, the remaining alpha of α3 = α2*(1-)/2 
will be passed on to the third family.
If neither H0,2 nor H0,3 in the second family are rejected, then no alpha will be passed onto the 
third family, i.e. α3 = 0 and none of the hypothesis tests in the third family is controlled for 
family-wise type I error and hence will not be considered as formal hypothesis tests.
Family 2 serves as a parallel gatekeeper for Family 3 which means that the formal hypothesis 
testing procedure will proceed to Family 3 if at least one of the two null hypotheses (H0,2 and 
H0,3) is rejected in Family 2. If one or both of H0,2 and H0,3 in Family 2 is rejected, then the 
remaining family-wise type I error rate α3 will be passed on to the hypothesis tests in the third 
family for which a regular Hochberg method will be used.

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c) Third family: Superiority tests of the two secondary endpoints
(4)
H0,4: 
The adjusted mean change from baseline to Week 26 in the T-score of the number 
of correct responses on Tower of London in iclepertin 10mg QD is worse than or equal to
that in placebo;
versus 
HA,4: The adjusted mean change from baseline to Week 26 in the T-score of the number 
of correct responses on Tower of London in iclepertin 10mg QD is better than that in 
placebo.
(5)
H0,5: 
The adjusted mean change from screening to Week 24 in PRECIS total score in 
iclepertin 10mg QD is worse than or equal to that in placebo;
versus 
HA,5: The adjusted mean change from screening to Week 24 in PRECIS total score in 
iclepertin 10mg QD is better than that in placebo.
If the maximum of p4 and p5 in Family 3 is < α3 which is the one-sided alpha passed down from 
Family 2 to Family 3, then both H0,5 and H0,6 are rejected. Otherwise, if the maximum of p4 and 
p5 is ≥ α3 which is the one-sided alpha passed down from Family 2 to Family 3, then the smaller 
p-value will be compared with α3/2, and the corresponding null hypothesis is rejected if the p-
value is < α3/2.
All further endpoints are not under the type-I error control, and hence, all analyses are 
considered exploratory. 
7.2
PLANNED ANALYSES
7.2.1
General considerations
The following patient analysis sets are defined for this trial:

Randomized Set (RS): includes all patients who signed informed consent and were 
randomized into the trial, regardless if a patient was treated with trial medication. The RS 
is used for efficacy analyses and patients in RS are analysed under the randomized trial 
medication. Patients randomized in error and discontinued from the study before the start 
of trial medication will be excluded from the RS.

Treated Set (TS): includes all patients who signed informed consent and were treated 
with at least one dose of the trial medication. Patients in TS are analyzed under the actual 
trial medication received at randomization. The TS is used for safety analyses as well as 
demographics and baseline characteristics.

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Data from patients who were screened but not randomized will be listed but not included in any 
summary or inferential statistics.
In general, baseline values are the measurements taken prior to the first administration of trial
medication at randomization (Visit 2), or Visit 1a if no measurements are planned at Visit 2,
(see Flow Chart). Further details will be provided in the TSAP.
7.2.2
Primary endpoint analyses
The primary analysis of the primary efficacy endpoint uses the Randomized Set. Subjects will be 
analysed according to the stratum to which they actually belong (not necessarily the stratum they 
are randomized to, and regardless of any mis-assignment to treatment based on identification of 
the wrong stratum), as such an error occurs before ranodmisation and is therefore consistent with 
the regulatory guidance. Intercurrent events are handled as specified in Section 7 above and 
missing data as a result from the strategy (including both actual missing outcomes and excluded 
outcomes) will be handled using a mixed effects model with repeated measures (MMRM) under 
the assumption of missing at random. Forchange from baseline to Week 26 in MCCB overall 
composite T-score, a restricted maximum likelihood (REML) based approach using MMRM will 
be conducted to compare the adjusted mean between iclepertin 10mg QD vs. placebo. The 
MMRM includes the fixed categorical effects of treatment at each visit, fixed categorical effect 
of the stratification factor using the screening MCCB overall composite T-score, and the fixed 
continuous covariates of baseline MCCB overall composite T-score at each visit. Subject is 
treated as random effect. Visit will be treated as the repeated measure with an unstructured 
covariance structure used to model the within-subject measurements. 
The statistical model is:
 = 
 +  +  + , where ~(0, ),
where 
 = response variable for subject ) in stratum + at visit , receiving treatment .
 = the baseline MCCB overall composite T −score of subject ), ) = 1, 2, . ..

 = coefficient of baseline effect at visit ,, , = 1, 2, . . . , 8
 = the effect of treatment . at visit ,, . = 1, 2
 = the effect of screening MCCB overall composite T −score stratum + for + = 1, 2,
and : ≡0 for stratum 1 of T −score < 30
 = the random error associated with ,th visit of the )th subject.
 = a 8 × 8 unstructured covariance matrix
The Kenward-Roger approximation will be used to estimate denominator degrees of freedom and 
adjust standard errors. The point estimates of the adjusted mean difference between treatment 
arms at each visit, together with the corresponding two-sided 95% confidence intervals and p-
values will be presented. The primary treatment comparison will be the contrast between 
treatments at Week 26.

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Procedures to follow if the MMRM analysis fails to converge will be described in the Trial 
Statistical Analysis Plan.
To assess the robustness of the primary analysis result, sensitivity analyses of the primary 
endpoint are planned in which the same strategy for handling intercurrent events as used for the 
primary analysis will be applied.

For subjects who had early treatment termination due to exacerbation or acute episode or an 
event considered to be drug-related, missing data after the intercurrent event will be imputed 
through a reference-based multiple imputation method, i.e., using the observed off-treatment 
data from patients in the same treatment arm to impute the missing off-treatment data. All 
other missing data, e.g. missing on-treatment data or missing data after other intercurrent 
events, will be imputed using the observed on-treatment data from all randomized subjects in 
the same treatment arm.

For all missing data, a reference-based approach using observed off-treatment data from the 
same treatment arm to impute missing data will be applied for multiple imputation. This 
would be a conservative approach to missing data assuming missing not at random.

For all missing data, apply a jump-to-reference (J2R) method for multiple imputation, i.e. 
assume subjects in BI arm switch to the placebo arm distribution following the missingness. 
This would be a conservative approach to missing data assuming missing not at random.
After applying the above different multiple imputation methods for the missing data (including 
the “set-to-missing” data), an Analysis of Covariance (ANCOVA) model including the fixed 
effects of treatment, categorical effect of stratification factor using screening MCCB overall 
composite T-score, and baseline MCCB overall composite T-score will be fitted for the primary 
endpoint at Week 26. Rubin’s rules will be applied to derive the single point estimates and the 
corresponding standard errors from the multiple imputations [R12-2094].
In addition, as a supplement to the strategy for handling the intercurrent events as used in the 
primary analysis and sensitivity analyses, we will conduct the following supplementary analyses 
for the primary endpoint:

Handle all intercurrent events using treatment policy approach and then apply the same 
MMRM model as used in the primary analysis assuming missing at random.

