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-2)
Phase: PHASE3
Conditions: Schizophrenia
Sponsor: Boehringer Ingelheim

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Clinical Trial Protocol
TITLE PAGE
Document Number:
c33087946-03
EudraCT No.
EU Trial No.
2020-003744-84
BI Trial No.
1346-0012
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-2)
Lay Title
Clinical trial of Iclepertin effect on cognition and functional 
capacity in schizophrenia.
Clinical Phase
III
Clinical Trial Leader
Phone: 
Fax: 
Coordinating 
Investigator
Phone:  
Fax:  
Version and Date
Version:  3.0
Date: 18 Sep 2023
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2023 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.

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CLINICAL TRIAL PROTOCOL SYNOPSIS
Company name
Boehringer Ingelheim 
Protocol date
16 Dec 2020
Revision date
18 Sep 2023
BI trial number
1346-0012
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-2)
Coordinating 
Investigator
Phone:  
Fax:  
Trial site(s)
Multi-centre trial conducted in approximately 16 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 of this trial 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.
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.

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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 the 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.
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 criteria:

Male or female patients who are 18-50 years (inclusive) of age 

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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
 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.
Main exclusion criteria

Patient 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.
1This includes home hospitalization for exacerbation in countries where it applies, however NOT hospitalization 
for social management and/or day programs.
2This includes home hospitalization, partial (day-time) hospitalization or ER visits.

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
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
NA
mode of 
administration
Oral (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. 
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 Period1
Randomized Treatment Period
Safety Follow-up Period18
End of Study
Visit
1
1a
2
3
4
5
6
7
8
9
10
EOT/1116
eEOT17
Follow-
up 1
☎
Follow-
up 2
Follow-
up 3
☎
Follow-
up 4
Follow-
up 5
☎
Follow-
up 619
EOS
Weeks
Screening
0
3
6
9
12
15
18
21
24
26
NA
Days from first randomized 
treatment 
-35 to 0
1 
22
43
64
85
106
127
148
169
183
NA
EOT or 
eEOT + 
7
EOT 
or 
eEOT 
+14
EOT 
or 
eEOT 
+17
EOT or 
eEOT 
+21
EOT 
or 
eEOT 
+24
EOT or 
eEOT + 
28
Clinic (on-site) visit
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Visit time window (days)
-35 to -28
-14 to -7
N/A
±3
±3
±3
±3
±3
±3
±3
±3
±3
NA
±1
±1
±1
±1
±1
+7
Informed consent2
X
Demographics
X
Medical history 
X
Height
X
Physical examination
X
X
X
X
X
X
X
X
Weight
X
X
X
X
X
X
X
X
X
Vital signs
X
X
X
X
X
X
X
X
X
12-lead ECG
X
X
X
X
X
X
X
X
X
Drug screen test (urine)3
X
(X)
X
X
X
X
X
X
(X)
Pregnancy test3
X
X
X
X
X
X
X
X
X
Safety Laboratory tests3
X
X
X
X
X
XH 
X
X
X
(X)
X
X
PK Sample4 
X
X
X
X
X
X
X
Bio-banking (optional)5
X
X
X
Speech sampling (optional)6
X
X
X
M.I.N.I.7
X
X
In-/exclusion criteria
X
X
Randomization
X
AiCure training8
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
Duplicate patient check
X
(re)Dispense & administer trial 
drug at site9
X
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 & SCoRS20
X
X
X
X
X
Tower of London
X
X
X
X
X
X
X
X
X
X
X
X
X

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FLOW CHART (con’t)
Trial Periods and Procedures
Screening Period1
Randomized Treatment Period
Safety Follow-up Period18
End of Study
Visit
1
1a
2
3
4
5
6
7
8
9
10
EOT/1116
eEOT17
Follow-
up 1
☎
Follow-
up 2
Follow-
up 3
☎
Follow-
up 4
Follow-
up 5
☎
Follow-
up 619
EOS
Weeks
Screening
0
3
6
9
12
15
18
21
24
26
NA
Days from first randomized 
treatment 
-35 to 0
1 
22
43
64
85
106
127
148
169
183
NA
EOT or 
eEOT + 
7
EOT 
or 
eEOT 
+14
EOT 
or 
eEOT 
+17
EOT or 
eEOT 
+21
EOT 
or 
eEOT 
+24
EOT or 
eEOT + 
28
Clinic (on-site) visit
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Visit time window (days)
-35 to -28
-14 to -7
N/A
±3
±3
±3
±3
±3
±3
±3
±3
±3
NA
±1
±1
±1
±1
±1
+7
PRECIS10
X
X
X
X
Adverse events11
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant therapy
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Substance use12
X
X
X
X
X
C-SSRS21
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
SAS/AIMS/BARS
X
X
X
X
X
X
Physician withdrawal checklist13
X
X
X
X
X
X
X
X
Patient Participation Completion 14
X
Duration in hours15
7
3
6.5
1
2
2
4.5
2
2.5
1
3
6.5
7
0.5
2
0.5
3
0.5
3
(X) Optional assessments at discretion of investigator
1The 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. 
2 For each patient, the main trial and study partner consents must be obtained.  Optional consents include bio banking and speech analysis.
3 Urine drug screen, pregnancy test and safety labs may be performed more frequently based on investigator discretion or if required locally.  Pregnancy tests are 
required for women of child-bearing potential only.  If urine (dipstick) pregnancy test is positive, a serum sample must be collected.

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4 Randomized treatment period:  
 
. For further details refer to Section 5.3 and Appendix 10.1.
5 One sample for DNA bio banking will be taken, preferably at Visit 2. However, DNA sample collection may occur at a later visit as long as the informed consent 
for bio banking remains valid.  At visit 2, plasma and serum bio banking samples are to be collected prior to IMP intake.  Plasma and serum bio banking samples are 
to be collected at (e)EoT.
6  Speech sample collection may not be available in all countries at initiation and therefore may be implemented as soon as it is available and approved by regulatory 
authorities and ethic committees in participating countries.
7 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.  
8 AiCure training may be repeated as needed.
9 At visit 2, all assessments must be completed prior to IMP intake.
10 At early EOT (eEOT), PRECIS should not be administered immediately after MCCB, to avoid bias.
11 For AEs 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 withdrawal AEs after stopping of study treatment.
12 Details on alcohol, nicotine and caffeine use will be collected.  
13
14 For patients not rolling over to the extension study:  after the individual patient’s end of the study, 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.
15 Duration of visits indicated in this Flow Chart are approximate estimates, actual time may vary as per site and patient requirements.
16 Visit 11 will be performed only by patients who prematurely discontinue trial drug but agree to continue trial participation.  For patients who have permanently 
discontinued study medication the following procedures are no longer required:  Dispense and administer IMP, IMP compliance check, AiCure review, PK Sampling, 
bio banking sampling.
17 If the patient permanently discontinues treatment early, the eEOT visit must be performed within 7 days of study drug discontinuation.  The patient should be 
followed up according to guidance provided in section 6.2.3.4.  For patients who permanently discontinue study medication the following procedures do not need to 
be performed:  Dispense and administer IMP, IMP compliance check, AiCure review, PK Sampling, bio banking sampling and Physician Withdrawal Checklist at 
visit 10. .For follow up of patients with Hb related issues, please refer to section 5.2.6.4
18 Safety follow-up visits must be completed after the EOT or early EOT visit. Each follow-up visit is to be scheduled from the EOT or early EOT visit (e.g. follow-
up visit 1 should be conducted 7 days ± 1 day from the EOT or early EOT visit).  
19 Patients who finish the 26 weeks of treatment period in this study and the 4 weeks of safety follow-up, can rollover to the extension trial after completing follow-up 
visit 6.
20 Study partner must complete the SCoRS and 
 interviews at least at Visit 2 and EOT (please refer to inclusion criterion # 8)
21 Additional collection of the C-SSRS at an unscheduled visit may be done based on the investigator’s discretion.  
XH Haematology panel A and B only. 

