An Open Label, Single Arm, Extension Trial to Examine Long-term Safety of Iclepertin Once Daily in Patients With Schizophrenia Who Have Completed Previous Iclepertin Phase III Trials (CONNEX-X)
Phase: PHASE3
Conditions: Schizophrenia
Sponsor: Boehringer Ingelheim

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Clinical Trial Protocol
TITLE PAGE
Document Number:
c33088336-03
EudraCT No.
EU Trial No.
2020-003745-11
BI Trial No.
1346-0014
BI Investigational
Medicinal Product(s)
Iclepertin (BI 425809)
Title
An open label, single arm, extension trial to examine long-term 
safety of Iclepertin once daily in patients with schizophrenia who 
have completed previous Iclepertin Phase III trials.(CONNEX-
X)
Lay Title
A study to test long-term safety of Iclepertin in people with 
schizophrenia who took part in a previous CONNEX study 
Clinical Phase
III
Clinical Trial Leader
Phone 
Fax:
Coordinating 
Investigator
Phone
Fax 
Version and Date
Version: 3.0
Date: 18 Sep 2023
Page 1 of 92
Proprietary confidential information.
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This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.
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~1lll1v lngelheim 

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CLINICAL TRIAL PROTOCOL SYNOPSIS
Company name
Boehringer Ingelheim 
Protocol date
15 Mar 2021
Revision date
18 Sep 2023
BI trial number
1346-0014
Title of trial
An open label, single arm, extension trial to examine long-term
safety of Iclepertin once daily in patients with schizophrenia who 
have completed previous Iclepertin Phase III trials (CONNEX-X)
Coordinating 
Investigator
Phone 
Fax 
Trial site(s)
Multi-centre approximately 42 countries
Clinical phase
III
Trial rationale
The Iclepertin phase III program is comprised of 3 pivotal trials that 
will investigate the efficacy and safety of Iclepertin in patients with 
schizophrenia over 26 weeks of treatment. Trial 1346-0014 is a roll-
over trial that will offer patients who have completed 26 weeks of 
treatment with Iclepertin or matching placebo, taken once a day, in 
any of the Iclepertin Phase III trials an opportunity to either continue 
or start to receive treatment with Iclepertin. Long-term safety data 
up to 1 year will be collected in this trial.
Trial objective(s)
The objective of this trial is to collect additional safety data in 
patients with cognitive impairment due to schizophrenia, who 
participated in and completed the 26-week treatment or matching 
placebo of one of the phase III clinical trial program for Iclepertin
(trial # 1346-0011, 1346-0012, 1346-0013)
Trial endpoints
The primary endpoint is the occurrence of treatment emergent 
adverse events (TEAEs) throughout the extension study.
Note: TEAEs are defined as all adverse events (AE) occurring 
between start of treatment in the extension trial and the end of its 
residual effect period (REP). AE that start before first drug intake in 
the extension trial and deteriorate under treatment during the 
extension trial will also be considered as ‘treatment-emergent’
The secondary endpoints are change from baseline in Clinical 
Global Impressions-Severity (CGI-S) to end of treatment (EOT) and 
Change from baseline in Hb to EOT.
Trial design
Multi-center, multi-national, open label, single arm extension trial in 
patients with cognitive impairment due to schizophrenia who have 
completed 26 weeks of treatment with 10 mg Iclepertin or matching 

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placebo, taken once daily in one of the three phase III (CONNEX)
parent trials (trial 1346-0011, 1346-0012 or 1346-0013).
Total number of 
patients entered
Apoximately 1400 patients
Number of patients on 
each treatment
Single arm 1400 patients on treatment with 10 mg Iclepertin
Diagnosis
Clinically stable outpatients with established diagnosis of 
Schizophrenia 
Main in- and exclusion 
criteria
Main Inclusion criteria:

Clinically stable outpatients who have been diagnosed with 
schizophrenia (as per Diagnostic and Statistical Manual of 
Mental Disorders, 5th edition (DSM-5)).

Patients, who completed 26 weeks of treatment in the parent 
trial, must enter the extension trial:
o
Within 2 weeks the end of treatment visit in 1346-0011, 
1346-0013 (i.e. Follow Up 1 timepoint including the 
applicable time windows).
o
At  the end of safety follow up in 1346-0012 (within 7 days 
of visit Follow Up 6).

Have a study partner, defined as any person capable of  
understanding trial related procedures, with a minimum of  8th 
grade level of education, who knows the patient well, has been 
capable of interacting with the patient on a regular basis. 
Preferably be the same person throughout the study.
Main Exclusion criteria:

Participant who developed DSM-5 diagnosis other than 
Schizophrenia or any condition that would prevent the patient 
from participating in the extension trial 

Any suicidal behavior and/ or suicidal ideation of type 5 based 
on the C-SSRS in parent trial and up to and including Visit 1 of
this study. 

Patients diagnosed with moderate or severe substance use 
disorder 

Haemoglobin- Hb drop below 100g/L (10g/dL) OR Hb 
decrease of  25% or more from baseline and is below lower 
limit of normal in parent trial (alert 3 from last measure Hb in 
parental trial)

Patients who have been diagnosed with hemoglobinopathies 
during the parent trial.
Test product(s)
Iclepertin
dose
10 mg q.d.
mode of 
administration
Oral (p.o)
Comparator product(s)
Not applicable
dose
Not applicable

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mode of
administration
Not applicable
Duration of treatment
1 year
Statistical methods
Descriptive analyses using summary statistics is planned for the 
primary endpoint of TEAEs and the secondary endpoints of change 
from baseline in haemoglobin and in CGI-S to EOT

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FLOW CHART
Trial Periods
Treatment
Follow-up
Visit
18
28
38
48
58
6
7
8
9
10
11
12
13
14
EOT
eEOT9
FU1
FU2
Weeks
0
4
8
12
16
21
26
29
32
35
38
41
44
48
52
N/A
54
56
Treatment day
1 
28
56
84
112
147
182
203
224
245
266
287
308
336
365
N/A
EOT/ 
eEOT
+14
EOT/
eEOT
+ 28
Visit time window (days)
N/A
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
Clinic (on-site) Visit2
X
X
X
X
X
X
X
☎
X
☎
X
☎
X
☎
X
X
X
X
Informed consent
X
Inform consent for 
biobanking14
X
Demographics
X
Medical history 
X
Physical examination
X
X
X
(X)
Weight
X1
X
X
X
(X)
Vital signs
X1
X
X
X
X
X
X
X
X
X
X
X
(X)
(X)
12-lead ECG
X
X
X
X
X
(X)
Drug screen test (urine)3
X1
X
X
X
X
X
Pregnancy test4
X1
X
X
X
X
X
X
X
X
X
X
X
X
Safety Laboratory tests3
Visit 3 and 5 Hematology panel only
X
XH
X
XH
X
X
X
X
X
X
X
PK Sampling12
X
X
X
X
X
Biobanking10
X
X
X
In-/exclusion criteria
X
Contact IRT
X
X
X
X
X
X
X
X
X
X
X
X
(re)Dispense & administer 
trial drug at site
X
X
X
X
X
X
X
X
X
X
IMP Compliance check
X
X
X
X
X
X
X
X
X
X
X
Termination of trial drug
X
X
X
X
X
CGI-S 
X
X
X
X
Adverse events5
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X5
Socioeconomic status
Concomitant therapy
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Substance use 6
X
X
X
C-SSRS7
X1
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
SAS/AIMS/BARS
X
X
Exit interviews (patient and 
study partner)
X13
Inform consent for exit 
interviews
                         X
       

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Trial Periods
Treatment
Follow-up
Visit
18
28
38
48
58
6
7
8
9
10
11
12
13
14
EOT
eEOT9
FU1
FU2
Weeks
0
4
8
12
16
21
26
29
32
35
38
41
44
48
52
N/A
54
56
Treatment day
1 
28
56
84
112
147
182
203
224
245
266
287
308
336
365
N/A
EOT/ 
eEOT
+14
EOT/
eEOT
+ 28
Visit time window (days)
N/A
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
Clinic (on-site) Visit2
X
X
X
X
X
X
X
☎
X
☎
X
☎
X
☎
X
X
X
X
Patient Participation 
Completion 
X
XH Hematology panel only.
(X) Optional assessments at the discretion of the investigator
1 If the procedure is performed at the last study visit for the parent trial, the procedure does not need to be repeated if visit 1 for trial 1346-
0014 occurs on the same day, including split visit.
2Visits denoted as ‘clinic’ visits are to be performed on-site.  Other visits may be conducted by telephone or on-site at the discretion of the 
investigator.  Visits may be re-scheduled if the patient is experiencing an acute episode of psychosis (relapse).
3 Safety lab and/ or drug screen test (urine), may be performed more frequently based on investigator discretion or if required locally. 
4 Pregnancy test are required for women of child-bearing potential only and may be performed more frequently based on investigator 
discretion or if required locally. If urine (dipstick) pregnancy test is positive, a serum test is required.
5 After the individual patient’s end of the trial, the investigator should report only any new occurrence of 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.
6 Details on alcohol, nicotine and caffeine use will be collected.
7 C-SSRS may be performed more frequently based on investigator judgment or local regulation.
8Site staff should contact patients by phone approximately 2 weeks after the clinic visit to discuss adherence with study medication.
9 Patients who permanently discontinue trial treatment should undergo the early End of Treatment (eEOT) visit as soon as possible, ideally 
within 7 days of IMP discontinuation, then complete the safety follow-up period.  
10 Collection of biobanking samples is optional. Serum/plasma samples will be collected at Visit 7 and EOT/Early EOT. Participants are
required to sign a separate informed consent for biobanking. Samples will be stored at a biobanking facility for future research
12 PK pre-dose/ trough sample collection within 30 minutes before IMP dosing. Note: No IMP dosing is applicable to EOT or eEOT vist. PK 
sample should be taken approximately 24 hours post last dose at the EOT.  PK sample should be taken as applicable at the eEOT (preferably 
approximately 24 hours post last dose). For further details please refer to Appendix 10.1.
13 Exit interviews are optional,  and will be done at any time between EOT/eEOT and FU2 (in approved countries only).
14 Biobanking consent can be collected at any visit prior to the collection of the sample at Visit 7.  

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TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS .....................................................................2
FLOW CHART........................................................................................................................5
TABLE OF CONTENTS ........................................................................................................7
ABBREVIATIONS................................................................................................................10
1.
INTRODUCTION...............................................................................................13
1.1
MEDICAL BACKGROUND.............................................................................13
1.2
DRUG PROFILE................................................................................................14
1.3
RATIONALE FOR PERFORMING THE TRIAL.........................................16
1.4
BENEFIT - RISK ASSESSMENT.....................................................................17
1.4.1
Benefits.................................................................................................................17
1.4.2
Risks .....................................................................................................................18
1.4.3
Discussion.............................................................................................................26
2.
TRIAL OBJECTIVES AND ENDPOINTS......................................................27
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS........27
2.1.1
Main objectives....................................................................................................27
2.1.2
Primary endpoint(s)............................................................................................27
2.1.3
Secondary endpoint(s) ........................................................................................27
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.........................29
3.1
OVERALL TRIAL DESIGN.............................................................................29
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)......................................................................................29
3.3
SELECTION OF TRIAL POPULATION .......................................................29
3.3.1
Main diagnosis for trial entry ............................................................................30
3.3.2
Inclusion criteria .................................................................................................30
3.3.3
Exclusion criteria ................................................................................................31
3.3.4
Withdrawal of patients from treatment or assessments..................................32
3.3.5
Discontinuation of trial treatment.....................................................................33
3.3.5.1
Withdrawal of consent to trial participation .........................................................34
3.3.5.2
Discontinuation of the trial by the sponsor...........................................................35
4.
TREATMENTS...................................................................................................36
4.1
INVESTIGATIONAL TREATMENTS ...........................................................36
4.1.1
Identity of the Investigational Medicinal Products..........................................36
4.1.2
Selection of doses in the trial and dose modifications......................................36
4.1.3
Method of assigning patients to treatment groups...........................................37
4.1.4
Drug assignment and administration of doses for each patient......................37

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4.1.5
Blinding and procedures for unblinding...........................................................37
4.1.5.1
Blinding................................................................................................................37
4.1.5.2
Unblinding and breaking the code ....................................................................37
4.1.6
Packaging, labelling, and re-supply...................................................................37
4.1.7
Storage conditions...............................................................................................38
4.1.8
Drug accountability.............................................................................................38
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS ................................................................................................38
4.2.1
Other treatments and emergency procedures..................................................38
4.2.2
Restrictions ..........................................................................................................39
4.2.2.1
Restrictions regarding concomitant treatment ......................................................39
4.2.2.2
Restrictions on diet and life style..........................................................................40
4.2.2.3
Contraception requirements..................................................................................40
4.3
TREATMENT COMPLIANCE........................................................................40
4.3.1
Medication adherence monitoring.....................................................................41
5.
ASSESSMENTS..................................................................................................42
5.2
ASSESSMENT OF SAFETY.............................................................................46
5.2.1
Physical examination ..........................................................................................47
5.2.2
Vital signs.............................................................................................................48
5.2.3
Safety laboratory parameters ............................................................................48
5.2.4
Electrocardiogram ..............................................................................................50
5.2.5
Other safety parameters.....................................................................................50
5.2.6
Assessment of adverse events.............................................................................51
5.2.6.1
Definitions of AEs ................................................................................................51
5.2.6.2
Adverse event collection and reporting ................................................................54
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS...................................................................................57
5.3.1
Assessment of pharmacokinetics .......................................................................57
5.3.2
Methods of sample collection .............................................................................58
5.4
ASSESSMENT OF BIOMARKER(S) ..............................................................58
5.5
BIOBANKING ....................................................................................................58
5.5.1
Methods and timing of sample collection..........................................................58
5.6
OTHER ASSESSMENTS...................................................................................58
5.7
APPROPRIATENESS OF MEASUREMENTS..............................................59
6.
INVESTIGATIONAL PLAN.............................................................................60
6.1
VISIT SCHEDULE.............................................................................................60
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS .................60
6.2.1
General Requirements........................................................................................60
6.2.2
Treatment period ................................................................................................62
6.2.3
End of Treatment visit and Early end of treatment visit ................................64
6.2.4
Follow-up period and trial completion..............................................................64
7.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE
...............................................................................................................................65