Handle all intercurrent events using hypothetical approach, i.e. censoring all data after the 
intercurrent event, and apply the MMRM model as used in the primary analysis assuming 
missing at random.

Consider different strategies for handling intercurrent events, e.g. consider different set of 
intercurrent events to be handled using treatment policy, consider using while on treatment 
strategies.
More details on the sensitivity analyses and the supplementary analyses will be provided in the 
TSAP.
To address the COVID-19 pandemic or other potential public health crisis, BI plans to 
investigate logistical mitigation measures introduced for COVID-19 and develop statistical 

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assessments accordingly, e.g. if the option for remote visits is introduced, BI will compare 
remote to in-person visits.
In addition, BI will summarize the prevalence of intercurrent events caused by COVID-19, e.g., 
COVID-19 infection as an AE; discontinuation of study treatment because of “administrative” 
reasons such as lack of availability of medical procedures and treatment, quarantine, travel 
restrictions, etc. The resulting intercurrent events lead to missing outcomes. Some patients may 
still be able to continue treatment if they have sufficient drug supply but may have missing
outcomes because of missing evaluation visits. The proposed primary estimand and analysis 
strategies should already address COVID-19 related intercurrent events.
Currently, the following subgroup analyses are planned on P3 results:

Baseline level of cognition (i.e., MCCB overall composite T-score)
As the same set of efficacy endpoints will be collected in three parallel pivotal phase III trials 
(1346-0011, 1346-0012, 1346-0013), BI plans to conduct random-effects and fixed effects meta-
analyses using the pooled data from these three trials for the primary, key secondary and 
secondary efficacy endpoints. In these pre-planned meta analyses, the same gatekeeping 
procedure as planned for the hypothesis tests in each individual phase III trial will be conducted
using a stand-alone family-wise type I error rate of one-sided alpha=0.025. These pre-planned 
meta-analyses will be conducted to provide a totality view of the data in the phase III clinical 
programs and to support the proposed indication.
7.2.3
Secondary endpoint analyses
For the two key secondary efficacy endpoints of change from baseline to Week 26 in SCoRS 
interviewer total score and adjusted total time T-score in VRFCAT, as well as the secondary 
efficacy endpoint of change from screening to Week 24 in PRECIS total score, the same strategy 
for handling the intercurrent events in the primary estimand analysis and a similar MMRM 
analysis used for the primary efficacy endpoint will be conducted to obtain the adjusted mean 
treatment effect between BI and placebo in terms of change from baseline to Week 26 (from 
screening to Week 24 for PRECIS total score). This MMRM model includes the discrete fixed 
effects of treatment at each visit, fixed categorical covariate of the stratification factor using the
screening MCCB overall composite T-score, and continuous fixed effects for the corresponding 
baseline endpoint value at each visit. Visit will be treated as the repeated measure with an 
unstructured covariance structure to model the within-subject measurements. Subjects will be 
considered as a random effect. The primary treatment comparison is the contrast between 
treatments at Week 26 (Week 24 for PRECIS total score). For change from baseline to Week 26 
in the T-score of number of correct responses on Tower of London, an analysis of covariance 
(ANCOVA) model including treatment, stratification factor of screening MCCB overall 
composite T-score (< 30, ≥ 30), and baseline number of correct responses on Tower of London 
T-score will be fitted to the data.

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Similar sensitivity and supplementary analyses as planned for the primary efficacy endpoint will 
also be conducted for the two key secondary efficacy endpoints.
7.2.5
Safety analyses
Adverse events will be coded using the Medical Dictionary for Drug Regulatory Activities
(MedDRA) coding dictionary. Standard BI summary tables and listings will be produced. 
All treated patients will be included in the safety analysis and will be summarized under the 
actual trial medication received at randomization. In general, safety analyses will be descriptive 
in nature and will be based on BI standards. No hypothesis testing is planned.
Statistical analysis and reporting of adverse events will concentrate on treatment-emergent 
adverse events. To this end, all adverse events occurring between the start of treatment and the 
end of the residual effect period will be considered ‘treatment-emergent’. The residual effect 
period is defined as 12 days after the last dose of trial medication. Adverse events that start 
before first drug intake and deteriorate under treatment will also be considered as ‘treatment-
emergent’.
Frequency, severity, and causal relationship of adverse events will be tabulated by system organ 
class and preferred term after coding according to the current version of the MedDRA.
Frequency tables for all adverse events, protocol-specified adverse event of special interest 
(AESI), serious adverse event (SAE), adverse event leading to death, adverse event leading to 
discontinuation, investigator assessed drug-related adverse event and serious related adverse 
event will be generated for treatment-emergent adverse events. In addition, summary statistics 
and descriptive analyses will be conducted for other safety parameters that are assessed using 
dedicated scales, including suicidality as assessed by C-SSRS, disease severity as assessed by 
PANSS total score and changes over time on AIMS, SAS and BARS scales for EPS and related 
movement impairments. 
Laboratory data will be analysed both quantitatively as well as qualitatively. The latter will be 
done via comparison of laboratory data to their reference ranges. Values outside the reference 

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range as well as values defined as clinically relevant will be highlighted in the listings. Treatment 
groups will be compared descriptively with regard to distribution parameters as well as with 
regard to frequency and percentage of patients with abnormal values or clinically relevant 
abnormal values.
Vital signs, physical examinations, or other safety-relevant data observed at screening, baseline, 
during the course of the trial and at the end-of-trial evaluation will be assessed with regard to 
possible changes compared to findings before start of treatment.
7.2.7
Interim Analyses
No interim analysis is currently planned but safety will be monitored by an external and 
independent DMC.
7.3
HANDLING OF MISSING DATA
Every effort will be made to collect complete data at the specific time points, even for subjects 
who terminated trial medication prematurely. If not specified otherwise, missing data are not
imputed and remain missing. Potential outliers will be reported and analysed as observed.
For the primary estimand analysis of the primary efficacy endpoint using the mixed strategy for 
handling intercurrent events, if a subject misses a visit, the missing data will not be imputed. The 
MMRM analysis will handle missing data based on a likelihood method under the “missing at 
random” assumption.
MCCB endpoints
All imputations will be carried out separately for each study visit since there may be differences 
in test performance at different time points.
For the domains of Working Memory (consisting Letter-Number Span test and Wechsler 
Memory Scale 3rd ed. Spatial Span subtest) and the Speed of Processing (consisting Trail Making 
Test Part A, Brief Assessment of Cognition in Schizophrenia – Symbol Coding subtest, and 
Category Fluency test – animal naming), if only one of the tests consisting of a domain has 
missing value at a visit, the corresponding domain score can still be derived using the observed 
test raw score for that visit. If more than one of the tests consisting of a domain have missing 
value at a visit, the corresponding domain score is missing at that visit.