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TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS .....................................................................2
FLOW CHART........................................................................................................................6
TABLE OF CONTENTS ........................................................................................................9
ABBREVIATIONS................................................................................................................13
1.
INTRODUCTION...............................................................................................17
1.1
MEDICAL BACKGROUND.............................................................................17
1.2
DRUG PROFILE................................................................................................18
1.3
RATIONALE FOR PERFORMING THE TRIAL.........................................20
1.4
BENEFIT - RISK ASSESSMENT.....................................................................21
1.4.1
Benefits.................................................................................................................21
1.4.2
Risks .....................................................................................................................21
1.4.3
Discussion.............................................................................................................28
2.
TRIAL OBJECTIVES AND ENDPOINTS......................................................29
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS........29
2.1.1
Main objectives....................................................................................................29
2.1.2
Primary endpoint(s)............................................................................................29
2.1.3
Secondary endpoint(s) ........................................................................................29
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.........................32
3.1
OVERALL TRIAL DESIGN.............................................................................32
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)......................................................................................33
3.3
SELECTION OF TRIAL POPULATION .......................................................33
3.3.1
Main diagnosis for trial entry ............................................................................35
3.3.2
Inclusion criteria .................................................................................................35
3.3.3
Exclusion criteria ................................................................................................37
3.3.4
Withdrawal of patients from treatment or assessments..................................39
3.3.4.1
Temporary discontinuation of trial treatment .......................................................39
3.3.4.2
Permanent discontinuation of trial treatment........................................................40
3.3.4.3
Withdrawal of consent to trial participation .........................................................41
3.3.4.4
Discontinuation of the trial by the sponsor...........................................................41
4.
TREATMENTS...................................................................................................42
4.1
INVESTIGATIONAL TREATMENTS ...........................................................42
4.1.1
Identity of the Investigational Medicinal Products..........................................42

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4.1.2
Selection of doses in the trial and dose modifications......................................43
4.1.3
Method of assigning patients to treatment groups...........................................43
4.1.4
Drug assignment and administration of doses for each patient......................43
4.1.5
Blinding and procedures for unblinding...........................................................44
4.1.5.1
Blinding.................................................................................................................44
4.1.5.2
Unblinding and breaking the code ........................................................................44
4.1.6
Packaging, labelling, and re-supply...................................................................45
4.1.7
Storage conditions...............................................................................................45
4.1.8
Drug accountability.............................................................................................45
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS ................................................................................................46
4.2.1
Other treatments and emergency procedures..................................................46
4.2.2
Restrictions ..........................................................................................................46
4.2.2.1
Restrictions regarding concomitant treatment ......................................................46
4.2.2.2
Restrictions on diet and lifestyle...........................................................................47
4.2.2.3
Contraception requirements..................................................................................48
4.3
TREATMENT COMPLIANCE........................................................................48
5.
ASSESSMENTS..................................................................................................49
5.1
ASSESSMENT OF EFFICACY........................................................................49
5.2
ASSESSMENT OF SAFETY.............................................................................53
5.2.1
Physical examination ..........................................................................................55
5.2.2
Vital signs.............................................................................................................55
5.2.3
Safety laboratory parameters ............................................................................55
5.2.4
Electrocardiogram ..............................................................................................58
5.2.5
Other safety parameters.....................................................................................58
5.2.6
Assessment of adverse events.............................................................................59
5.2.6.1
Definitions of AEs ................................................................................................59
5.2.6.2
Adverse event collection and reporting ................................................................62
5.2.6.3
Ocular AEs............................................................................................................63
5.2.6.4
Haemoglobin and anaemia....................................................................................63
5.2.6.5
AE for assessment of potential abuse liability......................................................64
5.2.6.6
Monitoring of adverse events after stopping the study medication ......................65
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS...................................................................................65
5.3.1
Assessment of pharmacokinetics .......................................................................65
5.4
ASSESSMENT OF BIOMARKERS.................................................................65
5.5
BIOBANKING ....................................................................................................65
5.5.1
Methods and timing of sample collection..........................................................66
5.6
OTHER ASSESSMENTS...................................................................................66
5.6.1
Speech sample collection ....................................................................................66
5.6.2
Medication adherence and reminder system....................................................66
5.6.3
Verification of current and past research study status with Verified Clinical 
Trials ....................................................................................................................67
5.7
APPROPRIATENESS OF MEASUREMENTS..............................................68

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6.
INVESTIGATIONAL PLAN.............................................................................69
6.1
VISIT SCHEDULE.............................................................................................69
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS .................69
6.2.1
General requirements.........................................................................................69
6.2.2
Screening period..................................................................................................71
6.2.3
Treatment period(s)............................................................................................71
6.2.3.1
Randomization (Visit 2)........................................................................................72
6.2.3.2
Visit 3 to Visit 10..................................................................................................72
6.2.3.3
End of the treatment period (EOT/Visit 11) .........................................................73
6.2.3.4
Early permanent discontinuation from treatment..................................................73
6.2.4
Safety Follow-up period......................................................................................75
6.2.5
Trial Completion.................................................................................................75
7.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE
...............................................................................................................................76
7.1
NULL AND ALTERNATIVE HYPOTHESES ...............................................77
7.2
PLANNED ANALYSES.....................................................................................79
7.2.1
General considerations .......................................................................................79
7.2.2
Primary endpoint analyses.................................................................................80
7.2.3
Secondary endpoint analyses .............................................................................82
7.2.5
Safety analyses.....................................................................................................83
7.2.6
Other Analyses ....................................................................................................84
7.2.7
Interim Analyses .................................................................................................84
7.3
HANDLING OF MISSING DATA ...................................................................84
7.4
RANDOMISATION ...........................................................................................85
7.5
DETERMINATION OF SAMPLE SIZE .........................................................86
8.
INFORMED CONSENT, TRIAL RECORDS, DATA PROTECTION, 
PUBLICATION POLICY, AND ADMINISTRATIVE STRUCTURE ........90
8.1
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED 
CONSENT ...........................................................................................................90
8.2
DATA QUALITY ASSURANCE ......................................................................91
8.3
RECORDS...........................................................................................................91
8.3.1
Source documents ...............................................................................................91
8.3.2
Direct access to source data and documents.....................................................92
8.3.3
Storage period of records ...................................................................................93
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS ..................................93
8.5
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY........93
8.5.1
Collection, storage and future use of biological samples and corresponding 
data.......................................................................................................................93
8.6
TRIAL MILESTONES.......................................................................................94
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL ...................................94
9.
REFERENCES....................................................................................................96
9.1
PUBLISHED REFERENCES............................................................................96
9.2
UNPUBLISHED REFERENCES....................................................................100