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7.1
NULL AND ALTERNATIVE HYPOTHESES ...............................................65
7.2
PLANNED ANALYSES.....................................................................................65
7.2.1
General considerations .......................................................................................65
7.2.2
Primary endpoint analyses.................................................................................65
7.2.3
Secondary endpoint analyses .............................................................................65
7.2.5
Safety analyses.....................................................................................................66
7.2.6
Other Analyses ....................................................................................................66
7.2.7
Interim Analyses .................................................................................................66
7.3
HANDLING OF MISSING DATA ...................................................................67
7.4
RANDOMISATION ...........................................................................................68
7.5
DETERMINATION OF SAMPLE SIZE .........................................................68
8.
INFORMED CONSENT, TRIAL RECORDS, DATA PROTECTION, 
PUBLICATION POLICY, AND ADMINISTRATIVE STRUCTURE ........69
8.1
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED 
CONSENT ...........................................................................................................69
8.2
DATA QUALITY ASSURANCE ......................................................................70
8.3
RECORDS...........................................................................................................70
8.3.1
Source documents ...............................................................................................70
8.3.2
Direct access to source data and documents.....................................................71
8.3.3
Storage period of records ...................................................................................72
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS ..................................72
8.5
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY........72
8.5.1
Collection, storage and future use of biological samples and corresponding 
data.......................................................................................................................72
8.6
TRIAL MILESTONES.......................................................................................73
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL ...................................73
9.
REFERENCES....................................................................................................75
9.1
PUBLISHED REFERENCES............................................................................75
9.2
UNPUBLISHED REFERENCES......................................................................79
10.
APPENDICES.....................................................................................................80
10.1
TIME SCHEDULE FOR PHARMACOKINETIC (PK) BLOOD 
SAMPLING.........................................................................................................80
10.2
DEFINITION OF STUDY PARTNER AND CAREGIVER..........................81
10.3
POTENTIAL MODIFICATION OF THE TRIAL CONDUCT IN CASE 
OF RESTRICTIONS DUE TO COVID-19 OR OTHER EXCEPTIONAL 
CIRCUMSTANCES ...........................................................................................82
11.
DESCRIPTION OF GLOBAL AMENDMENT(S) .........................................85
11.1
GLOBAL AMENDMENT 1 ..............................................................................85
11.2
GLOBAL AMENDMENT 2 ..............................................................................90

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ABBREVIATIONS
AD
Alzheimer’s disease
AE
Adverse Event
AESI
Adverse Event of Special Interest
AIMS
Abnormal involuntary movement scale
ALT
Alanine Aminotransferase
AMP
Auxiliary Medicinal Products
AST
Aspartate Aminotransferase
AUC
Area under the Curve
BARS
Barnes Akathisia Rating Scale
BI
Boehringer Ingelheim
BP
Blood Pressure
CA
Competent Authority
CGI-S
Clinical Global Impressions - Severity
CIAS
Cognitive Impairment Associated with Schizophrenia
Cmax
Maximum Concentration
CNS
Central Nervous System
COVID-19
Corona Virus Disease-19
CRA
Clinical Research Associate
CRF
Case Report Form, paper or electronic (sometimes referred to as “eCRF”)
CRO
Contract Research Organisation
CTP
Clinical Trial Protocol
CSF
Cerebrospinal fluid
C-SSRS
Columbia Suicidality Severity Rating Scale
CYP
Cytochrome P450
DILI
Drug Induced Liver Injury
dL
decilitre
DMC
Data Monitoring Committee
DSM – 5
Diagnostic and Statistical Manual of Mental Disorders 5th Edition
EC
Ethics Committee
ECG
Electrocardiogram
eCRF
Electronic Case Report Form

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eDC
Electronic Data Capture
eEOT
Early End of Treatment
EOT
End of Treatment
EudraCT
European Clinical Trials Database
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 Conference on Harmonisation
IEC
Independent Ethics Committee
IMP
Investigational Medicinal Product
IRB
Institutional Review Board
IRT
Interactive Response Technology
ISF
Investigator Site File
LPLT
Last Patient Last Treatment
MATRICS
Measurement and Treatment Research to Improve Cognition in 
Schizophrenia
MCCB
MATRICS Consensus Cognitive Battery
MCH
Mean corpuscular haemoglobin
MCHC
Mean corpuscular haemoglobin concentration
MCV
Mean corpuscular volume
MedDRA
Medical Dictionary for Drug Regulatory Activities
NOAEL
No-observed adverse-effect level
NTI
Narrow therapeutic index
PK
Pharmacokinetics
PI
Principal Investigator
PR
Pulse Rate

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PoCC
Proof of Clinical Concept
q.d.
quaque die (once a day)
RDW
Red cell distribution width
REP
Residual Effect Period
SAE
Serious Adverse Event
SOP
Standard Operating Procedure
TEAE
Treatment Emergent Adverse Event
TSH
Thyroid stimulating hormone
ULN
Upper Limit of Normal
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, no cure and long-term impairments in 
day-to-day, social and occupational functioning associated with the disease [R10-5101, R20-
1429] 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 facilities and are therefore less widely used (R16-2165; R16-
1363).
Data from several cross-sectional and longitudinal studies suggest that ameliorating cognitive 
deficits can benefit a range of functional measures, which may have significant economic 
impact (R10-5108). The potential to increase functional recovery is therefore a major unmet 
medical need and drives developing novel treatments for Cognitive Impairment Associated 
with Schizophrenia (CIAS). 
It has been long hypothesized that deficits in glutamatergic signaling plays a key role in 
neuropathology of schizophrenia, particularly negative and cognitive symptoms (R13-4521). 
Various glutamatergic transmission-enhancing agents have been tested for the treatment of 
negative symptoms and/or cognitive impairments in patients with schizophrenia, and 
produced inconsistent results. Most of these studies were of a small sample size, making 
interpretation of data difficult (R15-5877; R15-5838; R15-5584; R15-5615; R15-5578; R15-
5639; R13-4524; R13-4448; R15-5616). 
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 patient 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 CIAS and Iclepertin has the chance to be first to market 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 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. 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 as 12 days   after the last dose of 
trial medication. This is the period after the last dose with measurable drug levels and/or 
pharmacodynamic effects still likely to be present.
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,
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 interactions 
studied 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 NOAEL with multiple 
exposures at 10 mg in humans 6-7x below the NOAEL.   

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Clinical Pharmacology
Iclepertin has a half-life ranging from 37 to 59 hr.  Steady state is reached after 6 days of 
dosing with accumulation ratios for Cmax ranging from 1.96 to 2.63 and for AUC from 2.31 
to 3.21.  In the single rising dose study 1346.1 [c02820512] at 25 mg dose the effect of a high 
calorie, high fat meal resulted in an increased exposure with fed/fasted ratio for Cmax 142% 
and for AUC0-tz 126%.  The multiple rising dose study 1346.2 [c03572014] looked at the 
effect of a light meal, and the effect is much less pronounced. In phase II, patients were 
allowed to take Iclepertin "with or without" food as no clinically relevant effect on exposure 
was expected. In Phase III 10mg Iclepertin will also be administered with or without food as 
the expected increase of exposure is below the exposure already observed in previous trials, 
e.g. 1346-0009[c31477880].
As the mechanism of action involves enhancement of brain plasticity (which is higher during 
day than during night), we require morning dosing.  Pharmacokinetic (PK) parameters 
between young and elderly healthy subjects, and between Japanese, Chinese and Caucasian 
subjects are comparable[c03572014, c03760676, c03724403].
Iclepertin crosses blood-brain barrier and the required 50% glycine increase in the CSF was 
observed after multiple dosing of 10 mg Iclepertin [c03724403]. . 
Iclepertin is a sensitive substrate of CYP3A4, and co-administration of moderate to strong 
CYP3A4 inducers / inhibitors is not permitted, as this reduces / increases plasma 
concentrations of Iclepertin. CYP3A4 sensitive drugs with NTI are restricted during the 
treatment period. For CYP3A4 sensitive drugs without NTI investigators should assess if 
dose adjustments and/or monitoring of the underlying disease is clinically required for 
patients who are taking such drugs. List of prohibited medication is inserted in the 
Investigator site file (ISF), although the impact on common comedication in this target 
population is minimal.  Details can be found in the Investigator Brochure that is updated and 
provided to sites at regular intervals[c02155957].
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 Adverse Events (AEs) were related to the Central 
Nervous System (CNS), with headaches the most common and more frequent in the active 
groups than in placebo groups. Dizziness, somnolence and gastrointestinal disorders, such as 
nausea and vomiting, were also among the AEs reported more frequently on Iclepertin than 
placebo. 
Phase II trials of 12-week treatment duration in patients with schizophrenia and AD, like 
trials with other GlyT1 inhibitors such as bitopertin [R15-1266, R18-1054], detected 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.  

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There were no other clinically relevant findings in the clinical laboratory evaluation, 12-lead 
electrocardiogram (ECG), assessment of vital signs, or visual tests. No signal was observed 
for suicidal ideation or behaviour.
In Phase II trial 1346-0009 in patients with schizophrenia, proof of clinical concept (PoCC)
was demonstrated. Iclepertin improved cognition assessed as the change from baseline in 
MCCB (Measurement and Treatment Research to Improve Cognition in Schizophrenia 
[MATRICS] consensus cognitive battery) overall composite T-score after 12-week treatment 
(the primary endpoint). The largest improvements from baseline versus placebo were 
observed in the 10 and 25 mg dose groups; the 25 mg dose did not appear to provide an 
additional benefit over the 10 mg dose. Moreover, the 10 mg group showed most consistent 
efficacy across various analyses. 
In Phase II trial 1346-0023 in patients with mild to moderate AD, results showed no evidence 
for efficacy of Iclepertin compared with placebo for the evaluated endpoints.
Summary
In summary, the non-clinical and clinical Iclepertin data demonstrated an acceptable profile 
to support clinical trials in males and females, 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 GLYT1) inhibitor. Inhibition of GLYT1 increases the concentration of the 
NMDA receptor co-activator glycine in the synaptic cleft thus modulating the effect of 
NMDA receptors, which may lead to improvement of cognitive symptoms in patients with 
schizophrenia.
The efficacy and safety of Iclepertin has been investigated in patients with cognitive
impairment due to schizophrenia in a trial with 12 weeks of treatment duration. In the Phase 
II trial, 1346-0009, a total of 339 patients were exposed to Iclepertin at doses of 2 mg, 5 mg, 
10 mg, and 25 mg qd. PoCC was demonstrated for the primary endpoint of change from 
baseline in MCCB overall composite T-score after 12-week treatment [c31477880]. The 
adjusted mean change from baseline at Week 12 in MCCB overall composite T-score was 
nominally significant for the 10 mg and 25 mg treatment groups compared with placebo.

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The Iclepertin phase III program is comprised of 3 pivotal trials that will investigate the
efficacy and safety of Iclepertin in patients with schizophrenia over 26 weeks of treatment. 
Trial 1346-0014 is a roll-over trial that will offer patients who have completed 26 weeks of 
treatment with Iclepertin or placebo in any of the Iclepertin Phase III trials (1346-0011, 1346-
0012 and 1346-0013) an opportunity to either continue or start to receive treatment with 
Iclepertin. Long-term safety data up to 1 year will be collected in this trial.
To address future scientific questions, participants will be asked in this trial to voluntarily 
donate biospecimens for banking (please see section 5.5). If the participant agrees, banked 
samples may be used for future biomarker research and drug development projects, e.g. to 
identify participants that are more likely to benefit from a treatment or less likely to 
experience an AE, or to gain a mechanistic or genetic understanding of drug effects and 
thereby better match patients with therapies.
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 safe and well tolerated.
In addition, all entered subjects will continue on maintenance treatment with antipsychotic 
and other psychotropic medications. Background medication may be adjusted or changed by 
the investigator as deemed necessary to ensure the welfare of the subject. Although this is an 
experimental drug and an individual benefit cannot be guaranteed, PoCC Phase II trial 
demonstrated efficacy on cognition as assessed using MCCB overall composite score in the 
target population with schizophrenia.
So far, acquired clinical data suggest that Iclepertin improves cognition and this improved 
cognition is expected to lead to functional improvement in day-to-day activities. Patients with 
functional impairment related to schizophrenia 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, may benefit from treatment 
with Iclepertin.
Given the acceptable safety profile in clinical, nonclinical and toxicology studies performed 
to date, and careful monitoring planned during the study visits, the sponsor feels the risks to 
the participating patients are minimized and balanced by a potential benefit due to the 
intensive medical care received. Additional justification is the possibility to develop the first 
treatment options to improve cognition in patients with schizophrenia, which remains a high 
unmet medical need.