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For the other five domains (Verbal Learning, Reasoning and Problem Solving, Visual Learning, 
Attention / Vigilance, and Social Cognition) which has only one test, if the test has missing value 
at a visit, the corresponding domain score is missing.
If a domain score is missing at a visit, the missing T-score of this domain can be imputed using
the proprietary algorithm developed by MATRICS.
For baseline assessment, at least two-thirds of the cognitive domains (i.e., a minimum of five out 
of the seven domains for the MCCB overall composite score and a minimum of four out of the 
six domains for the MCCB neurocognitive composite score) need to be successfully assessed at 
baseline for it to be counted as a test occasion with non-missing baseline value.
For post-baseline assessments, at least half of the domains (i.e., a minimum of four out of the
seven domains for the MCCB overall composite score and a minimum of three out of the six 
domains for the MCCB neurocognitive composite score) need to be successfully assessed to be 
considered a test occasion with non-missing value.
SCoRS endpoints
For the 20-item SCoRS assessment, if six or more of the 20 items have missing response, which 
includes the response of “N/A”, for a subject at a visit, then the SCoRS total score for that 
subject at that visit is missing. If five or less of the 20 items have missing response, which 
includes the response of “N/A”, for a subject at a visit, then the item with missing response will 
be imputed first with the average of the non-missing item values for the subject at the visit, and 
then SCoRS total score for the subject at the visit will be derived as the sum of the non-missing 
item values and the imputed item values.
PRECIS endpoints
The PRECIS scale consisted of 28 items, among which the first 26 items are coming from six 
domains, i.e., memory, communication, self-control, executive function, attention and sharpness 
of though, and the last 2 items measure overall degree of bother associated with all domains. For 
the aforementioned six domains, the maximum numbers of items allowed to be missing within 
each domain are 3, 1, 0, 0, 3 and 0, respectively, so that each domain would have at least 3 non-
missing items. Within each domain, if the number of missing items exceed its allowable value, 
then the corresponding domain score would be considered missing, otherwise, the domain score 
is calculated as the average of the non-missing items scores under the domain. The PRECIS total
score is calculated when not more than 7 items are missing overall, and the total score is 
calculated as the average of the non-missing item scores of the first 26 items. 
A detailed description of the PRECIS items, the corresponding domains and the minimum 
number of non-missing items required for the domain scores is provided in Table 5.1:2. 

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Additional details on the handling of missing data will be specified in the TSAP prior to 
unblinding.
7.4
RANDOMISATION
Eligible subjects will be randomised in equal ratio to iclepertin 10mg arm and the placebo arm. 
The randomisation will be implemented in blocks to achieve balanced allocation to each 
treatment arm. In addition, randomisation will be stratified by two factors: 1) the screening 
MCCB overall composite T-score (two strata: < 30, ≥ 30) with the cut-off values based on the 
characteristics of the MCCB overall composite T-score from historical data [R19-3841], and 2) 
participation in the ocular substudy (Yes, No).
The randomization will be conducted via an interactive response technology (IRT). BI will 
arrange for the randomization and the packaging and labelling of trial medication. The 
randomization list will be generated using a validated system, which involves a pseudorandom 
number generator so that the resulting treatment will be both reproducible and nonpredictable. 
The block size will be documented in the CTR. Access to the codes will be controlled and 
documented.
7.5
DETERMINATION OF SAMPLE SIZE
Results from a phase II proof of clinical concept and dose ranging trial (1346-0009, c31477880) 
show the largest mean improvement of iclepertin vs. placebo in change from baseline to Week 
12 in MCCB overall composite T-score is about 2 points with the estimated standard deviation of 
approximately 5.8 at Week 12 (the estimated standardized effect size is about 0.35), and the 
largest mean improvement of iclepertin vs. placebo in change from baseline to Week 12 in 
SCoRS interviewer total score is 1 point with the estimated standard deviation of approximately
5.5 at Week 12 (the estimated standardized effect size is about 0.2). For this phase III trial with a 
treatment duration of 26 weeks and considering a treatment effect under the proposed primary 
estimand framework (i.e. definition of intercurrent events and the corresponding handling 
strategies), we assume a standardized effect size of 0.35 in the sample size calculation for the 
primary and the two key secondary efficacy endpoints and also assess the power of the proposed 
sample size under different assumptions of the standardized effect sizes for the key secondary 
efficacy endpoints.
The method of the two-sample t-test with equal variances and equal n’s using the software 
nQuery + nTerim 4.0 was used to calculate the sample size based on each of the primary and the 
key secondary efficacy endpoints individually. An effective sample size of 220 subjects per arm, 
440 subjects in total, will detect a standardized effect size of 0.35 in the primary efficacy 
endpoint, or in any of the two key secondary efficacy endpoints individually, with 95% power 
under one-sided type I error rate of 0.025. With 220 subjects per arm and one-sided type I error 
rate of 0.025, a standardized effect size of 0.31, 0.286, 0.268, and 0.25 can be detected for each 
of the primary and the two key secondary efficacy endpoints individually with 90%, 85%, 80%, 
and 75% power respectively.

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As a complex gatekeeping procedure is used for the hypothesis tests in this phase III trial and the 
controlled one-sided type I error rate for each hypothesis test depends on the result of other 
endpoints, it is very complicated, if not impossible, to derive the mathematical formula for the 
power of each efficacy endpoints considered in the gatekeeping procedure. As a result, we 
conducted simulations to approximate the power for each efficacy endpoint (i.e. the probability 
of rejecting each null hypothesis) using the gatekeeping procedure under five different scenarios 
of the standardized effect sizes for each efficacy endpoint with the truncation parameter 
ranging from 0.2 to 0.9, 220 evaluable subjects per arm, one-sided family-wide type I error rate 
of 0.025, and 0.2 correlation among efficacy endpoints. We also approximate the probability of 
rejecting H0,1 and one or both of H0,2 and H0,3 under the same five scenarios.
Simulation results as presented in Table 7.5: 1 show that with 220 evaluable subjects per arm, 
there is at least 95% power to detect an effect size of 0.35 in MCCB overall composite T-score, 
regardless of the effect sizes in SCoRS interviewer total score and the adjusted total time T-score
in VRFCAT. Furthermore if the effect sizes in both key secondary efficacy endpoints are 0.35 
(Scenario #1), then with 220 evaluable subjects per arm we have close to 90% power to detect 
such effect sizes and the probability of rejecting H0,1 and one or both of H0,2 and H0,3 is close to 
95%. If only one of the two key secondary efficacy endpoints has an effect size of 0.35 (Scenario 
#2), then with 220 evaluable subjects per arm we have close to 90% power to detect such an 
effect size and the probability of rejecting H0,1 and one or both of H0,2 and H0,3 is 88.9%. If one 
of the two key secondary efficacy endpoints has an effect size of 0.3 but not the other key 
secondary efficacy endpoint (Scenario #3), then with 220 evaluable subjects per arm we have 
78.6% power to detect such an effect size and the probability of rejecting H0,1 and one or both of 
H0,2 and H0,3 is 79.6%. The simulation results also show that the truncation parameter ranging 
from 0.2 to 0.9 does not impact the marginal powers for the primary and the two key secondary 
efficacy endpoints much. Hence we choose = 0.2 as this gives the desired probabilities of 
success for the primary endpoint (>90%) and for the key secondary efficacy endpoints (about 
80%), as well as larger probabilities of success for the two secondary efficacy endpoints under 
Scenarios #1, #2, #3 and #4 as compared with a larger value such as.
In summary with 220 evaluable subjects per arm, simulation results show satisfactory 
operational characteristics of the proposed gatekeeping procedure under Scenarios #1, #2 and #3 
which are considered plausible for this phase III trial.