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10.
APPENDICES...................................................................................................102
10.2
DEFINITION OF A STUDY PARTNER AND CAREGIVER....................103
10.3
POTENTIAL MODIFICATION OF THE TRIAL CONDUCT IN CASE 
OF RESTRICTIONS DUE TO COVID-19 OR OTHER EXCEPTIONAL 
CIRCUMSTANCES .........................................................................................104
11.
DESCRIPTION OF GLOBAL AMENDMENT(S) .......................................106
11.1
GLOBAL AMENDMENT 1 ............................................................................106
11.2
GLOBAL AMENDMENT 2 ............................................................................112

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ABBREVIATIONS
AD
Alzheimer’s disease
AE
Adverse Event
AESI
Adverse Event of Special Interest
ALCOA
Attributable, Legible, Contemporaneous, Original, Accurate 
ALT
Alanine Aminotransferase
APP
Application
AST
Aspartate Aminotransferase
AUC
Area under the Curve
BI
Boehringer Ingelheim
BP
Blood pressure
BUN
Blood urea nitrogen
CA
Competent Authority
CIAS
Cognitive Impairment Associated with Schizophrenia
CK
Creatine Kinase
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration
Cmax
Maximum Concentration
CIAS
Cognitive Impairment Associated with Schizophrenia
CNS
Central nervous system
COVID-19
Corona Virus Disease -19
CRA
Clinical Research Associate
CRO
Contract Research Organisation
CRT
Cognitive Remediation Therapy
CYP
Cytochrome P450
CSF
Cerebrospinal fluid
C-SSRS
Columbia Suicidality Severity Rating Scale
CTP
Clinical Trial Protocol
DDI
Drug drug interaction

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DILI
Drug Induced Liver Injury
dL
decilitre
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
eDC
Electronic Data Capture
eEOT
Early end of treatment 
eGFR
Estimated glomerular filtration rate
EOT
End of Treatment
EPS
Extrapyramidal symptoms
EudraCT
European Clinical Trials Database
FDA
Food and drug administration
GCP
Good Clinical Practice
GLYT 1
Glycine transporter 1
HAP
Human abuse potential
Hb
Haemoglobin
HIV
Human immunodeficiency virus
IB
Investigator’s Brochure
ICH
International Council on Harmonisation
IEC
Independent Ethics Committee
IRB
Institutional Review Board
IRT
Interactive Response Technology
ISF
Investigator Site File
MATRICS
Measurement and Treatment Research to Improve Cognition in 
Schizophrenia
LPLT
Last Patient Last Treatment
MCCB
MATRICS Consensus Cognitive Battery
MCH
Mean corpuscular haemoglobin

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MCHC
Mean corpuscular haemoglobin concentration
MCV
Mean corpuscular volume
MedDRA
Medical Dictionary for Drug Regulatory Activities
MINI
Mini International Neuropsychiatric Interview
MMRM
Mixed effects Model Repeated Measures
NMDA
N-methyl-D-aspartate
NOAEL
No-observed adverse-effect level
NTI
Narrow therapeutic index
PCP
Phencyclidine
PCRS
Placebo Control Reminder Script
PI
Principal investigator
p.o.
per os (oral)
PoCC
Proof of Clinical Concept
PK
Pharmacokinetics
PR
Pulse rate
PRECIS
Patient Reported Experience of Cognitive Impairment in Schizophrenia
q.d.
quaque die (once a day)
RDW
Red cell distribution width
REP
Residual Effect Period
SAE
Serious Adverse Event
SAS
Simpson Angus Scale
SCoRS
Schizophrenia Cognition Rating Scale
SCQ
Schizophrenia Caregiver Questionnaire
SOC
Standard of care
SOP
Standard operating procedure
TMS
Transcranial Magnetic Stimulation

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ToL
Tower of London
TSAP
Trial Statistical Analysis Plan
TSH
Thyroid stimulating hormone
ULN
Upper Limit of Normal
VRFCAT
Virtual Reality Functional Capacity Assessment Tool
WOCBP
Woman of childbearing 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, 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 signalling 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 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.

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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.
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 a 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.
Residual Effect Period
The Residual Effect Period (REP) of Iclepertin is defined as12 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.
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. 
Iclepertin is primarily metabolized by hepatic CYP3A and clinical drug-drug interaction 
(DDI) studies were conducted. 
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.
   

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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 (AD) have been treated with 
Iclepertin for 12 weeks. The most frequent AEs were related to the central nervous system 
(CNS), with headaches being 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 
electrocardiograms (ECG), assessment of vital signs, or visual tests. No signal was observed 
for suicidal ideation or behaviour.

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In the 1346-0009 Phase II trial, in patients with schizophrenia, proof of clinical concept 
(PoCC) was demonstrated. Iclepertin improved cognition assessed as the change from 
baseline in the MATRICS (Measurement and Treatment Research to Improve Cognition in 
Schizophrenia) consensus cognitive battery (MCCB) overall composite T-score after 12-
week treatment (i.e. 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 1346-0023 Phase II trial, in patients with mild to moderate AD, results showed no 
evidence for efficacy of Iclepertin compared with placebo for the evaluated endpoints.
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.
Iclepertin is a glycine transporter (GLYT1) inhibitor. Inhibition of GLYT1 increases the 
concentration of the NMDA receptor co-activator glycine in the synaptic cleft, which may 
lead to improvement of cognitive symptoms in patients with schizophrenia.
The efficacy and safety of BI 425890 has been investigated in a total of 339 patients were
exposed to Iclepertin at doses of 2 mg, 5 mg, 10 mg, and 25 mg qd in trial 1346-0009. The 
PoCC was demonstrated a 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 addition, patients will be provided with separate optional consent forms for the voluntary
collection of biospecimens and speech recordings. These are for further scientific research in 
this disease area. Please refer to Sections 5.5 and 5.6 for further information.

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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 patients 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 patient. 
Although this is an experimental drug and an individual benefit cannot be guaranteed, the 
PoCC Phase II trial demonstrated efficacy on cognition as assessed using the 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.
Eligible 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 [c31477880]. The frequency of patients with serious adverse events (SAE)s was low and 
was comparable across all treatment groups. The frequency of patients with AEs leading to 
discontinuation of trial medication was low. There were no deaths.