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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 SAEs was low and was comparable across 
all treatment groups. The frequency of patients with AEs leading to discontinuation of trial 
medication was also low. There were no deaths.

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Table 1.4.2:1 Overview over trial related risks 
Possible/ known 
risks of clinical 
relevance for this 
trial
Summary of data, rationale 
for the risk
Mitigation strategy
Investigational Medicinal Product (IMP)
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 [c02155957]for 
more details 
Management of symptoms, evaluation, 
and follow-up as needed to ensure 
subject safety, per investigators clinical 
judgment.
Decrease in 
Haemoglobin
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. 
PhII 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)].
On individual level we 
observed large overlap in 
Hb values between 
placebo and patients on 
Iclepertin.
Patients who have had 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 in parent trial (assessed by 
the central lab) will be excluded
from participation in this study.
Patients will be withdrawn from 
study treatment if more than 1 time 
drop in “haemoglobin level below 
100 g/L (10g/dL) OR Hb decreases 
by 25% or more from baseline and is 
below the lower limit of normal”.
Please refer to section 5.2.6.2.5- ‘Hb 
and anemia’ for more details

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Table 1.4.2:1 Overview over trial related risks (con’t)
Possible/ known 
risks of clinical 
relevance for this 
trial
Summary of data, rationale 
for the risk
Mitigation strategy
Ocular  AEs
The ocular safety of 
Iclepertin and its effects 
on ophthalmologic 
physiology in patient with 
schizophrenia were 
characterised in an ocular 
substudy as part of trial 
1346-0009, in which a 
subset of patients 
underwent special ocular 
safety assessments. 
No meaningful changes 
from baseline or 
differences between 
Iclepertin treatment 
groups and placebo were 
observed with regard to 
the analysed ocular safety 
variables.

Ocular AE will be monitored and 
followed up per investigators 
judgment (refer to section 5.2.6.2.4)

Verbatim description for each 
ocular AE is needed

For ocular AEs the patients must 
be sent to an ophthalmologist for 
detailed evaluation. Report from 
the ophthalmology examination 
will  be collected

Information from the 
ophthalmology examination will be 
collected in the Electronic Case 
Report Form (eCRF).
No long term 
use of Iclepertin
Patients have been treated 
with Iclepertin for up to 12 
weeks.  Effects of long 
term use of Iclepertin is not 
known. 
The preclinical studies 
support clinical trials of 
chronic long-term 
administration in adults, 
including WoCBP.
In trials conducted to date, 
Iclepertin has been well tolerated 
by patients and there is no evidence 
that the tolerability is expected to 
change with long term use.  The 
protocol is designed with frequent 
contact with patients and all AEs
will be collected in the trial.

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Table 1.4.2:1 Overview over trial related risks (con’t)
Possible/ known 
risks of clinical 
relevance for this 
trial
Summary of data, rationale 
for the risk
Mitigation strategy
Iclepertin- Drug Interactions
Moderate or 
Strong CYP3A4 
inhibitors 
Exposure of Iclepertin will 
increase in presence of a 
strong and moderate inhibitor.
Patients should not be entered
if taking any of the drugs listed in
the ISF or need such drug during
treatment period (refer section 3.3.3 and 
4.2.2.1)
Patients  requiring  Paxlovid (a strong 
CYP3A inhibitor) for the treatment of 
COVID-19 during the trial should stop 
taking Iclepertin at time point of 
Paxlovid start, and restart Iclepertin 1 
day after Paxlovid cessation.
CYP3A4 
sensitive drugs
with narrow 
therapeutic 
index (NTI)
Exposure of CYP3A4 
sensitive drugs with NTI 
decreases during treatment 
with Iclepertin
Trial procedures
General 
discomfort
blood draw
The potential 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.
Disease Related Risk
Worsening of 
Schizophrenia or 
relapse
Clinically stable patients with 
schizophrenia are entered 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 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/ known 
risks of clinical 
relevance for this 
trial
Summary of data, rationale 
for the risk
Mitigation strategy
Disease Related Risk
Potential 
exacerbation of 
existing or new 
side effects 
caused by 
treatment with 
antipsychotics 
(e.g. tardive 
dyskinesia, 
orthostatic 
hypotension)
No worsening of 
schizophrenia or the AEs of 
antipsychotics were seen in 
phase II study
All AE will be collected throughout 
the trial. 
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 ideations are 
common in this population. 
However, patients are in 
psychiatric treatment where 
continuous assessment of 
suicidal behavior and risk is 
well established.
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 subjects 
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/ known 
risks of clinical 
relevance for this 
trial
Summary of data, rationale 
for the risk
Mitigation strategy
Other risks
Genotoxicity, 
fertility and 
teratogenicity
Iclepertin and its 
metabolites 
:
• 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%
Drug-induced 
liver injury 
(DILI)
Rare but severe event, thus 
under constant surveillance 
by sponsors and regulators.
Timely detection, evaluation, and
follow-up of laboratory alterations in
selected liver laboratory parameters
to ensure patients´ safety.
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 
and 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 AE for assessment of 
potential abuse liability of Iclepertin
will be provided as part of ISF and 
relevant AEs must be reported 
including 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% 
This monitoring strategy is consistent 
throughout the program 

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Table 1.4.2:1 Overview over trial related risks (con’t)
Possible/ known 
risks of clinical 
relevance for this 
trial
Summary of data, rationale for 
the risk
Mitigation strategy
Other risks
Corona Virus 
Disease (COVID-
19)
Overall, the risk for patients 
with schizophrenia 
participating in the Iclepertin
CIAS clinical trials is 
considered increased in light 
of COVID-19 pandemic, due 
to the need for the study 
participant to leave his/her 
home, higher prevalence of 
medical comorbidities such as 
diabetes, COPD, and 
cardiovascular disease that 
may increase the risk of 
developing COVID-19 related 
complications.    Moreover, 
decreased Hb due to treatment 
with Iclepertin may lead to 
anemia and thus increase the 
risk of COVID-19 related 
complications.
In all clinical trials, appropriate risk 
minimization measures will be taken in 
accordance with the public health 
precautions implemented in the country 
where the study will be conducted 
(minimizing time at the clinic, replace 
physical visits with remote visits, 
minimizing the use of public 
transportation to the site etc.). The 
investigators will take the totality of 
information related to each 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. The 
investigator may decide to implement 
protocol deviations where this protects 
the safety, wellbeing and/or is in the best 
interest of the patient.Considering the 
risk, patients with ongoing severe or 
serious SARS-CoV-2 infection at visit 1
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.During the treatment period if patient 
experiences severe or serious 
symptomatic infection with SARS-CoV-
2, study medication will be temporarily 
stopped. If the study medication can’t be 
restarted within 8 weeks, patient should 
be permanently discontinued from the 
study.

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Table 1.4.2:1 Overview over trial related risks (con’t)
Possible/ known 
risks of clinical 
relevance for this 
trial
Summary of data, rationale 
for the risk
Mitigation strategy
Other risks
Patient retention 
risk  
Given the patient 
population and the long 
treatment period there is a 
risk of premature treatment 
discontinuation/patient 
withdrawal. 
All patients in this study will be on 
active treatment.
Study has been designed with 
frequent contacts between trial site 
and patients ensure the motivation and 
engagement. This will ensure frequent 
checks and reinforce compliance to 
trial treatment and background 
medication.
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 for assessment of 
potential abuse liability are 
described above.
In one of the Phase III (parent) 
study(1346- 0012), after completion 
of 26 weeks of treatment, all 
patients will be closely monitored 
during the 4 weeks in the safety 
follow up period to assess potential 
AEs of withdrawal from Iclepertin
treatment
Patients who stop therapy will 
undergo a 28 day off-drug follow-up 
period which will comprise of 2 visits 
with the site.  During these visits, the 
patient will be assessed.  It is expected 
that all AEs are followed until 
resolution or stabilization, in the
opinion of the investigator.  
A Data Monitoring Committee (DMC), independent from the Sponsor, will be established to 
review the safety data at regular intervals, and to recommend to the Sponsor whether to 
continue, modify, or stop the trial based on safety assessment. The tasks and responsibilities 
of the DMC members will be detailed in the DMC charter.

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1.4.3
Discussion
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 did not demonstrate relevant efficacy in the treatment of cognitive 
deficits of schizophrenia. Currently, there are no pharmacological treatments for CIAS 
approved by any regulatory agencies across the world. Pharmacological treatment of CIAS 
that would be available to all patients remains a high-unmet medical need. Considering the 
chronic and severe disease burden of CIAS, main cause of disability in this population, the 
potential therapeutic benefits are assessed to outweigh the currently understood potential 
risks of the treatment.

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2.
TRIAL OBJECTIVES AND ENDPOINTS
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS
2.1.1
Main objectives
The objective of this trial is to collect additional safety data in patients with cognitive 
impairment due to schizophrenia, who participated in and completed the 26-week treatment 
period with Iclepertin or matching placebo of one of the phase III clinical trial program for 
Iclepertin (trial # 1346-0011, 1346-0012, 1346-0013).
2.1.2
Primary endpoint(s)
The primary endpoint is the occurrence of treatment emergent adverse events (TEAEs)
throughout the extension study.
Note: TEAEs are defined as all AEs occurring between start of treatment in the extension 
trial and the end of its REP. AEs that start before first drug intake in the extension trial and 
deteriorate under treatment during the extension trial will also be considered as ‘treatment-
emergent’.
2.1.3
Secondary endpoint(s)
The secondary endpoints are:

Change from baseline in Clinical Global Impressions – Severity (CGI-S) to end of 
treatment (EOT)

Change from baseline in Hb to EOT.

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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN 
This is a multi-center, multi-national, open label, single arm extension trial in patients with
cognitive impairment due to schizophrenia who have completed 26 weeks of treatment with 
10 mg Iclepertin or matching placebo, taken once daily in one of the three phase III parent 
trials (trial 1346-0011, 1346-0012 or 1346-0013). Patients may be enrolled in this trial once 
the patient has signed the informed consent form and determined to have met all entry criteria 
for protocol 1346-0014. 
Patients previously on active treatment in parent trial will continue to receive Iclepertin
treatment and patients who were randomized to placebo in the parent trial will start receiving 
Iclepertin for the first time at Visit 1. Patients will receive treatment for 1 year.
After completion of the open label treatment, patients will have a 4-week safety follow-up.
In addition to the collection of AEs, patients will be required to complete a number of 
assessments to monitor for symptoms and patient reported outcomes.
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)
The main objective of this trial is to collect long term safety data in patients with CIAS. The 
primary endpoint therefore is the occurrence of TEAEs throughout the extension study.
An active control group is not planned in this extension study because there is no approved 
treatment for CIAS. Patients will be maintained on their background therapy, which may be 
adjusted according to investigator clinical discretion. This trial will provide an opportunity 
for patients who had received placebo in the parent trial to receive the active treatment. 
It is acknowledged that the data for this open-label, single-arm trial will likely be biased due 
to, among others, selection and reporting bias. However, considering lifelong nature and 
potentially devastating consequences of cognitive impairment associated with schizophrenia, 
this trial will offer an active treatment to all patients who completed any of the randomized 
phase III trial 1346-0011 or 1346-0012 or 1346-0013. The decision to enter this trial will be 
made by the patient following a discussion with the investigator.
The aim of the study is to allow treatment continuation to individual patients; therefore,
randomization, blinding and use of placebo would not be appropriate.
3.3
SELECTION OF TRIAL POPULATION
It is anticipated that approximately 1400 patients from approximately 240 sites, will 
complete one of the CONNEX studies (1346-0011, 1346-0012 and 1346-0013) and will 
consent to participate in this single arm extension trial where all patients will receive 
treatment with Iclepertin for 1 year. 

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Patients previously on active drug treatment will continue treatmet with Iclepertin, patients 
who received placebo will initiate treatment with Iclepertin for the first time at Visit 1 of the 
extension trial.
Re-screening of patients is not allowed.
3.3.1
Main diagnosis for trial entry
Clinically stable outpatients who have been diagnosed with schizophrenia (as per Diagnostic 
and Statistical Manual of Mental Disorders, 5th edition (DSM-5)) and have participated and 
completed one of the phase III trials with Iclepertin.
Please refer to section 8.3.1 (Source Documents) for the documentation requirements 
pertaining to the inclusion and exclusion criteria.
In case of questions related to inclusion/ exclusion criteria’s, please contact sponsor.
3.3.2
Inclusion criteria
1. Signed and dated written informed consent in accordance with ICH Harmonized 
Tripartite Guideline for Good Clinical Practice (ICH-GCP) and local legislation prior to 
admission to the trial (Visit 1).
2. Clinically stable outpatients who have been diagnosed with schizophrenia (as per DSM-
5).
3. Patients, who completed 26 weeks of treatment in the parent trial, must enter the 
extension trial within2: 

Within 2 weeks the EOT visit in 1346-0011, 1346-0013. (i.e. Follow Up 1 timepoint 
including the applicable time windows).