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Table 7.5: 1
Probability of success for each endpoint under different scenarios of 
effect sizes from simulations
Efficacy 
Endpoints
Primary:
MCCB 
Overall
Key 
Secondary: 
SCoRS 
total score
Key 
Secondary: 
VRFCAT
Secondary:
Tower of 
London
Secondary:
PRECIS
Primary 
and Key 
Secondary: 
reject H0,1
and (H0,2
and/or H0,3)
Scenario #1
(assumed 
standardized 
effect sizes)
0.35
0.35
0.35
0.275
0.275
Probability of 
rejecting null 
from 1000000
simulations
95.6%
89.3%
89.3%
75.2%
75.2%
94.6%
Scenario #2
(assumed 
standardized 
effect sizes)
0.35
0.1
0.35
0.2
0.275
Probability of 
rejecting null
from 1000000
simulations
95.6%
12.8%
88.6%
37.5%
60.9%
88.9%
Scenario #3
(assumed 
standardized 
effect sizes)
0.35
0.1
0.3
0.2
0.2

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Table 7.5: 1
Probability of success for each endpoint under different scenarios of 
effect sizes from simulations (con’t)
Efficacy 
Endpoints
Primary:
MCCB 
Overall
Key 
Secondary: 
SCoRS total 
score
Key 
Secondary: 
VRFCAT
Secondary:
Tower of 
London
Secondary:
PRECIS
Primary 
and Key 
Secondary: 
reject H0,1
and (H0,2
and/or H0,3)
Probability of 
rejecting null 
from 1000000 
simulations
95.6%
12.6%
78.6%
32.4%
32.4%
79.6%
Scenario #4
(assumed 
standardized 
effect sizes)
0.35
0.1
0.25
0.2
0.275
Probability of 
rejecting null 
from 1000000 
simulations
95.6%
12.5%
62.7%
30.0%
46.7%
65.2%
Scenario #5
(assumed 
standardized 
effect sizes)
0.35
0
0
0.2
0.275
Probability of 
rejecting null 
from 1000000 
simulations
95.6%
1.3%
1.3%
1.5%
2.0%
2.4%
With 220 evaluable subjects per arm, one-sided family-wise type I error rate =0.025, correlation between the endpoints = 0.2, truncation 
parameter = 0.2, and the gatekeeping procedure as shown in Figure 7.1: 1.
Based on the proportions of early treatment termination, subjects with missing data and missing 
data patterns as observed in our phase II trial 1346-0009 and anticipating higher proportions of 
early treatment termination based on previous literatures in long-term antipsychotic trials and 
more subjects with missing data in our phase III trial due to longer treatment duration, we project 
30% to 40% subjects will prematurely terminate treatment in our phase III trial. Since BI will 
take every measure to collect all data at the planned visits from early dropout subjects, we 
anticipate 25% to 50% of these early dropouts will have efficacy outcomes collected after 
treatment termination and can be used in the analysis. Based on these estimations, we will apply 

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25% correction for missing data in the sample size calculation for this phase III trial. This gives a 
total number of 586 randomized subjects for the phase III trial, with 293 randomized subjects in 
each treatment arm. 

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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 / EU regulation 536/2014, the Japanese GCP regulations (Ministry of Health and 
Welfare Ordinance No. 28, March 27, 1997) 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 as will be treated as “protocol deviation”.
Standard medical care (prophylactic, diagnostic and therapeutic procedures) remains the 
responsibility of the treating physician of the patient.
The investigator will inform the sponsor immediately of any urgent safety measures taken to 
protect the trial patients 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 
webpage: 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 
rule, no trial results should be published prior to finalisation of the Clinical Trial Report.
The certificate of insurance cover is made available to the investigator and the patients, and is
stored in the ISF.
8.1
TRIAL APPROVAL, PATIENT 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 patient participation in the trial, written informed consent must be obtained from each 
patient (or the patient’s legally accepted representative) according to ICH-GCP and to the 
regulatory and legal requirements of the participating country. Each signature must be personally 
dated by each signatory and the informed consent and any additional patient-information form 
retained by the investigator as part of the trial records. A signed copy of the informed consent 
and any additional patient information must be given to each patient or the patient’s legally 
accepted representative.”
The investigator or delegate must give a full explanation to trial patients and study 
partner/caregiver based on the patient information form. A language understandable to the 

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patient and study partner/caregiver should be chosen, technical terms and expressions avoided, if 
possible. 
The patient and study partner/caregiver must be given sufficient time to consider participation in 
the trial. The investigator or delegate obtains written consent of the patient’s and study 
partner´s/caregiver´s own free will with the informed consent form after confirming that the 
patient and study partner´s/caregiver´s 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 and in accordance with all 
applicable local regulations.
The consent and re-consenting process should be properly documented in the source 
documentation.
8.2
DATA QUALITY ASSURANCE
A risk-based approach is used for trial quality management. It is initiated by the assessment of 
critical data and processes for trial subject protection and reliability of the results as well as 
identification and assessment of associated risks. An Integrated Quality and Risk Management 
Plan 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 patients will be provided by the sponsor. See Section 4.1.5.2 for rules about 
emergency code breaks. For drug accountability, refer to Section 4.1.7.
8.3.1
Source documents
In accordance with regulatory requirements, the investigator should prepare and maintain 
adequate and accurate source documents and trial records that include all observations and other 
data pertinent to the investigation on each trial patient. Source data as well as reported data 
should follow the “ALCOA principles” and be attributable, legible, contemporaneous, original 
and accurate. Changes to the data should be traceable (audit trail).
Data reported on the CRF must be consistent with the source data or the discrepancies must be 
explained.