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Table 1.4.2:1 Overview over trial related risks 
Possible or 
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 IB for more details.
Management of symptoms, 
evaluation, and follow-up as needed 
to ensure patient 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 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 for 
more details.

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Table 1.4.2:1 Overview over trial related risks (con’t)
Possible or 
known risks of 
clinical relevance 
for this trial
Summary of data, rationale 
for the risk
Mitigation strategy
Investigational Medicinal Product 
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 AE 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 the patients must be sent
to an ophthalmologist for detailed 
evaluation. 
Report from the ophthalmology 
examination will need to be 
collected.
BI425809- 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 
4.2.21).
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
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.

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Table 1.4.2:1 Overview over trial related risks (con’t)
Possible or 
known risks of 
clinical relevance 
for this trial
Summary of data, rationale 
for the risk
Mitigation strategy
Disease Related Risk
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.
Other risks
Potential risk while 
operating 
machinery
General precaution for CNS 
active drugs
It is recommended that patients 
should exercise caution when 
driving or operating machinery 
after drug administration.

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Table 1.4.2:1 Overview over trial related risks (con’t),
Possible or 
known risks of 
clinical relevance 
for this trial
Summary of data, rationale 
for the risk
Mitigation strategy
Other risks
Human abuse 
potential (HAP)
According to the 2017 FDA 
guidance on “Assessment of 
Abuse Potential of Drugs”, 
assessment of 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 HAP 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 
AEs. 
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.
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 or 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 patient
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 anaemia 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 or 
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 AEs were
observed in patients treated 
with Iclepertin in comparison 
to those treated with placebo. 
Potential AEs after stopping 
study drug have not been 
formally investigated thus far 
and therefore cannot be fully 
excluded.
Monitoring AEs of interest for 
the assessment of potential 
abuse liability are described 
above (refer to placebo risks).
PWC-20 potential treatment 
discontinuation (withdrawal) 
symptoms in a standardized 
manner.
After completion of 26 weeks of 
treatment, all patients will be 
closely monitored for 4 weeks in
the safety follow up period to 
assess potential AEs of 
withdrawal from Iclepertin
treatment.

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Table 1.4.2:1 Overview over trial related risks (con’t)
Possible or 
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.
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 to help ensure the motivation, engagement and 
retention in this trial. These frequent checks / visits will help to reinforce compliance to trial 
treatment and background medication. For further follow-up after premature treatment 
discontinuation please refer to section 6.2.3.4.
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 treatment that improves cognition in patients with schizophrenia, which 
remains a high unmet medical need.
Considering the chronic and severe disease burden of CIAS, which is the 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.
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 the VRFCAT

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The secondary efficacy endpoints are as follows:

Change from baseline to Week 26 in the T-score of the number of correct responses 
on ToL.

Change from screening visit 1a to Week 24 in Patient Reported Experience of 
Cognitive Impairment in Schizophrenia (PRECIS) total score

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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN 
The overall trial design is as follows:
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) via Interactive Response Technology
(IRT) to balance the baseline cognitive level among groups.
Patients who finish 26 weeks of treatment with Iclepertin or placebo and the 4 week safety 
follow-up period in this study will be offered the opportunity for treatment with Iclepertin 10 
mg in a long-term safety extension study. Patients may enter the extension trial after 
completing follow-up visit 6. For further details please refer to Section 6.2.4.
As part of this research program, optional biobanking and optional speech sample collection 
will be done in order to address future scientific questions as described in Section 5.5 and 
5.6.1.
Roll-over extension OR
study completion
S
R
IIclepertin
10 mg once daily
Day 1
Day -35
Safety period
(no treatment)
Treatment
Iclepertin10 mg once daily
Placebo
once daily
Screen
Week 26
Multi-national
Placebo controlled
Parallel group trial
Double-blind
26-week
Multi-centre
Randomised
4-week
Week 30
(14 days)
R: stratification by 
screening MCCB score
Evaluate potential 
withdrawal-related adverse events 
(as part of the HAP strategy)

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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 AEs, 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 Table 1.4.2:1.
A 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.
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 

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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 patient 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.
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: 

Hb 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 Investigators judgement 

Stability of Schizophrenia symptoms or medications 

Liver enzyme elevation, e.g., Alanine Aminotransferase (ALT)/ Aspartate 
Aminotransferase (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 CTL.

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In case of re-screening, the patient will receive a new patient 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 the patient is re-screened within 12 weeks of the original screening visit, all 
procedures except for the MCCB, SCoRS, VRFCAT and ToL must be performed.  

If the re-screening occurs more than 12 weeks from the initial screening, then all Visit 
1 procedures 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 under the newly assigned patient number.
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 (Source Documents) for the documentation requirements 
pertaining to the in- and exclusion criteria.
3.3.2
Inclusion criteria
1. Patient must be capable of providing a signed and dated written informed consent by 
visit 1 in accordance with International Council on Harmonisation for Good Clinical 
Practice (ICH-GCP) and local legislation prior to 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 hospitalization1 or increase in level of psychiatric care2 due to worsening of 
schizophrenia within 12 weeks prior to randomization. 

 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 staying focused, 
difficulties remembering 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. 
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 hospitalization or ER visits.

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
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. 

Maximum daily benzodiazepine load of up to 1 mg lorazepam-equivalent as 
needed (pro re nata, prn). Table of relevant medications and their equivalencies
will be provided as a part of ISF

For any other psychoactive medications cannot exceed the maximum daily dose 
per local label of the country where the study is being conducted.
7. Women of childbearing potential (WOCBP)1 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.

The study partner must interact with the patient at a minimum one hour per week
and, preferably, at least 2 times a week. At least one interaction per week should 
be in person.

The study partner must have educational achievement of minimum 8th grade.

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.
1 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. Tubal ligation is NOT a method of permanent sterilisation. A postmenopausal state is defined as no 
menses for 12 months without an alternative medical cause. 

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3.3.3
Exclusion criteria
1. Patient with current DSM-5 diagnosis other than Schizophrenia, including but not 
limited to bipolar, schizoaffective, major depressive disorder etc. The Mini-International 
Neuropsychiatric Interview (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, or patients with dementia or epilepsy.
3. Severe movement disorders 

Leading to cognitive impairment (e.g. Parkinson’s dementia), or 

Interfering with the efficacy assessments, or

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:

Clozapine

Stimulants (e.g. methylphenidate, dextroamphetamine, modafinil)

Ketamine or esketamine

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.
11. Patients who are treated with any of the following within the last 35 days prior to 
randomization1:

Strong or moderate CYP3A4 inhibitors including grapefruit juice 
1 List of relevant medications will be provided as part of the ISF

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
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)1

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.