At the end of safety follow up in 1346-0012 (within the 7 days of  visit Follow Up 6 )
4. Women of childbearning 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.
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.
2 Patients who had a temporary treatment discontinuation during the parent trial, but who restarted treatment and  completed 
the planned EOT on study drug can be considered per investigator judgement

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5. Have a study partner, defined as any person capable of  understanding trial related
procedures, with a minimum of 8th grade level of education, who knows the patient well, 
has been capable of interacting with the patient on regular basis (at least once a week, 
either private or professional). Study partner does not need to attend visits with the patient 
but must be reachable by phone. Study partner should preferably be the same person 
throughout the study, if possible

Professional study partner (e.g. study nurse, social worker etc.) are allowed if not 
involved in administering any of the protocol assessments.
3.3.3
Exclusion criteria
1. Participant who developed DSM5 diagnosis other than Schizophrenia or any condition 
that would prevent the patient from participating in the extension trial (e.g. stroke, head 
trauma, developed dementia, severe uncontrolled movement disorders or other 
significant condition since enrolment into the parent phase III trial (1346-0011, 1346-
0012 or 1346-0013)).
2. Any suicidal behavior and/ or suicidal ideation of type 5 based on the C-SSRS in parent 
trial and up to and including Visit 1 of this study.

Patients with Suicidal Ideation type 4 in the C-SSRS (active suicidal thought with 
intent but without specific plan), in the past 3 months prior to and including Visit 1, 
can be entered in the study, if assessed and documented by a licensed mental health 
professional that there is no immediate risk of suicide.
3. Patients diagnosed with moderate or severe substance use disorder (other than caffeine
and nicotine), as defined in DSM-5 while the patient was in parent trial and prior to Visit 
1 of this study.
4. Positive urine drug screen ≥ 3 times during the parent trial based on central lab test. 
5. Patients who are currently or wish to participate in another investigational drug trial.
6. Any clinically significant  finding  in the judgment of the investigator such as :

Clinically significant finding on he Physical examination and/or  ECG from the last 
assessment done in the parent trial.

Vital signs (including blood pressure (BP) and pulse rate (PR)) 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.
7. Any significant central lab findings based on the last available lab result received during 
the parent trial such as:

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
Severe renal impairment defined as an eGFR < 30mL/min/1.73m²,

Indication of liver disease, defined by serum levels of either ALT (SGPT), AST
(SGOT), or alkaline phosphatase above 3 times upper limit or normal or

Hb drop below 100g/L (10g/dL) OR Hb decrease of 25% or more from baseline and
is below lower limit of normal in parent trial (alert 3 from last measure Hb in parental 
trial)

Patients who meet any of the withdrawal criteria before planned EOT (26 weeks) in
parent trial.
8. Patients who have been diagnosed with hemoglobinopathies during the parent trial.
9. Patients with known ongoing severe or serious infection with SARS-CoV-2.
10. Known history of Human Immunodeficiency Virus (HIV) and/or known on-going 
Hepatitis B or C infections. As well as 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.
11. Women who are pregnant, nursing, or who plan to become pregnant while in the trial.
12. Patients with an allergy to Iclepertin and/or any of the excipients (including serious
lactose intolerance). A list of Iclepertin and placebo ingredients are provided in the 
Investigator’s Brochure.
13. Patients who are currently treated  or expected to be treated with any of the following: 
strong or moderate CYP3A4 inhibitors, strong or moderate CYP3A4 inducers, CYP3A4 
sensitive substrates,including  grapefruit juice ad St. John’s wort (Hypericum 
perforatum) and substrates with a narrow therapeutic range (e.g., fentanyl, cyclosporine).
3.3.4
Withdrawal of patients from treatment or assessments
Measures to control the withdrawal rate include appropriate explanation of the trial
requirements and procedures prior to roll over from parent trial, as well as the explanation of 
the consequences of withdrawal. 
Every effort should be made to keep the patients in the trial and on treatment unless  there  is 
a medical reason to discontinue treatment or patient fully withdraws consent for further study 
participation.
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 to
trial participation and the reason must be documented in the patient files and CRF. If 
applicable, consider the requirements for AE collection reporting (please see sections 5.2.6.1
and 5.2.6.2).

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Every effort should be made to keep the entered patients on background medication with 
antipsychotics to prevent relapse.
3.3.5
Discontinuation of trial treatment
Temporary trial treatment discontinuation up to 8 weeks is allowed for medical or other 
reasons such as 

Resolution of Hb related issues

Planned surgery

SARS-CoV-2 infection

Current treatment with Paxlovid
Reasons of temporary trial treatment discontinuation and exact start and end dates must be 
documented.
Patients who permanently discontinue the trial treatment prior to 52 weeks of treatment
should complete an early end of treatment visit (eEOT) and the safety follow-up visits as 
outlined in the flow chart. Patients should be encouraged to complete these assessments as 
clinic visits. 
The reason for early discontinuation of trial treatment (e.g. AE, consent withdrawal for study
treatment) must be recorded in the eCRF. After the completion of the follow-up visits, the 
patient’s participation in the trial will be concluded.
In rare cases, if patient refuses or is unable to visit the site for safety follow up after early
discontinuation of trial treatment, the 14 and 28 day safety follow up visit may can be done 
remotely (e.g. by telephone) to collect as much patient safety data as possible.
An individual patient will discontinue trial treatment if:

The patient wants to discontinue trial treatment, without the need to justify the decision.

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

Haemoglobin:
o
If Hb level drops (below 100 g/L (10g/dL) OR Hb decreases by 25% or more from 
baseline and is below the lower limit of normal) and does not return to normal in 8
weeks.
o
More than 1 time drop in “haemoglobin level below 100 g/L (10g/dL) OR Hb 
decreases by 25% or more from baseline and is below the lower limit of normal”.

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
If patient experiences severe or serious symptomatic infection with SARS-CoV-2, study 
medication will need to be temporarily stopped for a maximum of up to 8 weeks. If the 
study medication cannot be restarted within 8 weeks, patient should be permanently 
discontinued from study treatment.

The patient can no longer be treated with trial medication for serious medical reasons 
(e.g., liver injury, stroke etc.), per investigator’s clinical judgement.

The patient has repeatedly shown to be non-compliant with important trial procedures 
and requirements and, in the opinion of both the investigator and sponsor representative, 
is not willing or able to stick to the trial requirements in the future.
Example: consider cases on an individual basis,  that have had repeatedly positive drug 
screen at 4 consecutive visits, or patients who are < 60% compliant with taking the study 
medication over 2 consecutive clinic visits.

The patient needs to take any restricted medication that may impact the patient’s safety 
to continue treatment, per investigator’s clinical judgment. Please consult with sponsor

Pregnancy: if a patient becomes pregnant during the trial the study medication will be 
stopped, the patient will be discontinued from the trial and the patient will be followed 
up until birth or otherwise termination of the pregnancy.
For further information, including the process for follow-up on the outcome of the pregnancy 
please see Section 5.2.6.2.
If new efficacy/safety information becomes available, Boehringer Ingelheim (BI) 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. 
3.3.5.1
Withdrawal of consent to trial participation
Patients may withdraw their consent to trial participation at any time without the need to 
justify their decision.
Withdrawal of consent to the trial participation means permanently stopping the study
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 options for continued follow up outside of the trial after trial 
discontinuation.
Given the patient’s agreement, the patient will undergo the procedures for eEOT, FUP1 and 
FUP2 as outlined in the Flowchart. 

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3.3.5.2
Discontinuation of the trial by the sponsor
BI 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 3.3.5.
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 3.3.5.1.
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.
All patients will be assigned to Iclepertin 10 mg once daily for 52 weeks.
4.1.1
Identity of the Investigational Medicinal Products
Table 4.1.1:1 Test product 1
Substance:
Iclepertin
Pharmaceutical formulation:
Tablet
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG
Unit strength:
10 mg
Posology:
10 mg once daily
QD
Mode of administration:
Oral
4.1.2
Selection of doses in the trial and dose modifications
The dose of 10 mg of Iclepertin once daily was selected based on the following strategy:
1.
Effective dose in improving cognition in PoCC/DF trial in patients with 
schizophrenia was 10 mg, as this dose separated best from placebo w.r.t. 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 small with decrease of 3.3 g/L in 10mg 
group and 4.5 g/L in 25mg. It is planned to monitor Hb.
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.

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4.1.3
Method of assigning patients to treatment groups
All patients will receive treatment with Iclepertin. Interactive Response Technology (IRT) 
will be used to dispense medication kits and manage initial/ resupply ordering of medication 
kits. The study site will be required to complete the appropriate module within the IRT 
system.
The investigator will receive all necessary instructions to access the IRT system from the 
Sponsor or chosen provider. Detailed IRT transactions and procedures will be documented in 
the user requirement specifications mutually agreed to by the sponsor and the IRT provider.
All medication kits assignments will occur in an open label fashion. 
4.1.4
Drug assignment and administration of doses for each patient
Dispensing of medication kits will begin at visit 1. Sufficient medication kits (plus backup) 
will be provided at each clinic 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 52 weeks.
The first dose of study medication will be taken at the end of Visit 1 under supervision of the
investigator or delegated site staff, after all Visit 1 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.
The last dose of study medication should be taken on the day before the EoT Visit.
A dose reduction of Iclepertin is not possible.
4.1.5
Blinding and procedures for unblinding
4.1.5.1
Blinding
This is an open label trial, all patients will be receiving same dose of Iclepertin.
4.1.5.2
Unblinding and breaking the code
Not applicable
4.1.6
Packaging, labelling, and re-supply
The IMPs will be provided by BI or a designated Contract Research Organisation (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.

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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 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 PI,

Availability of FDA Form 1572 (if applicable).
Investigational drugs are not allowed to be used outside the context of this protocol. They 
must not be forwarded to other investigators or clinics. Patients should be instructed to return 
unused investigational drug.
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 IMP 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 IMPs 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 

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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 listed 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 
7, EOT or eEOT (if applicable):
o
Antihistamines with prominent sedative side effects
o
Anticholinergics
o
Benzodiazepines
o
Other sedative medication 
o
Short-term opioids (for pain, cough or diarrhea)

Antihistamines and Anticholinergics:
o
Patients taking anticholinergics and/ or 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.
Allowed are:

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).

Vaccination with COVID-19 Vaccines is permitted as per local public health 
recomendations

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4.2.2.2
Restrictions on diet and life style
Nicotine and caffeine use if possible should remain stable during the treatment period.
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 
subjects exercise caution when driving or operating machinery during the treatment period.
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:
o
Combined (estrogen and progestogen containing) hormonal birth control that 
prevents ovulation (oral, intravaginal, transdermal)
o
Progestogen-only hormonal birth control that prevents ovulation (oral, injectable,
implantable)
o
Intrauterine device or intrauterine hormone-releasing system
o
Bilateral tubal occlusion or ligation
o
Vasectomised sexual partner with documented absence of sperm
o
Complete sexual abstinence when this is in line with the preferred and usual lifestyle 
of the patient (note: periodic abstinence such as calendar, ovulation, symptothermal, 
post-ovulation methods and withdrawal are not acceptable methods of 
contraception)
Male patients and their female partners:
There are no specific contraceptive requirements for male participants and their female 
partners.
4.3
TREATMENT COMPLIANCE
Patients are requested to bring all remaining trial medication including empty package 
material with them when attending visits.
Based on empty 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 package 100
Number of which should have been taken as directed by 
the investigator

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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 HAP of Iclepertin should be reported and managed as per the investigator´s 
judgement.
4.3.1
Medication adherence monitoring
During the study, medication adherence monitoring may be introduced. In which case, in 
countries where it has been locally approved, the study medication will be packaged in smart 
blister cards fitted with a sensor to allow for electronic tracking (date, time, and cavity) when 
a medication is removed from the package. Each wallet with the smart blister cards contains 
medication for 28 days of treatment. Participants must be instructed to return all blister packs 
(empty, partially empty, or full) at each on-site study visit. Site personnel will dispense the 
smart blisters and read the returned smart blisters at each clinic visit to determine medication 
adherence. Inconsistencies in the electronically captured dispensing data should be discussed  
with the participant and the explanation documented.

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5.
ASSESSMENTS

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5.2
ASSESSMENT OF SAFETY

Clinical Global impressions – Severity (CGI-S) will measure the severity of the illness. 
The CGI-S is a one-item evaluation completed by the clinician on the patient’s severity of 
psychopathology. The CGI-S is rated ordinal from 1 to 4 [R03-0520].
Ideally, the same investigator or site staff should assess CGI-S (refer also to section 6.2.1
for additional information).

Extrapyramidal Symptoms (EPS) will be assessed using 3 scales:
o
The Simpson Angus Scale (SAS) is a performance scale that measures drug-induced 
parkinsonism symptoms. The rater asks the patient to perform 10 tasks and rates 
responses on a scale of 0-4 (normal to severe). It consists of one item measuring gait 
(hypokinesia), six items measuring rigidity and three items measuring glabella tap, 
tremor and salivation, respectively. A total score of 0-40 is calculated (or scale score 
can be calculated by dividing the total by 10 to give a score between 0 and 4), with a 
raw score of < 3 identifying “normal” symptoms, ≥6 indicating a level of disorder for 
which treatment should be reconsidered, ≥12 requiring attention, and a score of ≥18 
“almost certainly” requiring modification of pharmacotherapy.
o
The Abnormal involuntary movement scale (AIMS) records the occurrence of tardive 
dyskinesia (TD) in patients receiving antipsychotic medications. The AIMS test is 
used to detect TD and to follow the severity of a patient's TD over time. These items 
are also scored from 0 (= normal/healthy) to 4 (= severely affected). The scores are 
summed to give an overall score of the involuntary movements. It assesses tardive 
movement disorders 
o
The Barnes Akathisia Rating Scale (BARS) is a rating scale that is administered by 
the investigator to assess the severity of drug-induced akathisia. The BARS is the 

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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.