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The current medical history of the patient 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 patient, documented in 
their medical records, would be acceptable.
Copies of source documents necessary for neurocognitive assessments (e.g. MCCB) will be 
provided to 
. Before sending or uploading those copies, the investigator must ensure that 
all patient identifiers (e.g. patient’s name, initials, address, phone number, social security 
number) have properly been removed or redacted from any copy of the patients’ source 
documents.
If the patient is not compliant with the protocol, any corrective action e.g. re-training must be 
documented in the patient file.
For the CRF, data must be derived from source documents, for example:

Patient identification: gender, year of birth (in accordance with local laws and regulations)

Patient participation in the trial (substance, trial number, patient number, date patient was 
informed)

Dates of patient’s visits, including dispensing of trial medication

Medical history (including trial indication and concomitant diseases, if applicable)

Medication history

Adverse events (onset date (mandatory), and end date (if available))

Serious adverse events (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)

Completion of patient’s participation in the trial (end date; in case of premature 
discontinuation document the reason for it).

Prior to allocation of a patient to a treatment into a clinical trial, there must be documented 
evidence in the source data (e.g. medical records) that the trial participant meets all inclusion 
criteria and does not meet any exclusion criteria. The absence of records (either medical 
records, verbal documented feedback of the patient or testing conducted specific for a 
protocol) to support inclusion/exclusion criteria does not make the patient 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 CRA, auditor and regulatory inspector 
(e.g. FDA). They may review all CRFs and informed consents. The accuracy of the data will be 
verified by direct comparison with the source documents described in Section 8.3.1. The sponsor 
will also monitor compliance with the protocol and GCP.

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8.3.3
Storage period of records
Trial site(s):
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.
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 PATIENT PRIVACY
Data protection and data security measures are implemented for the collection, storage and 
processing of patient data in accordance with the principles 7 and 12 of the WHO GCP 
handbook.
Individual patient 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 patient’s personal physician or to other 
appropriate medical personnel responsible for the patient’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, biobanking and 
future use of biological samples and clinical data, in particular

Sample and data usage has to be in accordance with the separate biobanking informed 
consent

The BI-internal facilities storing biological samples from clinical trial participants as well 
as the external banking facility are qualified for the storage of biological samples 
collected in clinical trials

An appropriate sample and data management system, incl. audit trail for clinical data and 
samples to identify and destroy such samples according to ICF is in place

A fit for the purpose documentation (biomarker proposal, analysis plan and report) 
ensures compliant usage

A fit for purpose approach will be used for assay/equipment validation depending on the 
intended use of the biomarker data

Samples and/or data may be transferred to third parties and other countries as specified in 
the biobanking ICF

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8.6
TRIAL MILESTONES
The start of the trial is defined as the date when the first patient in the whole trial signs 
informed consent.
The end of the trial is defined as the date of the last visit of the last patient in the whole trial
(“Last Patient Completed”). The end of the trial is defined as the "individual patient's end of the 
trial of the last patient" (with individual patient's end of trial defined for patients not rolling over 
(here Follow-Up Visit 2) and for patients rolling over ( day of first administration of study 
medication in the extension trial)
The “Last Patient Last Treatment” (LPLT) date is defined as the date on which the last patient
in the whole trial is administered the last dose of trial treatment (as scheduled per protocol or 
prematurely). Individual investigators will be notified of SUSARs occurring with the trial
medication until 30 days after LPLT at their site.
Early termination of the trial is defined as the premature termination of the trial due to any 
reason before the end of the trial as specified in this protocol.
Temporary halt of the trial is defined as any unplanned interruption of the trial by the sponsor 
with the intention to resume it.
Suspension of the trial is defined as an interruption of the trial based on a Health Authority 
request.
The IEC / competent authority in each participating EU member state will be notified about the 
trial milestones according to the respective laws.
A final report of the clinical trial data will be written only after all patients have completed the 
trial in all countries (EU or non-EU) to incorporate and consider all data in the report.
The sponsor will submit to the EU database a summary of the final trial results within one year 
from the end of a clinical trial as a whole, regardless of the country of the last patient (EU or 
non-EU).
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL
The trial is sponsored by Boehringer Ingelheim (BI).
A Coordinating Investigator is responsible to coordinate investigators at the different sites 
participating in this trial. Tasks and responsibilities are defined in a contract. 
A DMC will be established. Members of the DMC are independent of BI, they are physicians 
experienced in the treatment of the disease under investigation and a statistician. 

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The DMC will evaluate safety data. While DMC members may be unblinded, measures are in 
place to ensure the blinding for everyone else involved in the trial. Regular DMC meetings will 
be held at specified intervals. The DMC will recommend continuation, modification or 
termination of the trial as detailed in the DMC charter. DMC recommendations as well as the 
final BI decision will be reported to the appropriate Regulatory Authorities (RAs)/Health 
Authorities (HAs), IRBs/ECs, and to investigators as requested by local law. The tasks and 
responsibilities of the DMC are specified in a charter.
Relevant documentation on the participating (Principal) Investigators (e.g. their curricula vitae)
will be filed in the ISF.
The investigators will have access to the BI web portal Clinergize to access documents provided 
by the sponsor.
BI has appointed a Clinical Trial Leader (CT Leader), responsible for coordinating all required 
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 Clinical Trial Managers (CT Managers), 
Clinical Research Associates (CRAs), and investigators of participating countries.
The organisation of the trial in the participating countries will be performed by the respective 
local or regional BI-organisation (Operating Unit, OPU) in accordance with applicable 
regulations and BI SOPs, or by a Contract Research Organisation (CRO) with which the 
responsibilities and tasks will have been agreed and a written contract filed before initiation of 
the clinical trial.
Data Management and Statistical Evaluation will be done by BI according to BI SOPs.
Tasks and functions assigned in order to organise, manage, and evaluate the trial are defined 
according to BI SOPs. A list of responsible persons and relevant local information can be found 
in the ISF.
A central laboratory service, a central service evaluating ECG, a vendor for cognitive and 
neuropsychological assessments, a vendor for medication adherence monitoring, a vendor for 
duplication checks, a vendor for speech sample analysis and an IRT vendor will be used in this 
trial. Details will be provided in the respective manuals, available in the ISF.