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. Hb below lower limit of normal at Visit 1 assessed by the central lab.
18. History of haemolytic anaemia including hemoglobinopathies (for example thalassemia 
or sickle-cell anaemia), RBC membrane diseases or known G6PDH (Glucose-6-
phosphate dehydrogenase) deficiency; or current anaemia or patients planning to donate 
blood.
1 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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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 (ULN) 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.1
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 Investigators’ 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.
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 AE
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 discontinuation of trial treatment
Temporary trial treatment discontinuation is permitted. For treatment interruptions of > 10 
days, the sponsor should be informed.
1 Testing for SARS-CoV-2 is not the part of this trial. If required this needs to be done per local requirements

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Reasons for 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 treatment 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. AEs) 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 (eEOT) and safety follow up visits. 

Additionally the patient will be followed according to the flow chart until the planned 
Visit11 (26 weeks). 
Please refer to Flow Chart and section 6.2.3.4 and 6.2.4 for more information on 
continued trial participation.
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 treatment 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 clinical judgement. Please consult with sponsor.

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
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 the birth of the child 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 5.2.6.2.3.
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 trial treatment, 
plus no further participation in study visits or 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).
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 6.2.3.4.
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, please see section 3.3.4.1.
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 1
Substance:
Iclepertin
Pharmaceutical formulation:
Tablet
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
10 mg
Posology:
1 tablet once daily
Mode 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 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 provided at 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. 
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 the split visit, after all Visit 2 assessments have been completed.
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 study medication at home on the day of the 
clinic visit as patients will be dosed at the site.  Dosing should occur approximately 24 hours 
after the drug administration from the preceding day.  

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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 the independent DMC, the 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 
time-point of unblinding the database for analysis are documented in the Trial Statistical 
Analysis Plan (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 there were decreases in Hb that 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 the 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 PK samples taken from placebo patients.  
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 unblinded.
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 patients. 

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The reason for unblinding must be documented in the source documents and/or appropriate 
eCRF 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 clinical 
research organization (CRO). They will be packaged and labelled in accordance with the 
principles of Good Manufacturing Practice. 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.
4.1.7
Storage conditions
Drug supplies will be kept in their original packaging and in a secure limited access storage 
area according to the recommended 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.
4.1.8
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 (CTP) by the Institutional Review Board (IRB) / 
ethics committee (EC),

Availability of a signed and dated clinical trial contract between the sponsor and the 
investigational site,

Approval/notification of the regulatory authority, e.g. competent authority (CA),

Availability of the curriculum vitae of the Principal Investigator (PI),

Availability of a signed and dated CTP,

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 

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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 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.
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 performed at 
visit 2, visit 6, EOT/Visit 11 and eEOT (if applicable). 
o
Antihistamines with prominent sedative side effects,
o
Anticholinergics
o
Benzodiazepines

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o
Other sedative medications 
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 patient’s 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 opioid 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:

Non-systemic use (topical, inhalation or nasal administration) of antihistaminics and 
anticholinergics is allowed.

Short-term opioid therapy up to 4 weeks per time, for example with cough syrup or 
pain killer, is allowed (except fentanyl).

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 please refer to the ISF)  

Vaccination with a COVID-19 vaccine 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.  Patients should not donate blood while they are 
participating in the study.
Effects of Iclepertin on driving abilities have not been tested so far. It is recommended that 
patients 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.

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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 patients and their female partners.
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.
AEs related to the HAP of Iclepertin should be reported and managed as per the 
investigator´s judgement.
In addition to compliance calculations, 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
Continuous 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.
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 [R16-4322, 
R13-2345]. Each item is rated on a 4-point scale. Higher ratings reflect a greater degree of 
impairment. 

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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 [R20-0374]. 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 patients, 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 
ensure that the patient 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):
Patients are shown two images presented on opposite sides of the tablet screen.  Each image 
shows a different configuration of 3 coloured balls arranged on 3 pegs. The patient is required 
to accurately determine the total number of times the balls in one picture would have to be 

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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. 
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
Communication
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

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5.2
ASSESSMENT OF SAFETY
will be used to evaluate broad, 
psychopathology associated with schizophrenia disease state.  The 
 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 
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 patients’ disease state.
Extrapyramidal symptoms (EPS) will be assessed using 3 scales:

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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
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. 

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, the global clinical assessment of akathisia is rated on a 
6-point scale 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.
Patients 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. Patients 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 patients with active moderate or severe symptomatology within a specified 
time prior to screening. The life time 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 patient 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. 
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.  

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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 descretion.  
C-SSRS results will be reported in terms of AEs as described in Section 5.2.6.1.4.
Penn Physician Withdrawal Checklist (PWC-20) is a short, reliable instrument that has 
been developed to detect potential treatment discontinuation (withdrawal) symptoms [R20-
4170].  This 20-item questionnaire will be administered first at visit 10 or at the early EOT 
visit, for patients who prematurely discontinue study drug, and then during the 4-week 
follow-up period after termination of treatment with Iclepertin to collect potential symptoms 
and AEs related to dependence and withdrawal in a structured manner.  Collection of AEs 
should be done before administering the PWC-20.  Note: for AE reporting in eCRF and on 
SAE form (when applicable) the standards as outlined in section 5.2.6 apply.  Symptoms that 
are exclusively determined to be due to the underlying disease without presenting any 
worsening, do not require AE reporting.  
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. 
The central laboratory will send reports to the investigator (except for blinded Hb related 
parameters (Haematology panel A), for further details refer to Section 4.1.5.1 and Section 

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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 electronic data 
capture (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 
Bilirubin Total, fractionated if 
increased
Creatine Kinase (CK)
CK-MB – only if CK is elevated
C-Reactive Protein
Gamma-Glutamyl Transferase 
Lactic Dehydrogenase
Lipase
Amylase
Cholesterol, total
Triglycerides
Calcium
Sodium
Potassium 
Glucose
HbA1c
Urea (BUN)
Creatinine
Estimated Glomerular filtration 
rate (eGFR)*
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 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.
**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.
**** 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).

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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 patients 
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 after Visit 1 will be reported as an 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. 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 an AE, 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: 
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 AE 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 AE. 
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 
 per investigators judgment.

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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 eCRF 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 SAE is defined as any AE, which fulfils at least one of the following criteria:
-
results in death,
-
is life-threatening, which refers to an event in which the patient was at risk of death at 
the time of the event; it does not refer to an event that hypothetically might have 
caused death if more severe,
-
requires inpatient hospitalisation or prolongation of existing hospitalisation
-
results in persistent or significant disability or incapacity,
-
is a congenital anomaly / birth defect,
-
is deemed serious for any other reason if it is an important medical event when based 
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.

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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 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 C-SSRS reports of suicidal ideation type 4 or 5 and all reports of suicidal behaviour must 
be reported as SAEs by the investigator.  
For each instance of suicidal ideation type 1, 2 or 3 after the start of the trial, the investigator 
is to decide, based on clinical judgment, whether this event represents an AE as defined in the 
protocol.  If it is considered an AE then it must be reported as a serious on the SAE form and 
on eCRF AE page as serious, as this is listed on the “BI Always Serious AE list”.
For “self-injurious behaviour, no suicidal intent” standard AE/SAE reporting rules are to be 
applied.  
5.2.6.1.5
Adverse events of special interest
The term AESI relates to any specific AE that has been identified at the project level as being 
of particular concern for prospective safety monitoring and safety assessment within this trial, 
e.g. the potential for AEs based on knowledge from other compounds in the same class. 
AESIs need to be reported to the sponsor’s Pharmacovigilance Department within the same 
timeframe that applies to SAEs, please see 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 and/or ALT ≥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.