Columbia Suicidality Severity Rating Scale (C-SSRS)
The C-SSRS is a semi-structured, investigator-rated interview, developed by clinical experts 
in cooperation with the FDA, assessing both suicidal behavior and suicidal ideation. It does 
not give a global score, but provides some categorical and some severity information 
specifically for behavior and ideation.
The computer-automated C-SSRS interview may be administered using a tablet device.
Subjects who do not have suicidal behavior or ideation will answer a limited number of 
questions and will usually complete the assessment in about 3 minutes. Subjects with 
significant suicidal ideation or behavior may require up to 10 minutes to answer all relevant 
questions. This assessment should be conducted early in the visit. At the conclusion of each 
assessment, the site will have access to the C-SSRS results via a web-based portal. The 
results include the findings for suicidal ideation, intensity of ideation, suicidal behavior, and 
lethality / medical damage (for actual suicide attempts only).
FromVisit 1 the assessment ‘since last visit’ will be performed at each clinic visit (‘Since 
Last Visit version’). The investigator is to review/ consider the C-SSRS results for 
plausibility and clinical relevance. Doubtful results may be repeated or results may be 
validated by a consulting psychiatrist. If there is a confirmed positive report of suicidal 
behavior or suicidal ideation type 4 or 5 after start of trial, the investigator is to immediately 
interview the subject during the clinic visit (if the investigator did not administer the C-SSRS 
leading to the positive report), and/ or is to consult a psychiatrist if considered necessary.
For any positive suicidal ideation (type 1 to 5) or suicidal behavior, the rater must document 
additional details in the comment fields in the C-SSRS in Pathway.  
If there is any new suicidality or increase in suicidality, please comment on the clinical 
significance and any additional follow-up actions that may be performed in the eCRF.  
If the positive report is confirmed, appropriate actions for the subject’s safety have to be 
initiated and followed up as deemed necessary. The C-SSRS may be repeated at an 
unscheduled visit at the investigator’s discretion.C-SSRS results will be reported in terms of 
AEs as described in Section 5.2.6.1.4
5.2.1
Physical examination
A complete physical examination will be performed at the time points specified in the 
flowchart. It includes at a minimum general appearance, neck, lungs, cardiovascular system, 
abdomen, extremities, and skin. 

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Body weight will be measured at the time points specified in the flowchart.
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 flowchart, prior to blood 
sampling.
This includes systolic and diastolic BP and PR (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 flowchart.
All analyses will be performed by a central laboratory, the respective reference ranges will be 
provided in the ISF. 
Patients do not have to be fasted for the blood sampling for the safety laboratory. 
Instructions regarding sample collection, sample handling/ processing and sample shipping 
are provided in the Laboratory Manual.
The central laboratory will send reports to the investigator. It is the responsibility of the 
investigator to evaluate the laboratory reports. Clinically relevant abnormal findings as 
judged by the investigator will be reported as AEs (please refer to section 5.2.6).
In case the criteria for hepatic injury are fulfilled, a number of additional measures will be 
performed (please see section 5.2.6.1 and the DILI Checklist provided in the ISF  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.
Laboratory values that are out of range should be commented on lab report print-outs and 
evaluated by the investigator for clinical significance. 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 CTP, at any time point during the study, per 
investigators discretion. Clinically significant abnormal laboratory results should also be
reported by the investigators in the eCRF AE page (from subsequent visits test).

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Table 5.2.3:1 
Safety laboratory tests
Category
Test Name
Haematology (refer 
to section 5.2.6.2.5)
Hb
Hematocrit (Hct) MCV, MCH, 
RDW, MCHC Red Blood Cell 
Count/ Erythrocytes
Reticulocyte Count
Reticulocyte index
Total iron binding capacity
Serum ferritin
Serum iron
Platelet Count/ Thrombocytes
White Blood Cells/ 
Leukocytes
Diff. Automatic (manual if
diff. automatic is 
abnormal)
- Neutrophils
- Eosinophils
- Basophils
- Monocytes
- Lymphocytes
Folate 
Vitamin B12
Chemistry
AST(GOT)
ALT(GPT)
Alkaline Phosphatase (AP)
Bilirubin Total, fractionated if
increased
Creatine Kinase (CK)
CK-MB – only if CK is elevated
C-Reactive Protein
Gamma-Glutamyl Transferase
(GGT/γ-GT)
Lactic Dehydrogenase (LDH)
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 Ketones
Urobilinogen
Urine Bilirubin
Urine blood
Urine pH
Urine Leukocyte esterase
Urine Drug Screen 
**** (Preliminary 
and confirmatory 
testing)
Amphetamines
Barbiturates
Cannabis
Cocaine
Methadone
Opiates
PCP (Phencyclidine)

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* 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 and Prolactin – only at EOT/ eEOT
*** To be done locally at site with central lab provided kit.
**** Patients will be considered drug screen positive, if the confirmatory test is positive.
5.2.4
Electrocardiogram
The 12-lead ECGs will be recorded as scheduled in the flowchart. Twelve-lead ECGs (I, II, 
III, aVR, aVL, aVF, V1 – V6) will be recorded using equipment provided by a central ECG 
vendor. The ECGs will be recorded for at least 10-second duration after the subjects have 
rested for at least 5 minutes in a supine position and prior to lab sampling. Electrode 
placement will be performed according to the method of Einthoven/Goldberger (ankles and 
wrists). At all time points indicated in the Flow Chart, single ECGs will be recorded. ECG 
recordings at planned time points may be repeated for quality reasons like alternating current 
artefacts, muscle movements and electrode dislocation. In this case the repeated ECG 
recordings will be used if quality was better.
The investigator or a designee will evaluate whether the ECG is normal or abnormal and 
whether it is clinically significant, if abnormal. The electronic version of the ECG is regarded 
as source data. Dated and signed printouts will be stored in the patient’s medical file if there 
is no validated and certified e-medical record for ECG data.
Additional ECGs may be collected by the investigator for safety reasons. Clinically relevant 
abnormal findings noticed after baseline assessment will be reported as AEs and followed up 
and/or treated locally until normal or stable condition.
All ECGs will be transmitted electronically to the central ECG vendor in order to enable a 
centralized and independent re-evaluation of all 12-lead ECGs. A centralized and 
independent re-evaluation will be done. Central evaluation on individual ECG level will be 
performed by the vendor and a report will be provided to the site. Abnormalities detected 
during this centralized ECG evaluation will not necessarily qualify as AE. Decisions on 
eligibility for the trial and treatment or further follow-up of any findings are in the 
responsibility of the investigator. Abnormalities detected in central evaluation needs to be 
reviewed and if considered clinically significant to be reported as new AE, if identified after 
first dose in this extension trial. These Clinically relevant abnormal findings will be managed 
as medically appropriate, per investigators clinical judgment.
5.2.5
Other safety parameters
. Refer to Section 5.2. In addition 
investigator may use CGI-S and 
 clinical judgment for assessing schizophrenia worsening/ 
relapse.
Schizophrenia worsening: Fluctuation in the severity of symptoms is common and should 
be managed and reported as per the clinical judgment of the investigator. Adjustment of

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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 visit due to psychotic symptoms) due to worsening of 
psychotic symptoms increased 
 per investigators judgment
5.2.6
Assessment of adverse events
5.2.6.1
Definitions of AEs 
5.2.6.1.1
Adverse Event
An AE is defined as any untoward medical occurrence in a patient or clinical investigation 
subject administered a medicinal product and which does not necessarily have to have a 
causal relationship with this treatment.
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product.
The following should also be recorded as an AE in the CRF and BI SAE form (if applicable):
Worsening of the underlying disease or of other pre-existing 
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. However, if these abnormalities are 
AEs of the parent trial and still ongoing after first dose in extension trial, they should not be 
recorded as baseline conditions. In such situations section 5.2.6.2 should be followed.
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 

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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: An event that possibly leads to disability will be handled as “deemed serious 
for any other reason” and, therefore, reported as an SAE.
5.2.6.1.3
AEs considered “Always Serious”
In accordance with the European Medicines Agency initiative on Important Medical Events, 
BI has set up a list of AEs, which by their nature, can always be considered to be “serious” 
even though they may not have met the criteria of an SAE as defined above.
The latest list of “Always Serious AEs” can be found in the eDC system. A copy of the latest 
list of “Always Serious AEs” will be provided upon request. These events should always be 
reported as SAEs as described in section 5.2.6.2.
Cancers of new histology and exacerbations of existing cancer must be classified as a serious 
event regardless of the time since discontinuation of the drug and must be reported as 
described in 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 judgement whether this event represents an AE as defined in the 
protocol. If it is considered an AE then it must be reported as serious on the SAE form and  
eCRF AE page , as as “suicidal ideation” is included in the 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 AESI relates to any specific AE that has been identified at the project level as being of 
particular concern for prospective safety monitoring and safety assessment within this trial, 
e.g. the potential for AEs based on knowledge from other compounds in the same class. 
AESIs need to be reported to the sponsor’s Pharmacovigilance Department within the same 
timeframe that applies to SAEs, please see section 5.2.6.2.2.
The following are considered as AESIs:
Potential Severe DILI
A potential severe DILI that requires follow-up is defined by the following alterations of 
hepatic laboratory parameters:

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
an elevation of AST (aspartate transaminase) and/or ALT (alanine aminotransferase) ≥3
fold ULN combined with an elevation of total bilirubin ≥2 fold ULN measured in the
same blood draw sample, or in samples drawn within 30 days of each other, or

ALT, and / or AST elevations ≥10 fold ULN.
These lab findings constitute a hepatic injury alert and the patients showing these lab
abnormalities need to be followed up according to the “DILI checklist” provided in the ISF.
In case of clinical symptoms of hepatic injury (icterus, unexplained encephalopathy,
unexplained coagulopathy, right upper quadrant abdominal pain, etc.) without lab results
(ALT, AST, total bilirubin) available, the investigator should make sure these parameters are
analysed, if necessary in an unscheduled blood test. Should the results meet the criteria of
hepatic injury alert, the procedures described in the DILI checklist should be followed.
5.2.6.1.6
Intensity (severity) of AEs
The intensity (severity) of the AE should be judged based on the following:
Mild:
Awareness of sign(s) or symptom(s) that is/are easily tolerated.
Moderate:
Sufficient discomfort to cause interference with usual activity.
Severe:
Incapacitating or causing inability to work or to perform usual activities.
5.2.6.1.7
Causal relationship of AEs
Medical judgement should be used to determine whether there is a reasonable possibility of a 
causal relationship between the 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 

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of drug administration; an allergic reaction weeks after discontinuation of the drug 
concerned).

Continuation of the event despite the withdrawal of the medication, taking into 
account the pharmacological properties of the compound (e.g. after 5 half-lives).
Of note, this criterion may not be applicable to events whose time course is prolonged 
despite removing the original trigger.

Additional arguments amongst those stated before, like alternative explanation (e.g. 
situations where other drugs or underlying diseases appear to provide a more likely 
explanation for the observed event than the drug concerned).

Disappearance of the event even though the trial drug treatment continues or remains 
unchanged.
5.2.6.2
Adverse event collection and reporting
5.2.6.2.1
AE Collection
The investigator shall maintain and keep detailed records of all AEs in the patient files.
The following must be collected and documented on the appropriate CRF(s) by the 
investigator (special notes on the SAE form reporting when needed):
For AEs with onset date in parent trial that are still ongoing after first dose of trial drug 
in extention trial:
•
All ongoing AEs from the parent trial at the time of first dose of drug in this 
extension study, must be re-recorded and followed up in the extension trial.
•
Updates for SAEs or AESIs from the parent trial that are ongoing after first drug 
dose in this extension trial must also be captured/updated in the concerned parent 
trial (1346-0011, 1346-0012 and 1346-0013) in addition to being recorded in this 
extension trial, as long as the database for the concerned parent trial is not locked.
However, concerning reporting on the SAE form, the follow-up report will only be 
sent on the parent trial SAE form; no new SAE form is to be completed for the 
extension trial in such a situation.
Note: 
If the intensity of an ongoing AE from parent trial changes after first trial drug 
administration in the extension trial, the AE with the new intensity will be handled as a new 
event; this means it is only recorded in the extension trial eCRF.
Example: If the intensity increased then the new AE name/term should contain “Worsening 
of…” or “Exacerbation of…”
Considerations for reporting on the SAE form, when intensity change qualifies as 
worsening/exacerbations of an event that had already been reported on the SAE form:
-
corresponding follow up report to be sent on the parent trial SAE form with date of 
worsening as event end date.
-
extension trial SAE form to be sent as initial report for the extension trial for new 
event “Worsening/Exacerbation of…” with date of worsening as onset date.