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9.
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9.2
UNPUBLISHED REFERENCES
c02155957
c02820512
Investigator’s Brochure BI 425809 (iclepertin)
Clinical Trial Report of 
Trial 1346.1. BI 425809 (iclepertin). 05 May 2015
c33087946
Clinical Trial Protocol of Trial 1346-0012.
c33088336
  Clinical Trial Protocol of Trial 1346-0014. 
c03572014
Clinical Trial Report of 
Trial 1346.2. BI 425809 (iclepertin). 04 July 2016
c03724403
Clinical Trial Report of Trial 
1346.3. BI 425809 (iclepertin). 01 February 2016
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Clinical Trial Report of 
Trial 1346.9. BI 425809 (iclepertin). 01 September 2020
U13-2547
Nonclinical Report: Increase of glycine in rat CSF by BI 
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10.
APPENDICES

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10.2
DEFINITION OF STUDY PARTNER AND CAREGIVER
Who can be a study partner?
Who can be a Caregiver?
Study partner is any person who knows 
the patient well, has been capable of 
interacting with the patient on regular 
basis, preferably consistent throughout 
the study, either private or professional
Caregiver is a study partner who is taking 
informal (unpaid) care of the patient, 
which can be direct or indirect, including 
e.g. organizing or checking things for the 
patient, making phone calls, managing 
bills, 
arranging 
things 
and 
doing 
paperwork related to the patient, do 
shopping, cooking, cleaning, laundry, 
etc.
Every patient enrolled in the study must 
have a study partner
Patients do not need to have a caregiver 
but must have a study partner. Therefore,
having a caregiver is optional.
Must sign study partner IC
Will be asked to complete additional 
questionnaires (SCQ, EQ-5D-5L) for 
caregiver assessment consent on study 
partner IC 
The study partner must interact with the 
patient minimum 1 hour per week and, 
preferably, at least 2 times a week. At 
least one interaction per week should be 
in person.
As caregiver, study partner should spend 
an average of approximately 4 hours per 
week or more with care giving (direct or 
indirect, see above).
Don’t need to be co-resident with the patients.
Must have educational achievement of minimum 8th grade.
Professional study partner (e.g. study 
nurse, social worker etc.) are allowed if 
not involved in administration of any of 
the protocol assessments.
Professional study partners cannot be 
caregiver as they are providing paid care.
Will provide input to SCoRS, PANSS, 
SPGI-S, SPGI-C.
Study partners who are NOT caregivers, 
will not complete, EQ-5D-5L and SCQ to 
assess caregiver’s Quality of life and the 
burden of caregiving
In addition to SCoRS, PANSS, SPGI-S, 
SPGI-C, the care-giver will complete EQ-
5D-5L and SCQ to assess caregiver’s 
Quality of life and the burden of 
caregiving.

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10.3
POTENTIAL MODIFICATION OF TRIAL CONDUCT IN CASE OF 
RESTRICTIONS DUE TO COVID-19 OR OTHER EXCEPTIONAL 
CIRCUMSTANCES
In case of any restrictions during the COVID-19 pandemic or any other exceptional 
circumstances (e.g. emergency, natural disaster, patient specific situations, etc.), study conduct 
may need to be adjusted based on the investigator’s discretion and agreed with the sponsor.
Local regulatory and legal requirements of the participating country needs to be respected for all 
modifications. Patients need to be informed about the modifications and agree to them before 
implementation.
If on-site / clinic visits are not possible because the site/institution is limiting or restricting on-
site visits due to COVID-19 (or any other exceptional circumstances), some of the visit 
procedures (including study partner contacts and assessments) can be done via home visit or 
telephone / video conference or locally (e.g. at a local lab, diagnostic centre, GP visit, etc.).
All COVID-19/exceptional circumstances related deviations from the original schedule of visits 
and procedures will be documented, and the implications will be considered for the analysis of 
trial data.
The following contingency measures will be introduced to ensure patient safety and appropriate 
trial continuation based on a thorough benefit-risk assessment of treatment continuation versus 
early discontinuation, to be judged by the investigator on an individual patient level whereby 
patient safety always needs to be at the centre of decision-making (see Section 1.4).
The following study data should be collected/ reported during home and/or remote visit and/ or 
obtained locally: 
Birth control check (for women of childbearing potential)
Safety and pregnancy test
Vital Signs
ECG
Adverse Events
Concomitant Therapies
All scheduled scales and questionnaires (if possible)
Study medication compliance check
Birth control check (for women of childbearing potential)/ pregnancy test
The Investigator or designee must confirm with the patient (and study partner, if possible) that 
a reliable birth control method is being used consistently.
Women of childbearing potential should have a pregnancy test performed if indicated in the 
Flow Chart or is required based on local regulations or investigator discretion.

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Safety assessments
If home visits are possible, some assessments can be done at the patient’s home (e.g. blood 
and urine samples, including PK samples, if applicable, can be collected and sent to the 
central lab, vital signs). 
If blood sampling or analysis by the central lab is not possible, safety lab analyses can be 
performed at a local laboratory. The results of the lab tests must be reported to the investigator 
who ensures medical review and proper documented in the eCRF. 
At a minimum the haematology panels should be done. Other safety laboratory tests may be 
performed at the Investigator’s discretion. 
For the rare situations in which the safety laboratory test cannot be done, the investigator’s 
reasoning and decision-making process must be documented in source notes at the site.
ECG
The ECG assessment can be done locally. The ECG report must be transferred to the 
investigator who ensures medical review and proper documentation in the eCRF. 
In rare situations in which the ECG(s) cannot be done, (even locally) and if ECG is normal or 
does not have any clinically significant findings at prior visits (per investigator’s clinical 
judgment), the Investigator needs to consider the overall patient medical status, including 
premorbid conditions, before allowing the patient to continue on study treatment. 
In case ECG(s) cannot be done but the patients will be permitted to continue in the study and 
continue receiving the investigational product, this should be documented in the source 
documentation.
Study Medication Compliance check
Patients can report and/or send photos of used study medication kits to the site staff, if needed 
and if possible. Medication kits including empty blister cards must to be return to the clinic. This 
may be done at the next visit, if in-person visits are permitted or arrangements can be made to 
have a courier retrieve the kit from the patient and return it to the site.
In addition, the site should monitor medication adherence through the AiCure portal, if possible.
Direct-to-patient shipment of trial medication
If a patient is not able to come to a visit as planned but the investigator considers it favorable and 
safe for the patient to continue on trial medication, the trial medication can be shipped from site 
directly to the patient (if acceptable according to local laws and regulations). Such shipments 
require the use of a sponsor approved courier to the patient’s home. 
When scheduling visits every effort should be made to ensure a continuous supply of trial 
medication for the patient, whilst also taking into account that the next kit(s) of trial medication 
may need to be shipped from the site to the patient’s home and, that medical pre-requisites 
should be performed and confirmed prior to shipment of new supplies.

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Primary and secondary endpoint assessments: MCCB, SCoRS and VRFCAT
The MCCB, SCoRS and VRFCAT are designed to be conducted in person. If it is not possible to 
conduct the visit in person, please contact the sponsor immediately.