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

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5.2.6.2
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 eCRF(s) by the 
investigator:

For patients who roll-over to the extension trial:
o
From signing informed consent (1346-0012) 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 that are ongoing at the time of rollover to the 
extension trial must also be updated in the parent trial (1346-0012) in addition to 
being recorded in the extension trial, as long as the database for the parent trial is not 
locked.  On the SAE form, updates for events reportable on the SAE form with onset 
in the parent trial are only reported into the parent trial.

For patients who do not roll-over to the extension trial:
o
From signing the informed consent onwards until the 28 days (Follow-up 6 visit) 
after the EOT visit: all AEs (serious and non-serious) and all AESIs.
o
After the individual patient’s end of study: 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 eCRF.

For patients who permanently discontinue trial medication prematurely
o
From signing the informed consent onwards until the 28 days after the early EOT
visit: all AEs (serious and non-serious) and all AESIs.
o
From Follow-up visit 6 up to the individual patient’s planned end of study: until 
the individual patient’s planned end of the study, the investigator must report
treatment related SAEs / AESIs and the following events regardless of causal 
relationship:

anaemia, 

all SAEs from C-SSRS assessments, 

any occurrences of cancer 

all deaths/ fatal AEs.  
o
After the individual patient’s planned end of study: 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 eCRF.

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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 study 
must be followed up until they have resolved, have been assessed as “chronic” or “stable” , or 
no further information can be obtained.
5.2.6.2.3
Pregnancy
In rare cases, pregnancy might occur in a clinical trial. Once a 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 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.
5.2.6.3
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 vision-related 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 AEs. 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.  

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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 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 study 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 study has been reached.

The investigator should further evaluate the patient status and report the AE “anaemia”
based on investigator’s 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 an 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 study 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 and section 6.2.3.4.
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.

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5.2.6.6
Monitoring of adverse events after stopping the study medication
All patients will be closely monitored during the safety follow up period to assess potential 
AEs of withdrawal from Iclepertin treatment. In addition, patients will undergo assessments 
with 
, CGI-S, PGI-S and C-SSRS.
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS
5.3.1
Assessment of pharmacokinetics
During the randomized treatment period, PK samples will be collected as specified in the 
flow chart
5.4
ASSESSMENT OF BIOMARKERS
Not applicable.
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.

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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 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 time points see Flow Chart.  Blood will be drawn for 
Deoxyribonucleic Acid (DNA), plasma and serum banking purposes.  Any analysis on DNA, 
plasma or serum samples will not be reported in the 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 a new potential marker of abnormal mental conditions, e.g. 
cognitive impairment in disorders like Schizophrenia. Speech analysis includes various 
evaluations of language, e.g. semantic coherence or syntactic complexity. 
For use in future exploratory investigations, voluntary speech samples will be collected after 
a 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 patient 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 patient 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. 
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 and therefore may be 
implemented as soon as it is available and approved by regulatory authorities and ethic 
committees in participating 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 patients in the study.  
All patients must consent to the use of 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 

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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 
patients 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 patient’s personal 
smartphone. If a patient 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 
patients will use a provisioned device. 
Patients using a daily oral antipsychotic should be registered in the platform during screening 
and begin confirming appropriate compliance to their background antipsychotic to ensure 
stability prior to randomization. At visit 2, patients 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 

Patients 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 patient 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 patient reports that a dose was taken but not logged in the app, 
site personnel should reclassify this dose to “site reported” using the dashboard. 

Patients who are consistently non-compliant with study medication should be 
discussed with the sponsor. 
Monitoring of background antipsychotic treatment 
Patients using a daily oral antipsychotic should be registered in the platform during screening 
to confirm stability of their background antipsychotic prior to randomization. Patients 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 analysed 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 enrolment 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 
patient, 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.  

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Following proper informed consent and after issuing a study patient number, each patient 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 patient 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 accepted measurements that are 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 the 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 performed 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.

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 administering MCCB and VRFCAT. 

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 

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stabilizes, per investigators judgment. All safety assessments including 
 C-
SSRS should be conducted, if possible.

It is the responsibility of the PI 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 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, or as an
AE if noted during treatment or follow up period, as applicable.

Safety labs (including urinalysis) and/or urine drug screen, 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,
required.
For study partners who also serve are also caregivers:
 Please refer to Appendix 10.2 for definition of study 
partner vs. caregiver.

For caregiver assessments, in-person visit is preferred. However, if not possible, the 
caregiver may come on another day to fill-in the 
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.

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6.2.2
Screening period
Screening Period (Visit 1 and Visit 1a)

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.  

All consented patients must be recorded on the enrolment log and registered in the 
IRT system as a screened patient.

Visit 1 may be performed over multiple days within the screening period. 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.

Duplicate patient check: The patient IRT number and identifiers will be recorded on 
the VCT 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 vendor that 
the patient is currently not participating in another trial in their database. Once email 
is received the site can continue screening.

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 a 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 (VeraSci) as soon as possible.  
The Screening MCCB T-score is required for randomization via the IRT at visit 2.

Please refer to the general requirements in Section 6.2.1.

Eligibility Assessment: 
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 screen failure in IRT.

Rescreening: Patients who fail screening may be re-screened once after a discussion 
between investigator and sponsor. Please see section 3.3 for further details regarding 
re-screening.
6.2.3
Treatment period(s)

Please refer to the general requirements in Section 6.2.1.

At Visit 2, and throughout the treatment period, patients should be reminded to take 
the trial drug as instructed, refer to Section 4.1.4.

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
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.

Please refer to Appendix 10.3 for guidance in case of any exceptional circumstances.  
Sites should consult with sponsor before making any modifications.  
6.2.3.1
Randomization (Visit 2)

At the start of Visit 2, the investigator or designee should ensure that all Visit 1 and 
Visit 1a procedures have been successfully completed 

The MCCB should be performed before any other efficacy assessment.

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 assessments can be done per the convenience of the patient and 
site, either on day 1 or day 2.
o
To reduce burden on the study partner, it is recommended to perform the 
 and the SCoRS on the same day.
o
In case of a split visit, the second day will be the day of first study drug intake.

For patients who have signed the optional Biobanking consent form, biobanking 
(plasma and serum) samples should be collected before the intake of the first dose of 
study medication (refer to Section 5.5.1).  The DNA sample may be collected at visit 
2 or at another visit as long as the biobanking consent is has not been revoked.

The MCCB overall T-score from the visit 1 (screening) is required to randomize 
the patient at visit 2. 
o
In case the 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 study medication will be done on site using the AiCure medication 
adherence monitoring app and under supervision by delegated trial staff.