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Considerations for reporting on the SAE form, when intensity change qualifies as worsening 
/exacerbation of an event and requires for the first time reporting on the SAE form (meeting 
for the first time seriousness/AESI criteria):
-
only extension trial SAE form to be sent; as initial report for the extension trial for 
new event “worsening/exacerbation of…” with date of worsening as onset date.
For AEs with onset date after first dose of trial drug in extension trial:
Only to be reported in extension trial (concerning both eCRF and SAE form (when 
applicable)):

From first dose of trial medication onwards until completion of 28 days follow 
up period (FU2) after the EOT visit: all AEs (non-serious and serious) and all 
AESIs.

After the individual patient’s end of the trial: the investigator does not need to 
actively monitor the patient for new AEs but should report any occurrence of 
cancer and trial treatment related SAEs and trial treatment related AESIs of which 
the investigator may become aware of by any means of communication, e.g. 
phone call. Those AEs should be reported on the BI SAE form (see section 
5.2.6.2.2), but not on the CRF.
5.2.6.2.2
AE reporting to the sponsor and timelines
The investigator must report SAEs, AESIs, and non-serious AEs which are relevant for the 
reported SAE or AESI, on the BI SAE form immediately (within 24 hours ) to the sponsor’s 
unique entry point (country specific contact details will be provided in the ISF). The same 
timeline applies if follow-up information becomes available. In specific occasions, the 
investigator could inform the sponsor upfront via telephone. This does not replace the 
requirement to complete and send the BI SAE form.
With receipt of any further information to these events, a follow-up SAE form has to be 
provided. For follow-up information the same rules and timeline apply as for initial 
information. All (S)AEs, including those persisting after individual patient’s end of trial must 
be followed up until they have resolved, have been assessed as “chronic” or “stable” , or no 
further information can be obtained.
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).

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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.
5.2.6.2.4
Ocular AEs
Before drug administration at Visit 1 site staff will remind patients to report “any unusual 
visual perception they may experience”
During the study, if patients report a change in perception or any ocular adverse events, 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.
5.2.6.2.5
Haemoglobin and anemia
Additional monitoring of patients who experience a decrease in Hb or anemia, as outlined 
below is required. In general patients should be monitored using the Haematology panel 
(refer to Table 5.2.3:1)
Any decrease in Hb should be managed as required per Investigators clinical judgement.
Hb will be evaluated using the last on-treatment value from the parent trial in which values 
are blinded, therefore, site will be alerted if the following occurs:
Scenarios and Actions:
Alert 1:
•
Hb decrease > 20 g/L (2 g/dL) compared to baseline value 
o
Patients may continue on the study medication.  
o
The hematology panel should be performed at the next visit (or earlier, per 
investigator’s judgement). Hematology panel should be repeated at subsequent visits 
until resolution or stabilization or until subject completion. 
Alert 2
•
Hb value is below the normal reference range
o
Patients may continue on the study medication.  
o
Haematology panel should be performed at the next visit (or earlier, per 
investigator’s judgement).  Haematology panel should be repeated at subsequent 
visits until resolution) or stabilization (alerts are  no longer triggered) or until 
subject completion.

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o
The investigator should further evaluate the patient status and report the AE 
“Anaemia” based on investigators clinical judgment. Once Alert 2 is no longer 
trigged, the investigator may evaluate whether or not the AE “Anaemia” is resolved.
Alert 3
•
Hb value < 100 g/L (10g/dL) OR 
decrease of ≥25% from baseline and is below the lower limit of normal
o
Patients will need to temporarily stop the study medication. 
o
Report as an AE “Anaemia”
o
Patient should be referred to a specialist for further management.*
o
Haematology panel should be performed at the next visit (or earlier, per 
investigator’s judgement). Haematology panel should be repeated at subsequent 
visits until resolution or stabilization or until subject completion. 
o
After first drop:

If Hb value does not return to normal within 8 weeks, patient should be 
permanently discontinued from study treatment and eEOT should be conducted. 

If Hb values returns to normal within 8 weeks, study medication can be restarted 
per investigators clinical judgment.
o
If Hb drops second time (Hb value <100 g/L (10g/dL) OR decrease of ≥25% from 
baseline and is below the lower limit of normal) after restart of study medication,
patient should be permanently discontinued from study treatment and eEOT should 
be conducted.
*Note - The specialist evaluation should be documented in the source. Any clinically relevant 
finding or diagnosis from this consultation should be considered while reporting AE(s).
5.2.6.2.6
AE suggestive of study medication abuse potential 
To assess the abuse potential of Iclepertin, investigators are required to provide detailed 
descriptions of specific types of AEs and scenarios that are suggestive of study medication 
abuse (e.g. inappropriate medicating dosing). Detailed information should be recorded in the 
source documents and eCRF and if applicable, on the SAE form. A list of AEs potentially 
indicating study medication abuse will be provided as part of ISF.
5.2.6.2.7
Monitoring of potential 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 
 and C-SSRS.
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS
5.3.1
Assessment of pharmacokinetics
PK samples will be collected as specified in flow chart before dosing the patient. Patients will 
be asked to:

record the time of drug intake on three consecutive days before PK visits

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
record if the drug intake was with or without food on the three consecutive days 
before PK visits

record the time when they had last meal intake on the day of the visit with PK 
sampling.
5.3.2
Methods of sample collection
A detailed description of sample collection and handling is provided in the laboratory
manual. For quantification of drug plasma concentrations of Iclepertin, venous blood will be 
collected using a pre-labelled potassium ethylenediamine-tetraacetic acid (EDTA) containing 
blood drawing tube at the times indicated in Appendix 10.1.
Plasma samples will be discarded at latest 6 months after the final clinical trial report has 
been signed.
5.4
ASSESSMENT OF BIOMARKER(S)
Not applicable.
5.5
BIOBANKING
Participation in biobanking is voluntary and not a prerequisite for participation in the trial. 
The aim of the collection/banking is to be able to analyse long term and late effects of 
treatment, as well as to potentially evaluate the persistence effect on biomarkers  in prolonged 
treatment. Biobanking will occur in countries where it has been locally approved and only 
after a separate biobanking informed consent has been given in accordance with local ethical 
and regulatory requirements. Samples will be collected only in countries where all applicable 
local regulatory and ethics.
approvals have been obtained for biobanking.
5.5.1
Methods and timing of sample collection
Detailed instructions on sampling, preparation, processing, shipment and storage are provided 
in the laboratory manual. For sampling timepoints see Flow Chart . Blood will be drawn for 
plasma and serum banking purposes.
5.6
OTHER ASSESSMENTS
Socioeconomic status will assess patient’s working or employment status and housing 
situation (living alone, with family, etc.). A dedicated page to assess socioeconomic status 
will be available in the eCRFs.

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Exit interview, in selected countries, and where it has been locally approved, trained 
independent moderators will interview approximately 40  patients and approximately 15
study partners at EOT or within a time window of approximately 4 weeks after. Participants 
will respond to open-ended questions on their experience in performing daily tasks and 
activities whilst taking Iclepertin including meaningfulness and importance of the changes 
they experienced in daily functioning. Participants will also respond to open-ended questions 
on their overall experience of treatment and participation in the clinical study. For 
participants who prematurely discontinue the study, the interview can be conducted after their 
eEOT. Participation in the interview is optional, details will be described in an optional  
inform consent form. Further details will be provided in a separate interview manual.
5.7
APPROPRIATENESS OF MEASUREMENTS
All measurements performed during this trial are acceptable measurements and commonly 
used in monitoring safety aspects or assessing treatment response in patients with CIAS.
The scheduled measurements are appropriate to see drug induced changes in physical 
examination, vital signs, ECG and standard laboratory values. These primary and secondary 
safety measurements are standard and accepted for evaluation of safety and tolerability of an 
oral drug, and they are widely used in this kind of studies. The period of 1 year of treatment 
with Iclepertin is deemed appropriate to collect additional safety data in patients with 
cognitive impairment due to schizophrenia 
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 are to 
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 date 
schedule calculated from Visit 1. 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
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.
In addition, the site staff members who are administering the 
C-
SSRS
 CGI-S, SAS, AIMS, BARS, 
 require 
vendor certification.  
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 AE.
Patients do not have to come fasted for any trial visits. 
Safety labs, urine drug screen, pregnancy test, physical exam, vital signs assessment, C-SSRS
may be performed more frequently based on investigator discretion or if required locally.
The following are preferences for the conduct of the assessments:

All other assessments can be completed per the convenience of patient and site at all 
respective visits.

Assessment of each rating scale 
CGI-S) should 
preferentially be done by the same rater for a given patient throughout the study 
period. However, for
the consistency of time of day is more 
important than the consistency of the rater.

The global impression anchor scales (CGI-S) should preferably be assessed after 
 at the respective visits when they are scheduled.

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
During the 
 assessments and throughout the visit, patients are allowed to take 
short breaks as needed, in the judgement of the rater/investigator.

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. 

Study procedures for visits 6, 7, 9, 13, EOT and eEOT can be split into 2 sequential 
days in which case the following is preferred:
o
Each assessment should be completed on the same day.
o
o be done on the first day of the visit  
o
The remaining assessments can be done per convenience of the patient and site on 
day 1 or day 2
o
are recommended to be done on the same day to reduce the 
burden to the study partner (applicable for V6, V13 and EOT/ eEOT) It is 
important that the patient and the study partner portions should be done same day 
or consecutive days as the interview refers to a specific timeframe.
o
CGI-S anchor scale to be done after 
 . The CGI-S rater should base their 
assessment after review of information about that patient at that visit, including 
the 
 ratings.
o
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.
Other important considerations:
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.
Study partner requirements:

Input from study partners will be required on the following assessments as indicated 
in the flow chart. 

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
If the study partner is not available for in person ratings, telephone interview is 
acceptable. The study partner must be available within visit window for a telephone 
interview at the visits indicated in the flowchart where study partner questionnaires 
are required.

Preferably the study partner should remain constant throughout the trial period
For study partners who are also caregivers:

Study partners who are also caregivers will be asked to complete the
 (optional assessments) as indicated in the flowchart. 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.
6.2.2
Treatment period

Treatment period is from Visit 1 to (e)EOT Visit

Please refer to the general requirements in section 6.2.1

Please refer to Appendix 10.3 for guidance in case of any exceptional circumstances.  
Sites should consult with sponsor before making any modifications.  

Please refer to flow chart for procedures to be performed at each visit.
Visit 1:

Signed informed consent must be obtained from   the patient before performing any 
study related procedure.

Study partner must sign informed consent form before performing any relevant study 
related procedure (V6). 

All procedures for parent trial last visit should be completed before first dose of this 
extension trial.

Some procedures that have been performed at the last visit for the parent trial do not 
need to be repeated. Refer to Flow chart. 

The patient is recorded on the enrolment log and registered in the IRT system. 

Please refer to the general requirements in section 6.2.1

Drug of abuse testing; At visit 1 the investigator should remind the patients of the 
importance of not taking drugs of abuse during the study and that urine testing will 
be repeated throughout the trial. 

Medical history will be collected from parent trial.

Baseline conditions:
•
Any Baseline Conditions/ Medical History entries that are ongoing at the end of 
participation in the parent trial are to be re-recorded  in the extension trial case 
report form (CRF)

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•
If concomitant medication is being taken for a Baseline Condition/ Medical 
History reported in the parent trial, re-record the Baseline Condition/ Medical 
History in the extension trial CRF.
•
Any AE from the parent trial that is Resolved with ‘sequelae’ should be entered 
as a Baseline Conditions/ Medical History in the extension trial.
•
For any newly identified Baseline Condition/Medical History in the extension 
trial:
-
Any newly identified baseline condition that has been identified and was 
relevant at the time of the subject participation in the parent trial and the 
parent trial is not locked- record this information in the parent trial and in the 
extension trial CRFs, as applicable.
-
Any newly identified baseline condition that has been identified and was 
relevant at the time of the subject participation in the parent trial and the 
parent trial is locked- record this information in the extension trial CRF.
-
Any newly identified baseline condition that has started after participation of 
the parent trial and is present at the start of the extension trial, record the 
extension trial only.

Concomitant Medications/Non-Drug Therapies
• Any Concomitant Therapy/Non-Drug Therapies that are ongoing at the end of 
participation in the parent trial are to be recorded  in the extension trial CRF.
• For newly identified Concomitant Therapy/Non- Drug Therapies in the extension 
trial:
-
Any newly identified Concomitant Therapy/Non- Drug Therapies that has 
been identified and was relevant at the time of the subject participation in 
the parent trial and the parent trial is not locked- record this information in 
the parent trial and in the extension trial CRFs, as applicable.
-
Any newly identified Concomitant Therapy/Non- Drug Therapies that has 
been identified and was relevant at the time of the subject participation in 
the parent trial and the parent trial is locked- record in the extension trial 
CRF.
-
Any newly identified Concomitant Therapy/Non- Drug Therapies that have 
started after participation of the parent trial and  is occurring at the  start of 
the  treatment of the extension trial, record the extension trial only.

First intake of trial drug will be done at the site.

Adherence monitoring: at visit 1 patients should receive information on adherence 
monitoring system and it’s packaging (if site is participating and if approved at the 
time of the visit).

Medication kits will be dispensed
For treatment visits (including Visit 1 as applicable):

Patients should be instructed to bring all trial medication (used and unused kits/ 
packaging including blisters) with them to these clinic visits.

Sufficient trial drug at each on site visit will be dispensed 

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
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.