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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
11.1
GLOBAL AMENDMENT 1
Date of amendment
30 Nov 2020
EudraCT number
EU number
2020-003726-23
BI Trial number
1346-0013
BI Investigational Medicinal 
Product(s)
BI 425809 (iclepertin)
Title of protocol
A phase III randomized, double-blind, placebo-
controlled parallel group trial to examine the 
efficacy and safety of BI 425809 (iclepertin) once 
daily over 26 week treatment period in patients 
with schizophrenia (CONNEX-3)
Global Amendment due to urgent safety reasons
Global Amendment
X
Section to be changed
Header of the protocol
Description of change
Inconsistent trial number in the protocol header 
(1346-0011 instead of correct trial number 1346-
0013)
Rationale for change
Editorial change and correction of typo

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11.2
GLOBAL AMENDMENT 2
Date of amendment
04 Nov 2022
EudraCT number
EU number
2020-003726-23
BI Trial number
1346-0013
BI Investigational Medicinal 
Product(s)
iclepertin
Title of protocol
A phase III randomized, double-blind, placebo-
controlled parallel group trial to examine the 
efficacy and safety of iclepertin once daily over 26 
week treatment period in patients with 
schizophrenia (CONNEX-3)
Global Amendment due to urgent safety reasons
Global Amendment
X
Section to be changed
Title page and whole document
Description of change
BI 425809 replaced by iclepertin
Rationale for change
The International Nonproprietary Names for 
Pharmaceutical Substances listed iclepertin for BI 
425809.
Section to be changed
Title page
Description of change
Name of Clinical Trial Leader replaced
Rationale for change
Change of Clinical Trial Leader
Section to be changed
Synopsis and sections 2.1.3 and 7
Description of change
Clarified that the key secondary efficacy endpoint 
for the VRFCAT is the adjusted total time T-score.
Rationale for change
Clarification 
Section to be changed
Flowchart and Abbreviations
Description of change
PCRS added 
Rationale for change
Administrative error / allow for consistency 
between section 5.1 and flow chart
Section to be changed
Flowchart footnotes
Description of change
Addition of footnote #18 
Rationale for change
Clarify that study partner is required for SCoRS 
and PANSS interviews at least at Visit 2 and EOT
Section to be changed
Abbreviations
Description of change
Updates of CGI-S and CGI-C descriptions
Rationale for change
Administrative error
Section to be changed
Sections 1.4.2 and 5.2.6.3
Description of change
Remove the fact that ophthalmologic assessment 
must be performed in case of moderate to severe 
intensity only.

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Rationale for change
Request from FDA to have all ocular AEs assessed 
by an ophthalmologist.
Section to be changed
Sections 1.4.2 and 3.3.4.1
Description of change
Clarification that Paxlovid should not be used 
concomitantly with the study drug. Patients who 
require treatment with Paxlovid should temporarily 
discontinue the study drug.
Rationale for change
Paxlovid as a strong inhibitor of CYP3A may 
increase plasma concentrations of medicinal 
products that are primarily metabolised by CYP3A.
Iclepertin is metabolised by CYP3a and therefore 
plasma concentrations of iclepertin may increase 
significantly with concomitant Paxlovid use.
Section to be changed
Description of change
Rationale for change
Section to be changed
Section 3.3.2
Description of change
Inclusion criteria #5 updated to permit patients who 
are on 2 anti-psychotics that at least one has to be 
within the approved label dose range and the other 
must not exceed the maximum daily dose per local 
label.
Rationale for change
Clarification on the doses of background 
antipsychotics that can be used.
Section to be changed
Section 3.3.2
Description of change
Inclusion criteria #6 updated – removed reference 
to hypnotic load up to 0.25 mg brotizolam 
equivlance. Clarified that other psychoactive 
medications cannot exceed the maximum daily 
dose per local label.
Rationale for change
Clarification of the criteria to ensure that patients 
should not be taking both 1 mg lorazepam plus 0.25 
mg brotizolam during the trial and that patients may 
take a lower dose of other psychoactive medication 
however the dose should not exceed the maximum 
daily dose per local label. 
Section to be changed
Section 3.3.3
Description of change
Exclusion criteria #2 updated to exclude patients 
with epilepsy.
Rationale for change
Clarification that patients with epilepsy cannot be 
included.

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Section to be changed
Section 3.3.3
Description of change
Exclusion criteria #8 updated to exclude use of 
esketamine as well as ketamine.
Rationale for change
Clarification
Section to be changed
Section 3.3.3
Description of change
Exclusion criteria #10 updated to exclude only 
those patients who have previously been treated 
with iclepertin.
Rationale for change
Patients previously treated with iclepertin cannot be 
enrolled however those patients who may have 
screen failed in another trial with iclepertin could 
be considered for the CONNEX trial.
Section to be changed
Section 3.3.3
Description of change
Exclusion criteria #11 updated including related 
footnote
Rationale for change
There are a number CNS acting medications that 
can be used to treat epilepsy but also other 
symptoms. Patients who take antiepileptics for 
treatment of epilepsy should be excluded however 
epileptics as monotherapy can be used for treatment 
of other conditions.
Section to be changed
Section 3.3.3
Description of change
Exclusion criteria #18 updated to exclude patients 
who currently have anemia.
Rationale for change
Patients who had anemia in the past and currently 
do not have anemia could be enrolled.
Section to be changed
Section 3.3.3
Description of change
Exclusion criteria #26 updated
Rationale for change
Clarification that list of ingredients can be found in 
the Investigator’s Brochure
Section to be changed
Section 3.3.4
Description of change
Added guidance related to lost to follow-up patients 
and included a reference to retention guide.
Rationale for change
Ensure sites are aware of the procedures in case a 
patient is lost-to-follow-up
Section to be changed
Section 3.3.4.2
Description of change
Removal that patients need to be followed until 
EOT+28 days
Rationale for change
Clarification 
Section to be changed
Section 3.3.4.2
Description of change
Addition of new reason for withdrawing (patients 
need to take restricted medications)

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Rationale for change
For safety reasons, patients should not take 
prohibited medications during the treatment period 
however if these medications are necessary, then 
the patient should permanently discontinue the 
study drug.
Section to be changed
Section 4.2.2.1
Description of change
Removal of quetiapine as an example for sedative 
medications
Rationale for change
To reduce confusion since quetiapine is an 
antipsychotic and patients should continue to take 
their background antipsychotic as prescribed by 
their treating physician.
Section to be changed
Section 4.2.2.1
Description of change
Clarify that short term use of opioids for pain, 
cough or diarrhea 
Rationale for change
Clarification
Section to be changed
Section 4.2.2.1
Description of change
Addition of vaccination for COVID-19 in the 
permitted therapies
Rationale for change
Patients are permitted to receive a COVID-19 
vaccination during the trial and in accordance with 
local public health recommendations.
Section to be changed
Section 5.1
Description of change
Addition of PCRS description
Rationale for change
Correction
Section to be changed
Section 5.1
Description of change
Addition of reference to section 6.2.1 for CGI-S
Rationale for change
Clarification of expectations for this scale.
Section to be changed
Section 5.1
Description of change
Updated number of items included in the SCQ
Rationale for change
Correction
Section to be changed
Section 5.1
Description of change
Addition of HCRU details that are collected.
Rationale for change
Clarification. These were previously described in 
section 2.2.2.1.1.
Section to be changed
Section 5.2
Description of change
Removal of number of items for AIMS
Rationale for change
Administrative error
Section to be changed
Section 5.2.3
Description of change
Confirmation that re-test is permitted at visit 1a in 
case patients are drug screen positive at Visit 1
Rationale for change
Clarification
Section to be changed
Section 5.2.6.7