Two medication kits will be dispensed at visit 2.  These kits 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

 blood samples will be collected during the treatment period as per the 
Flow chart.  
 
. 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.

At each visit, the patient will receive a new supply of study medication, as allocated 
by the IRT system.  

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
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 assessments can be done per the convenience of the patient and 
site, either on day 1/ day 2.
o
To reduce burden on study partner, it is recommended to perform 
 and 
SCoRS on the same day.

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 the treatment period (EOT/Visit 11)

The final MCCB assessment must be performed after the patient completes the 26 
week randomized treatment period. 

The EOT visit may be split into 2 sequential days, in which case:
o
The MCCB and VRFCAT should be performed on the first day; 
o
The remaining assessments can be done per the convenience of the patient and 
site, either on first day or the second day of the EOT visit.
o
To reduce burden on the study partner, it is recommended to perform 
 
and SCoRS on the same day.
For patients who did not prematurely discontinue the study medication:
For patients who had permanently discontinued study medication (Visit 11):

The following procedures do not need to be completed at visit 11:
o
IMP compliance check
o
AiCure related activities
o
PK sampling
o
Collection of biobanking samples for those patients who had provided 
consent.
6.2.3.4
Early permanent discontinuation from treatment

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.

If a patient permanently discontinues the study medication, an eEOT visit must 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 reason for discontinuation of treatment must be 
recorded in the eCRF.

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.

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o
The remaining assessments can be done per the convenience of the patient and 
site, either on the first day or the second day of the eEOT visit.
o
To reduce burden on study partner, it is recommended to perform 
 and 
SCoRS on the same day.

After the eEOT visit, patients should complete the safety follow-up visits and 
continue with the scheduled trial visits, until the end of the planned end of trial for 
that patient unless they withdraw consent to participate in the study. 
o
Refer to the Retention Guide in your ISF for further instructions.

If it is not possible to complete all visits in clinic, at least phone contacts should occur 
at the scheduled visit time points. It is vital to explain to these patients the importance 
of continued trial participation.  Additional information is provided in the ISF.

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 the trial medication at any time during their 
planned treatment period as long as there is no safety concern, in the opinion of 
the investigator.
Table 6.2.3.4: 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 (primary, key secondary and secondary 
endpoints).
In case patient does not 
agree to option 1, then 
present 
Early D/C Option 2
Focus on key efficacy endpoints MCCB, SCoRS and 
VRFCAT (at minimum, the MCCB should be completed) 
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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6.2.4
Safety Follow-up period

The follow-up period consists of 6 visits, of which 3 are completed by phone (follow-
up 1, follow-up 3 and follow-up 5).

Patients must complete all of the safety follow-up visits so that the potential effects of 
stopping the study drug may be evaluated.  

Patients who complete the 26 weeks of treatment plus all of the safety follow-up visits
may be eligible to participate in the open label extension trial with Iclepertin 10 mg 
(BI trial 1346-0014)
o
The extension trial will be 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 on the same day as completing the 
Follow-up 6 visit.
6.2.5
Trial Completion
Each individual patient’s end of study will depend on several factors including whether or not 
the patient completed the trial treatment plus the safety follow-up, or if the patient has 
prematurely discontinued treatment and either continued with trial participation or stopped 
trial participation early. 

Patients who complete 26 weeks of trial treatment and 4 weeks of safety follow-up:  
completion of follow-up visit 6 is considered to be the patient’s end of study.

Patients who prematurely stop the trial treatment and continue with trial participation:  
after completing the eEOT and the safety follow-up visits, the patient will be followed 
according to the flow chart until the planned V11 (26 weeks) or EOT +28 days, 
whichever is longer.  The last study visit will be the end of study for that patient.

Patients who prematurely stop the trial treatment and do not continue with trial 
participation:  patients should be encouraged to complete the eEOT and safety follow-
up visits, if possible.  The last study visit will be the end of study for that patient.  
Patients should continue to take their background therapy for schizophrenia, as prescribed by 
the investigator or treating physician.  
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 to section 5.2.6.2.1).

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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 AEs 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 
ToL 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.
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.

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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 . 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 ToL 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 ToL 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 analysed under the 
actual trial medication received at randomization. The TS is used for safety analyses 
as well as demographics and baseline characteristics.
Data from patients who were screened but not randomized will be listed but not included in 
any summary or inferential statistics.

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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 randomisation 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. For change 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.
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.

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
For patients 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 patients 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 patients 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 
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 

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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 the number of correct responses on 
ToL, 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 ToL T-score will be fitted to the data.
Similar sensitivity and supplementary analyses as planned for the primary efficacy endpoint 
will also be conducted for the two key secondary efficacy endpoints.

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7.2.5
Safety analyses
AEs will be coded using the Medical Dictionary for Drug Regulatory Activities (MedDRA). 
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 AEs will concentrate on treatment-emergent AEs. To this 
end, all AEs occurring between the start of treatment and the end of the REP will be 
considered ‘treatment-emergent’. The REP is defined as 12 days after the last dose of trial 
medication. AEs that start before first drug intake and deteriorate under treatment will also be 
considered as ‘treatment-emergent’.
Frequency, severity, and causal relationship of AEs will be tabulated by system organ class 
and preferred term after coding according to the current version of the MedDRA.
Frequency tables for all AEs, protocol-specified AESI, SAE, AE leading to death, AE leading 
to discontinuation, investigator assessed drug-related AE and serious related AE will be 
generated for treatment-emergent AEs. 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 
 
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 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.
Withdrawal-related safety analysis
In addition to the main safety analysis, withdrawal-related safety analysis will be conducted 
separately and descriptive for AEs emerging during the off-treatment safety follow-up period. 
New AEs emerging during this 4-week safety period, compared to while the patient is still 
on-treatment, will be identified and assessed by contrasting the following analysing treatment 
periods:

4-week withdrawal period for AEs occurring from 1 day after last dose to 28 after last 
dose of trial medication, and

Strictly on-treatment period for AEs occurring from the start of treatment to the last 
dose of trial medication. 

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This withdrawal-related safety analysis will also assess vital signs descriptively. 
Change in withdrawal symptoms based on PWC-20 will be analysed descriptively.  
7.2.6
Other Analyses
Pharmacokinetic analysis
Plasma concentrations of Iclepertin at related time points will be analysed descriptively as
further explained in Appendix 10.1.
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 
patients 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 patient 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.
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.

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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 patient at a visit, then the SCoRS total score for 
that patient 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 patient at a visit, then the item with missing 
response will be imputed first with the average of the non-missing item values for the patient
at the visit, and then SCoRS total score for the patient 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.
Additional details on the handling of missing data will be specified in the TSAP prior to 
unblinding.
7.4
RANDOMISATION
Eligible patients 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 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).