A phone call to discuss adherence to study medication should be done 
approximately 2 weeks after each visit from V1 to V5.

Pre dose PK samples will be collected during the treatment period as per the Flow 
chart. Patients should not take trial medication before coming to the clinic on visit 
days. Refer to section 5.3 and Appendix 10.1 for more details.

At Visit 14, patients will be instructed to take the last dose of study medication on 
the day before the EOT Visit.
Unscheduled visits
Unscheduled visits can be done at any time at the discretion of the investigator.
6.2.3
End of Treatment visit and Early end of treatment visit 
Please refer to the flow chart for procedures to be completed.  
The final 
 assessment at the EOT Visit should be performed after the patient 
completes the 52 week treatment period. 

Patients who permanently discontinue trial treatment early should undergo the eEOT 
visit, ideally within 7 days of IMP discontinuation, then complete the safety follow up 
period. 

Termination of trial medication eCRF pages will be completed.

Exit interviews will be requested as an optional procedure for subjects and their study 
partners in selected countries, approximately 4 weeks after EOT. The interview will be 
conducted after a separate exit interview informed consent has been given in accordance 
with local ethical and regulatory requirements. 
6.2.4
Follow-up period and trial completion

Patients who complete 52 weeks of treatment or permanently discontinue medication 
early will be followed at FU1 and FU2. Refer to flow chart for procedures. The planned 
observation period is defined as 52 weeks of treatment.

Patients who have been early discontinued from study treatment because of Hb related 
withdrawal criteria, should be monitored and followed up during the safety follow up 
with Haematology panel.

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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
7.1
NULL AND ALTERNATIVE HYPOTHESES
The objective of this trial is to collect additional safety data in patients with cognitive 
impairment due to schizophrenia, who have completed 26 weeks of treatment in one of the 
parent phase III clinical trial program for Iclepertin (trial # 1346-0011, 1346-0012, 1346-
0013). No hypothesis testings will be performed. Analysis relating to the primary endpoint 
will be descriptive in nature.
7.2
PLANNED ANALYSES
7.2.1
General considerations
The treated set (TS) will consist of all patients who enter this roll-over trial and receive at 
least one dose of open-label study medication. Treated set will be used in all of the analyses 
which will be descriptive in nature.
Unless otherwise specified, baseline will be defined as the last measurements (including 
measurements in the parent trial) before first drug intake in this extension trial. Additional 
details will be provided in the TSAP. For the secondary endpoint of Hb level, baseline will be 
defined as the last on-treatment value from the parent trial, i.e. the last available value 
collected at or before the end of treatment visit of the parent trial.
7.2.2
Primary endpoint analyses
All safety analyses will be performed on the treated set. 
Primary endpoint analysis will be a descriptive anlaysis of the frequency of subjects with 
TEAEs.
Further analyses of AEs will be part of the planned safety analyses in Section 7.2.5.
7.2.3
Secondary endpoint analyses
For the secondary endpoints of Hb level and CGI-S, descriptive statistics assessing the
change from baseline to EOT will be provided.

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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 AEs with an onset between 
start of treatment and end of the REP, a period of 12 days after the last dose of trial
medication, will be assigned to the on-treatment period for evaluation.
All treated patients will be included in the safety analysis. 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 adverse 
events, i.e. all AEs occurring between start of treatment and end of the REP. 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 at database 
lock.
The frequency of subjects with (S)AEs will be summarised by primary system organ class 
(SOC) and preferred term (PT). The SOCs will be sorted by default alphabetically and PTs 
will be sorted by frequency within an SOC. Separate frequency tables will be provided for 
patients with different treatment emergent AEs.
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 summarised. 
Vital signs, physical examinations, or other safety-relevant data observed at baseline, during 
the course of the trial and at the end-of-trial evaluation will be assessed with regard to 
possible changes compared to findings before start of treatment.
7.2.6
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
Interim analyses could be performed to support MAA/NDA submission and registration or 
upon request from Health Authorities. All of the above specified analyses may be presented 
at each interim analysis. No statistical adjustment due to multiple testing is required for these 

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interim analyses since no confirmatory hypothesis testings are planned for this trial. Interim 
analysis will include all available data collected up to the snapshot date. Safety will be 
monitored by an external and independent DMC.
7.3
HANDLING OF MISSING DATA
If not specified otherwise, missing data will not be imputed and will remain missing. 
Potential outliers will be reported and analysed as observed.

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Any additional details on the handling of missing data will be specified in the TSAP.
7.4
RANDOMISATION
There will be no randomization for this extension trial. All subjects entered this trial will be 
treated open-label with the Iclepertin 10mg.
7.5
DETERMINATION OF SAMPLE SIZE
Not applicable as this is an extension trial. The total number of patients included in this trial 
will correspond to the number of patients who have completed one of the three parent phase 
III trials (1346-0011 or 1346-0012 or 1346-0013) and who did not prematurely discontinue 
trial medication, and fulfilled the eligibility in this trial and are willing to participate.

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8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY, AND
ADMINISTRATIVE STRUCTURE
The trial will be carried out in accordance with the Medical Devices Directive (93/42/EEC)
and the harmonised standards for Medical Devices (ISO 14155, current version).
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-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 BI 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 Institutional Review Board (IRB / Independent Ethics Committee 
(IEC and CA according to national and international regulations. The same applies for the 
implementation of changes introduced by amendments.
Prior to their participation in the trial, written informed consent must be obtained from each,
patient (or the patient’s legally accepted representative) and the patient’s study partner
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.”

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The investigator or delegate must give a full explanation to trial patients based on the patient
information form. A language understandable to the patient should be chosen, technical terms 
and expressions avoided, if possible. 
The patient must be given sufficient time to consider participation in the trial. The 
investigator or delegate obtains written consent of the patient’s own free will with the 
informed consent form after confirming that the patient 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.
The consent and re-consenting process should be properly documented in the source 
documentation.
8.2
DATA QUALITY ASSURANCE
A risk-based approach is used for trial quality management. It is initiated by the assessment 
of critical data and processes for trial subject protection and reliability of the results as well as 
identification and assessment of associated risks. An Integrated Quality and Risk 
Management Plan documents the rationale and strategies for risk management during trial 
conduct including monitoring approaches, vendor management and other processes focusing 
on areas of greatest risk.
Continuous risk review and assessment may lead to adjustments in trial conduct, trial design 
or monitoring approaches. 
A quality assurance audit/inspection of this trial may be conducted by the sponsor, sponsor’s 
designees, or by IRB / IEC or by regulatory authorities. The quality assurance auditor will 
have access to all medical records, the investigator’s trial-related files and correspondence, 
and the informed consent documentation of this clinical trial.
8.3
RECORDS
CRFs for individual patients will be provided by the sponsor. For drug accountability, refer to 
section 4.1.7.
8.3.1
Source documents
In accordance with regulatory requirements, the investigator should prepare and maintain 
adequate and accurate source documents and trial records that include all observations and 
other data pertinent to the investigation on each trial patient. Source data as well as reported 
data should follow the “ALCOA principles” and be attributable, legible, contemporaneous, 
original and accurate. Changes to the data should be traceable (audit trail).

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Data reported on the CRF 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.
Copies of source documents necessary for neurocognitive assessments (e.g. MCCB) will be 
provided to the assigned vendor. Before sending or uploading those copies, the investigator 
must ensure that all patient identifiers (e.g. patient’s name, initials, address, phone number, 
social security number) have properly been removed or redacted from any copy of the 
patients’ source documents.
If the patient is not compliant with the protocol, any corrective action e.g. re-training must be 
documented in the patient file.
For the CRF, data must be derived from source documents, for example:

Patient identification: gender, year of birth (in accordance with local laws and 
regulations)

Patient participation in the trial (substance, trial number, patient number, date patient was 
informed)

Dates of patient’s visits, including dispensing of trial medication

Medical history (including trial indication and concomitant diseases, if applicable)

Medication history

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 CRF and all source 
documents/data, including progress notes, copies of laboratory and medical test results, which 
must be available at all times for review by the CRA, auditor and regulatory inspector (e.g.

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FDA). They may review all CRFs and informed consents. The accuracy of the data will be 
verified by direct comparison with the source documents described in section 8.3.1. The 
sponsor will also monitor compliance with the protocol and GCP.
8.3.3
Storage period of records
Trial site(s):
The trial site(s) must retain the source and essential documents (including ISF) according to 
contract or the local requirements valid at the time of the end of the trial (whatever is longer).
Sponsor:
The sponsor must retain the essential documents according to the sponsor’s SOPs.
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS
BI is responsible to fulfil their legal and regulatory reporting obligation in accordance with
regulatory requirements. 
8.5
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY
Data protection and data security measures are implemented for the collection, storage and 
processing of patient data in accordance with the principles 7 and 12 of the WHO GCP 
handbook.
Individual patient data obtained as a result of this trial is considered confidential and 
disclosure to third parties is prohibited with the following exceptions:
Personalised treatment data may be given to the patient’s personal physician or to other 
appropriate medical personnel responsible for the patient’s welfare. Data generated at the site
as a result of the trial need to be available for inspection on request by the participating 
physicians, the sponsor’s representatives, by the IRB / IEC and the regulatory authorities.
8.5.1
Collection, storage and future use of biological samples and corresponding data 
Measures are in place to comply with the applicable rules for the collection, biobanking and 
future use of biological samples and clinical data, in particular

Sample and data usage has to be in accordance with the separate biobanking informed 
consent

The BI-internal facilities storing biological samples from clinical trial participants as 
well as the external banking facility are qualified for the storage of biological samples 
collected in clinical trials

An appropriate sample and data management system, incl. audit trail for clinical data 
and samples to identify and destroy such samples according to ICF is in place

A fit for the purpose documentation (biomarker proposal, analysis plan and report) 
ensures compliant usage

A fit for purpose approach will be used for assay/equipment validation depending on 
the intended use of the biomarker data

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
Samples and/or data may be transferred to third parties and other countries as 
specified in the biobanking ICF
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 “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 Suspected Unexpected Serious Adverse Reactions 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.
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 (to the parent trial treatment assignments) 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 

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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 PIs (e.g. their curricula vitae) will be filed in the
ISF.
The investigators will have access to the BI web portal Clinergize to access documents 
provided by the sponsor.
BI has appointed a Clinical Trial Leader, 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 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 and an IRT 
vendor will be used in this trial. Details will be provided in the respective manuals, available 
in the ISF.

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9.
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9.2
UNPUBLISHED REFERENCES
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Trial 1346.1. BI 425809. 05 May 2015
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. Clinical Trial Report of 
Trial 1346.2. BI 425809. 04 July 2016
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1346.3. BI 425809. 01 February 2016
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BI 425809. 17 March 2016
c31477880
 Clinical Trial Report of 
Trial 1346.9. BI425809. 01 September 2020
U13-2547
 Nonclinical Report: Increase of glycine in rat CSF by BI 
425809. BI425809-
-1310-E. Version 01. 22 November 
2013.

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10.
APPENDICES
10.1
TIME SCHEDULE FOR PHARMACOKINETIC (PK) BLOOD SAMPLING
Table 10.1: 1 Time schedule for PK blood sampling during treatment course 1
Visit
Day
Time Point [hh:min]
CRF Time/ PTM
Event
Sample No
4
84
Preferably within 30 min 
before drug 
administration
~0:30
Pre-dose PK 
Blood
1
7
182
2
11
266
3
EOT
365
~1 day after last dose
~24:00*
Post-dose 
PK
4
(e) EOT
-
~as applicable after last 
dose
~24:00*
-
*PK sample should be collected within the visit window. Precise collection timepoint must be 
captured in the eCRF.

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10.2
DEFINITION OF STUDY PARTNER AND CAREGIVER
Who can be a study partner?
Who can be a Caregiver?
Study partner is any person who knows 
the patient well, has been capable of 
interacting with the patient on regular 
basis, preferably consistent throughout 
the study, either private or professional
Caregiver is a study partner who is taking 
informal (unpaid) care of the patient, 
which can be direct or indirect, including 
e.g. organizing or checking things for the 
patient, making phone calls, managing 
bills, 
arranging 
things 
and 
doing 
paperwork related to the patient, do 
shopping, cooking, cleaning, laundry, 
etc.
Every patient enrolled in the study must 
have a study partner
Patients do not need to have a caregiver 
but 
must 
have 
a 
study 
partner.  
Therefore, having a caregiver is optional.
Must sign study partner IC
Will be asked to complete additional 
questionnaires 
for 
caregiver asses
tudy 
partner IC 
The study partner must interact with the 
patient on a regular basis at least once a 
week. 
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.