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Description of change
Addition of reference to section 3.3.4.2 in case of 
patient becomes pregnant
Rationale for change
Clarification
Section to be changed
Section 5.6.2
Description of change
Confirm that patients must consent to the use of 
AiCure app but it won’t be a reason for 
discontinuation if the patients to continue after 
randomisation 
Rationale for change
The trial aims to retain as many patients as is 
possible to minimize the amount of missing data 
from randomized patients.
Section to be changed
Section 5.6.3
Description of change
Confirm that Verified Clinical Trials will be used 
only for countries that have not opted-out by local 
amendment
Rationale for change
Clarification
Section to be changed
Section 6.2.1
Description of change
Removal of examples of scales that should be done 
by the same rater
Rationale for change
Ideally, all scales should be performed by the same 
rater whenever possible to minimize the amount of 
variability in the data created by rater differences.
Section to be changed
Section 6.2.1
Description of change
Description added for CGI-S requirements 
Rationale for change
To clarify that the clinical global impression used 
in the trial should be based on the global impression 
including the patient’s functioning based on the 
SCoRS assessment. 
Section to be changed
Section 6.2.2
Description of change
Updated paragraph regarding patient and study 
partner informed consents
Rationale for change
Clarification that patient can start the trial 
procedures after the patient has provided their 
written informed consent and even if the study 
partner informed consent is not yet signed.
Section to be changed
Section 6.2.3
Description of change
Addition of reference to appendix 10.3 
Rationale for change
Ensure sites are aware of potential adaptations in 
case of exceptional circumstances 
Section to be changed
Section 6.2.4.1
Description of change
Clarified which procedures patients need to 
complete if they roll-over into the extension trial 
after completion of the EOT visit

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Rationale for change
Clarification.
Section to be changed
Sections 6.2.5.1
Description of change
Update of the different scenarios in case of early 
discontinuation and clarify re-start trial medication
Rationale for change
Clarification
Section to be changed
Section 7.2.1
Description of change
Clarification that randomized set will exclude 
patients randomized by error and discontinued from 
the study before the start of trial medication
Rationale for change
Clarification that they will be excluded from the RS
Section to be changed
Section 7.2.2
Description of change
Update of the statistical model
Rationale for change
Corrections 
Section to be changed
Section 10.1
Description of change
Update of the day for visit 3
Rationale for change
Correction
Section to be changed
Section 10.2
Description of change
Revise wording to indicate that the caregiver will 
be asked to complete the additional questionnaires
Rationale for change
Clarification that caregiver will be asked to 
complete additional questionnaires (but not 
mandatory)
Section to be changed
Section 10.3
Description of change
Addition of exceptional circumstances in addition 
to COVID-19
Rationale for change
Ensure to include emergency, natural disaster, 
patient specific situations
Section to be changed
Section 10.3
Description of change
Clarification that study partner contacts and 
assessments can be also impacted
Rationale for change
Clarification
Section to be changed
Section 10.3
Description of change
Include analysis by the Central Lab in addition to 
blood sampling
Rationale for change
Include description in case the Central Lab is in 
lockdown or if transportation routes to the central 
lab are disrupted such that samples cannot arrive in 
time to be analyzed.
Section to be changed
Section 10.3
Description of change
Include also secondary endpoints description in 
case of any exceptional circumstances.

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Rationale for change
Clarification that those assessments cannot be 
performed remotely as it would result in reduced 
quality.
11.3
GLOBAL AMENDMENT 3
Date of amendment
18 Sep 2023
EudraCT number
EU number
2020-003726-23
BI Trial number
1346-0013
BI Investigational Medicinal 
Product(s)
iclepertin
Title of protocol
A phase III randomized, double-blind, placebo-
controlled parallel group trial to examine the 
efficacy and safety of iclepertin once daily over 26 
week treatment period in patients with 
schizophrenia (CONNEX-3)
Global Amendment due to urgent safety reasons
Global Amendment
X
Section to be changed
Whole document
Description of change
Change from “Iclepertin” to “iclepertin”
Rationale for change
Editorial change
Section to be changed
Flow Chart and footnotes
Description of change
Added footnote 21: C-SSRS may be repeated based 
on investigator descretion
Rationale for change
DMC recommendation
Section to be changed
Flowchart and footnotes
Description of change
Substance use added to the flowchart and 
description in footnotes
Rationale for change
To align with the CRF
Section to be changed
Section 4.3 – Compliance 
Description of change
Clarification on calculation of compliance based on 
tablets removed from blisters
Rationale for change
To ensure the formula is consistent with the 
protocol text.
Section to be changed
Section 5.2 – Assessment of safety
Description of change
Reinforce documenting details for any positive 
suicidal ideation and to provide comments on the 
clinical significance and any additional follow-up 
action items. The C-SSRS may be repeated at an 
unscheduled visit based on investigator discretion.

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Rationale for change
DMC recommendation
Section to be changed
Section 9.2 – Unpublished references
Description of change
Update from 01 February 2016 to 01 February 2019
Rationale for change
Correction of typo
Section to be changed
Appendix 10.1 – Time schedule for PK blood 
sampling
Description of change
Added “preferably within 30 minutes before dose to 
on treatment PK sampling timepoints, added 
“approximately” to other PK sampling timepoints.
Added reminder that actual times are collected in 
the eCRF.
Rationale for change
Clarification

 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c32699831
4.0
clinical-trial-protocol-version-04
A phase III randomized, double-blind, placebo-controlled parallel group trial to
examine the efficacy and safety of iclepertin once daily over 26 week treatment
period in patients with schizophrenia (CONNEX-3)
Author-Clinical Trial Leader
19 Sep 2023 13:23 CEST
Approval-Clinical Program Leaders
19 Sep 2023 13:39 CEST
Author-Trial Clinical
Pharmacokineticist
19 Sep 2023 14:25 CEST
Approval-Biostatistics
19 Sep 2023 18:46 CEST
Approval-
 Medicine
20 Sep 2023 00:14 CEST
Verification-Paper Signature
Completion
20 Sep 2023 07:17 CEST

Boehringer Ingelheim 
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Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c32699831
4.0