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The randomization will be conducted via 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 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 patients 
per arm, 440 patients 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 patients 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.
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 patients 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 patients 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 on VRFCAT. Furthermore if the effect sizes in both key secondary efficacy 

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endpoints are 0.35 (Scenario #1), then with 220 evaluable patients 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 patients 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 patients 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 patients 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.
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 
H1,0 and (H2,0 
and/or H3,0)
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%
Efficacy 
Endpoints
Primary:
MCCB 
Overall
Key 
Secondary: 
SCoRS 
total score
Key 
Secondary: 
VRFCAT
Secondary:
Tower of 
London
Secondary:
PRECIS
Primary and Key 
Secondary: reject 
H1,0 and (H2,0 
and/or H3,0)

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Table 7.5: 1
Probability of success for each endpoint under different scenarios of 
effect sizes from simulations (con’t)
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
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 patients per arm, one-sided family-wise type I error=0.025, correlation between the endpoints is 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, patients 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 patients with missing data in our phase III trial due to longer 

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treatment duration, we project 30% to 40% patients 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 patients, 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 25% correction for missing data in the sample size 
calculation for this phase III trial. This gives a total number of 586 randomized patients for 
the phase III trial, with 293 randomized patients 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 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 
web page: trials.boehringer-ingelheim.com. The rights of the investigator and of the sponsor
with regard to publication of the results of this trial are described in the investigator contract. 
As a 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 IRB / Independent EC (IEC and 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 
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 

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patient and the study partner / caregiver 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 patient 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
eCRFs 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 4.1.8.
8.3.1
Source documents
In accordance with regulatory requirements, the investigator should prepare and maintain 
adequate and accurate source documents and trial records 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 eCRF must be consistent with the source data or the discrepancies must 
be explained.
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.

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Copies of source documents necessary for neurocognitive assessments (e.g. MCCB) will be 
provided to VeraSci. 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 eCRF, 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

AEs and outcome events (onset date (mandatory), and end date (if available))

SAEs (onset date (mandatory), and end date (if available))

Concomitant therapy (start date, changes)

Originals or copies of laboratory results and other imaging or testing results, with proper 
documented medical evaluation (in validated electronic format, if available)

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 eCRF 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 eCRFs 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 world health 
organization 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".  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 / CA 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. 
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.

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The investigators will have access to the BI web portal Clinergize to access documents 
provided by the sponsor.
BI has appointed a CTL, 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, 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.
REFERENCES
9.1
PUBLISHED REFERENCES
R10-5108
Barnett JH, Robbins TW, Leeson VC, Sahakian BJ, Joyce EM, Blackwell 
AD. Assessing cognitive function in clinical trials of schizophrenia. 
Neurosci Biobehav Rev 2010 ; 34; 1161-1177.     
R10-5111
Buchanan RW, Davis M, Goff D, Green MF, Keefe RSE, Leon AC, 
Nuechterlein KH, Laughren T, Levin R, Stover E, Fenton W, Marder SR    
A summary of the FDA-NIMH-MATRICS workshop on clinical trial 
design for neurocognitive drugs for schizophrenia. Joint FDA-NIMH-
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9.2
UNPUBLISHED REFERENCES
c02155957
Investigator’s Brochure BI 425809
c02820512
 Clinical Trial Report of 
Trial 1346.1. BI 425809. 05 May 2015
c03572014
 Clinical Trial Report of 
Trial 1346.2. BI 425809. 04 July 2016
c03724403
. Clinical Trial Report of Trial 
1346.3. BI 425809. 01 February 2016

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c03760676
 Clinical Trial Report of Trial 1346.4. 
BI 425809. 17 March 2016
c31477880
 Clinical Trial Report of 
Trial 1346.9. BI425809. 01 September 2020
c33088336
Clinical Trial Protocol of Trial 1346-0014
U13-2547
 Nonclinical Report: Increase of glycine in rat CSF by 
Iclepertin. BI425809-Rosenbrock-1310-E. Version 01. 22 November 
2013.

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10.
APPENDICES

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10.2
DEFINITION OF A 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 (
) 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, 
, 
In addition to SCoRS, 
, 
, the caregiver will complete 

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10.3
POTENTIAL MODIFICATION OF THE 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 circumstance), 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, etc.).
All COVID-19/exceptional circumstance 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
AEs
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 is properly documented in the source documents.  
Local lab results are to be entered into the eCRF.  Clinically relevant changes should be 
recorded as an AE in the eCRF (refer to section 5.2.6.1.1).
At a minimum, the haematology panels should be performed.  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 when 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.
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
27 Oct 2022
EudraCT number
EU number
2020-003744-84
BI Trial number
1346-0012
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-2)
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
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
Footnote number for MINI was changed to 7 and 
for AiCure was changed to 8.
Rationale for change
Correction
Section to be changed
Flowchart footnotes
Description of change
Addition of footnote #20
Rationale for change
Clarify that study partner is required for SCoRS 
and 
 interviews at least at Visit 2 and EOT
Section to be changed
Sections 1.4.2 and 5.2.6.3
Description of change
Change the requirement for ophthalmologic 
assessments to be performed in case of moderate to 
severe vision related AEs.
Rationale for change
Request from FDA to have all ocular AEs assessed 
by an ophthalmologist.

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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.
Section to be changed
Section 3.3.3
Description of change
Exclusion criteria #8 updated to exclude the use of 
esketamine as well as ketamine.
Rationale for change
Clarification
Section to be changed
Section 3.3.3

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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 BI 425809 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)
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 

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antipsychotic and patients should continue to take 
their background antipsychotic as prescribed by 
their treating physician.
Section to be changed
Section 4.2.21
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 reference to section 6.2.1 
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 
.
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 5.2.6.2.3
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

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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 
 requirements 
Rationale for change
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
Sections 6.2.3.4
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 10.2
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, 

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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
Rationale for change
Clarification that those assessments cannot be 
performed remotely as it would result in reduced 
quality.

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11.2
GLOBAL AMENDMENT 2
Date of amendment
18 Sep 2023
EudraCT number
EU number
2020-003744-84
BI Trial number
1346-0012
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-2)
Global Amendment due to urgent safety reasons
Global Amendment
X
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
3.3 Selection of Trial Population
Description of change
Corrected typo in drug name (BI 425908 was 
changed to Iclepertin)
Rationale for change
Editorial correction
Section to be changed
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
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.
Rationale for change
DMC recommendation
Section to be changed
Description of change
Rationale for change

 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c33087946
3.0
clinical-trial-protocol-version-03
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-2)
Author-Clinical Trial Leader
19 Sep 2023 12:40 CEST
Author-Trial Statistician
19 Sep 2023 13:05 CEST
Approval-Clinical Program 
19 Sep 2023 13:39 CEST
Author-Trial Clinical
Pharmacokineticist
19 Sep 2023 16:18 CEST
Approval-
 Medicine
20 Sep 2023 00:14 CEST
Verification-Paper Signature
Completion
20 Sep 2023 17:01 CEST

Boehringer Ingelheim 
Page 2 of 2
Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c33087946
3.0