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10.3
POTENTIAL MODIFICATION OF THE TRIAL CONDUCT IN CASE OF 
RESTRICTIONS DUE TO COVID-19 OR OTHER EXCEPTIONAL 
CIRCUMSTANCES
No patient should be entered in the study unless all Visit 1 procedures are completed in the 
clinic as per the standard CTP.
In case of any restrictions during the COVID-19 pandemic or any other exceptional 
cirmcumstances (e.g. emergency, natural disaster, patient specific situations etc.) study 
conduct may need to be adjusted based on the investigator’s discretion (and agreed with the 
sponsor).
Local regulatory and legal requirements of the participating country needs to be respected for 
all modifications. Patients need to be informed about the modifications and agree to them 
before implementation.
If on-site / clinic visits are not possible because the site/institution is limiting or restricting 
on-site visits due to COVID-19 (or any other exceptional circumstances), some of  the visit 
procedures (including study partner contacts and assessments)  may be done as a home visit 
or telephone / video conference or locally (e.g. at a local lab, diagnostic centre, etc).
All COVID-19/ exceptional circumstances related deviations from the original schedule of 
visits and procedures will be documented, and the implications will be considered for the 
analysis of trial data.
The following contingency measures have been 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).
In exceptional circumstances, due to administrative delays to site becoming regulatory ready 
for the first patient visit, the enrolment may be approved by the sponsor after discussion.
The following study data should be collected/ reported during home and/or remote visit: 
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

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Birth control check (for women of childbearing potential) during phone/ remote visit
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 flowchart or is required based on local regulations or investigators discretion. 
Safety assessments
If home visits are possible, some assessments can be done at the patient’s home (e.g. 
collection of blood and urine samples to be sent to the central lab, vital signs). 
If blood sampling or analysis by the central lab is not possible, safety lab analyses can be 
performed at a local laboratory. The results of the lab tests must be reported to the 
investigator who ensures medical review and proper documentation.  
At a minimum the hematology panels should be done.  Other safety laboratory tests may 
be performed at the Investigator’s discretion. 
For the rare situations in which the safety laboratory test cannot be done, the investigator’s 
reasoning and decision-making process must be documented in source notes at the site.
ECG:
The ECG assessment can be done locally. The ECG report must be transferred to the 
investigator who ensures medical review and proper documentation in the eCRF. 
In rare situations in which the ECG(s) cannot be done, (even locally) and 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 kit to their site staff, if 
needed and 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.  
Direct-to-patient shipment of trial medication
If a patient is not able to come to a visit as planned but the investigator considers it favorable 
and safe for the patient to continue on trial medication, the trial medication can be shipped 
from site directly to the patient (if acceptable according to local laws and regulations). Such 
shipments require the use of a sponsor approved courier to the patient’s home. 
When scheduling visits every effort should be made to ensure a continuous supply of trial 
medication for the patient, whilst also taking into account that the next kit(s) of trial 
medication may need to be shipped from the site to the patient’s home  and, that medical pre-
requisites should be performed and confirmed prior to shipment of new supplies.

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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
This is the original protocol.
11.1
GLOBAL AMENDMENT 1
Date of amendment
09 Mar 2023
EudraCT number
EU number
2020-003745-11
BI Trial number
1346-0014
BI Investigational Medicinal 
Product(s)
Iclepertin
Title of protocol
An open label, single arm, extension trial to 
examine long-term safety of Iclepertin once daily 
in patients with schizophrenia who have 
completed previous Iclepertin Phase III 
trials.(CONNEX-X)
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
Protocol synopsis
Description of change
Number of countries change from 32 to 42
Rationale for change
Addition of countries in the parent trials
Section to be changed
Protocol synopsis
Description of change
Main in and exclusion criteria  added Follow up 1 
visit window  for subjects entering the study from 
studies 1346-0011 and 1346-0013. Added for 
subjects entering the study from study 1346-0012 
within 7 days of Follow Up 6
Rationale for change
To clarify, that subjects have the visit window of 
the last visit from parent trial to  enter the study.
Section to be changed
Flow chart 
Description of change
Added a separate line item for informed consent  
for biobanking, and footnote #14 to clarify 
biobanking can be collected anytime before Visit 
7.
Rationale for change
Clarification  of the required timepoint in which it 
should be performed
Section to be changed
Flow chart
Description of change
Addition of 
 at EOT, addition of CGI-S at 
visit 6, removing CGI-S from visit 4, 7 and 11
I 
I 

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Rationale for change
To align the assessment of CGI-S with the timing 
of the SCoRS
Section to be changed
Flow chart
Description of change
Days of first treatment changed to treatment days
Rationale for change
To clarify day 1 is the first day of treatment
Section to be changed
Flow chart footnotes
Description of change
Footnote 13 was corrected to 12
Rationale for change
correction
Section to be changed
Flow chart, flowchart footnotes and section 5.6 
Other Assessments
Description of change
Added Exit interviews  and Informed consent for 
exit interview. Addition of footnote #13
Rationale for change
Implementation of optional patient and study 
partner interviews to collect feedback on their 
study experience.
Section to be changed
Abbreviations
Description of change
Addition of Abbreviations; HIV and 
Rationale for change
Correction
Section to be changed
Table 1.4.2:1 and section 5.2.6.2.4
Description of change
Change from Vision AEs nomenclature to Ocular 
AEs and change the requirement for 
ophthalmologic assessments must to be performed 
in case of moderate to severe intensity vision
Rationale for change
Request from FDA to have all ocular AEs 
assessed by an ophthalmologist.
Section to be changed
Table 1.4.2:1  and section 3.3.5
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
1.4.3
Description of change
Addition of reference R20-0592 listed in section 
9.1
Rationale for change
Correction of administrative error
Section to be changed
Description of change
Rationale for change to be 
changed

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Section to be changed
Description of change
Rationale for change to be 
changed
Section to be changed
Inclusion criteria
Description of change
Inclusion criteria #3, added Follow up1 visit 
window  for subjects entering the study from 
studies 1346-0011 and 1346-0013. Added for 
subjects entering the study from study 1346-0012 
within 7 days of Follow Up 6
Rationale for change
To clarify, that subjects have the visit window of 
the last visit from parent trial to  enter the study.
Section to be changed
Section 3.3.3
Description of change
Exclusion # 1, added phase III trial numbers
Rationale for change
Clarification
Section to be changed
Section 3.3.3
Description of change
Exclusion Criteria #12 updated
Rationale for change
Clarification that list of ingredients can be found 
in the Investigator’s Brochure
Section to be changed
Section 3.3.5
Description of change
Addition of new reason for withdrawing (patient 
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 3.3.3.5.2
Description of change
Bullet correction in reasons for trial 
discontinuation by sponsor
Rationale for change
Clarification, correction of formatting error.
Section to be changed
Section 4.2.2.1
Description of change
Clarify that short term use of opioids for pain, 
cough or diarrhea
Rationale for change
Clarification
Section to be changed
Section 4.2.2.1
Description of change
Addition of vaccination for COVID-19 in the 
permitted therapies
Rationale for change
Patients are permitted to receive a COVID-19 
vaccination during the trial and in accordance with 
local public health recommendations.
Section to be changed
Section 4.3
Description of change
Clarification on calculation of compliance based 
on empty table counts (number of tablets removed 
from package).

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Rationale for change
Clarification
Section to be changed
Description of change
Rationale for change
Correction 
Section to be changed
Description of change
Rationale for change to be 
changed
Correction
Section to be changed
Description of change
Rationale for change to be 
changed
Clarification, they were previously described in 
section 2.2.2
Section to be changed
Section 5.2
Description of change
Correction on CGI-S rating 1-4 
Rationale for change to be 
changed
Correction
Section to be changed
Description of change
Rationale for change to be 
changed
Section to be changed
Section 5.6
Description of change
Rationale for change
Clarification 
Section to be changed
Section 5.6 
Description of change
Addition of exit interview details
Rationale for change
To collect subject and study partner overall 
experience of treatment and participation in the 
clinical study including meaningfulness and 
importance of experienced changes.
Section to be changed
Section 6.2.1
Description of change
Addition of scales that require rater vendor  
certification
Rationale for change
Clarification
Section to be changed
Section 6.2.1
Description of change
Rationale for change
Clarification
Section to be changed
Section 6.2.1
Description of change
Clarification of preferences if visits are split into 
sequential days 
Rationale for change
Clarification
Section to be changed
Section 6.2.1 

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Description of change
Clarification study partner must be available 
within study window
Rationale for change
Clarification
Section to be changed
Section 6.2.2
Description of change
Medical history removed the word pooled
Rationale for change
Clarification 
Section to be changed
Section 6.2.2
Description of change
Added reference to appendix 10.3 for guidance on 
exceptional circumstances.
Rationale for change
Ensure sites are aware of potential adaptations in 
case of exceptional circumstances
Section to be changed
Sections 6.2.2 and 8.1
Description of change
Updated paragraph regarding patient and study 
partner informed consents
Rationale for change
Clarification that patient can start  trial procedures
if the study partner informed consent is not yet 
signed.
Section to be changed
Sections 6.2.2
Description of change
Clarification of timing when the subject receives 
information on the  adherence monitoring system
Rationale for change
Clarification
Section to be changed
Sections 6.2.3
Description of change
Addition of exit interviews description and it’s 
consent 
Rationale for change
To describe the timing  of the optional exit 
interviews and it’s consent 
Section to be changed
Sections 6.2.4
Description of change
Definition of the planned observation period
Rationale for change
To clarify the plan observation period 
comprehends the 52 weeks of treatment
Section to be changed
Section 7.2.1
Description of change
Added the following definition : For the 
secondary endpoint of Hb level, baseline will be 
defined as the last on-treatment value from the 
parent trial, i.e. the last available value collected at 
or before the end of treatment visit of the parent 
trial
Rationale for change
Clarification
Section to be changed
Section 9.1
Description of change
Addition of missiong reference R03-0520
Rationale for change
Correction 
Section to be changed
Section 10.1
Description of change
Correction on visit 7 day deleted 187 and entered 
182
Rationale for change
correction
Section to be changed
Section 10.2

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Description of change
Study partner interaction with patient change 
from minimum listed to “on a regular basis at least 
once a week”
Rationale for change
To align with inclusion criteria #5
Section to be changed
Section 10.2
Description of change
Revise wording to indicate that the caregiver will 
be asked to complete the additional questionnaires
Rationale for change
Clarification that caregiver will be asked to 
complete additional questionnaires (but not 
mandatory)
Section to be changed
Section 10.3
Description of change
Addition of exceptional circumstances in addition 
to COVID-19
Rationale for change
Ensure to include emergency, natural disaster, 
patient specific situations
Section to be changed
Section 10.3
Description of change
Clarification that study partner contacts and 
assessments can be also impacted
Rationale for change
Clarification
Section to be changed
Section 10.3
Description of change
Addition; In exceptional circumstances, due to 
administrative delays to site becoming regulatory 
ready for the first patient visit, the enrolment may 
be approved by the sponsor.
Rationale for change
To allow case by case consideration of enrollment 
delay in exceptional circumstances  
Section to be changed
Section 10.3
Description of change
Include analysis by the Central Lab in addition to 
blood sampling, removed erroneous reference to 
CRF
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
Rationale for change
Clarification that those assessments cannot be 
performed remotely.
11.2
GLOBAL AMENDMENT 2
Date of amendment
18 Sep 2023
EudraCT number
EU number
2020-003745-11

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BI Trial number
1346-0014
BI Investigational Medicinal 
Product(s)
Iclepertin
Title of protocol
An open label, single arm, extension trial to 
examine long-term safety of Iclepertin once 
daily in patients with schizophrenia who have 
completed previous Iclepertin Phase III 
trials.(CONNEX-X)
Global Amendment due to urgent safety reasons
Global Amendment
X
Section to be changed
Flowchart 
Description of change
Substance use added to the flowchart for eEOT
Rationale for change
To align with the CRF
Section to be changed
Flowchart footnote
Description of change
Added “including split visit” to footnote 
number 1. 
1 If the procedure is performed at the last study 
visit for the parent trial, the procedure does not 
need to be repeated if visit 1 for trial 1346-
0014 occurs on the same day, including split 
visit.
Rationale for change
Clarification
Rationale for change
DMC recommendation
Section to be changed
Table 1.4.2:1 Overview over trial related risks
Description of change
Sucidiality section updated to clarify in case of 
a positive report of suicidal behavior and/or
suicidal ideation, additional follow-up may be 
completed as per Investigator discretion. 
Rationale for change
DMC Recommendation
Section to be changed
Inclusion Criteria
Description of change
Footnote added to inclusion criteria #3: 
Patients who had a temporary treatment 
discontinuation during the parent trial, but who 
restarted treatment and  completed the planned 
EOT on study drug can be considered per 
investigator judgement
Rationale for the change
Clarification
Section to be changed
Exclusion Criteria
Description of change
Removed  the following wording to exclusion 
criteria #4; the treatment period of trial 1346-
0011, 1346-0012 or 1346-0013.
Rationale for change
Clarification as all positive results for urine 
drug screening are being considered, including 
follow up visits.
I 
I 

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Section to be changed
5.2
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
Appendix 10.1
Description of change
Added “preferably” within 30 minutes before 
dose to on treatment PK sampling timepoints, 
added “approximately” to other PK sampling 
timepoints.
Added reminder that actual times are collected 
in the eCRF.
Rationale for change
Clarification

 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c33088336
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clinical-trial-protocol-version-03
An open label, single arm, extension trial to examine long-term safety of Iclepertin
once daily in patients with schizophrenia who have completed previous Iclepertin
Phase III trials. (CONNEX-X)
Author-Clinical Trial Leader
19 Sep 2023 17:07 CEST
Author-Trial Clinical
Pharmacokineticist
19 Sep 2023 17:19 CEST
Author-Trial Statistician
19 Sep 2023 17:29 CEST
Approval-Head Medicine
20 Sep 2023 00:13 CEST
Approval-Clinical Program Leaders
20 Sep 2023 14:12 CEST
Verification-Paper Signature
Completion
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Meaning of Signature  
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Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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