Clinical trial NCT03859973
Conditions: Schizophrenia
Sponsor: Boehringer Ingelheim
Start date: 2019-04-15; Completion date: 2022-11-04
Enrollment: 200 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a study in adults with schizophrenia. The study tests whether a medicine called BI 425809 together with brain training improves mental abilities.

Participants take study medication once a day for 12 weeks. At the start of the study, the participants are put into 2 groups. It is decided by chance who gets into which group. One group gets BI 425809 tablets every day. The other group gets placebo tablets every day. Placebo tablets look like the BI 425809 tablets, but contain no medicine. During the study, all participants do brain training using a computer.

The doctors regularly test mental abilities of the participants. The results of the mental ability tests are compared between the groups. The doctors also check the general health of the patients.

Detailed description:

Arms: arm 1: None arm 2: None
Interventions: intervention 1: BI 425809 intervention 2: Placebo
Intervention descriptions: intervention 1: Tablet intervention 2: Tablet

Protocol documents:
Prot_000.pdf: 


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CLINICAL TRIAL PROTOCOL SYNOPSIS
Company name
Boehringer Ingelheim
Protocol date
21 Dec 2018
Revision date
21 Jul 2020
BI trial number
1346-0038
Title of trial
A phase II randomized, double-blinded, placebo-controlled parallel 
group trial to examine the efficacy and safety of BI 425809 once daily 
with adjunctive Computerized Cognitive Training over 12 week 
treatment period in patients with schizophrenia
Coordinating 
Investigator:
Trial site(s):
Multi-centre trial
Clinical phase:
II
Trial rationale
This proof of concept (PoC) study will assess whether a drug aimed at 
improving cognition is better than placebo in patients with 
schizophrenia on a background of cognitive enrichment with 
adjunctive Computerized Cognitive Training (CCT).
Trial objective(s)
The primary objective of this trial is to provide PoC data to assess the 
effect on cognition of oral once daily administration of BI 425809 
given for 12 weeks in patients with schizophrenia on stable 
antipsychotic treatment and adjunctive Computerized Cognitive 
Training (CCT).
Other objectives of this trial are to explore endpoints to assess 
functioning and well-being of patients with schizophrenia, and to 
evaluate safety and pharmacokinetics of BI 425809.
Trial endpoints
The primary efficacy endpoint is change from baseline in 
neurocognitive function as measured by the neurocognitive composite 
score of the MCCB after 12 weeks of treatment.
The secondary endpoints of efficacy and safety are as follows:
∀
Change from baseline in cognitive function as measured by 
the overall MCCB composite score (including social 


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cognition) after 12 weeks of treatment
∀
Change from baseline in the effect of cognitive deficit on day-
to-day functioning as measured by SCoRS total score after 12 
weeks of treatment
∀
Change from baseline in PANSS total score after 12 weeks of
treatment
∀
Percentage of patients with (S)AEs (including clinically 
relevant abnormalities of physical examination, vital signs, 
ECG test and laboratory tests)
Trial design
This is a 12-week, multi-center, multi-national, randomized, double-
blind, placebo controlled parallel group trial in patients with 
schizophrenia on stable antipsychotic treatment
Number of patients
randomized
200 patients
Number of patients on 
each treatment
100 patients in active drug treatment arm; 100 patients in placebo 
drug arm
Diagnosis
Patients with established Schizophrenia (as per Diagnostic and 
Statistical Manual of Mental Disorders, 5th Edition (DSM-5)) who 
are clinically stable
Main in- and exclusion 
criteria
Main inclusion criteria are as follows:
1. Male or female patients who are 18-50 years (inclusive) of age at 
time of consent
2. Established schizophrenia DSM-5 with the following clinical 
features:
o
Outpatient, with no hospitalization for worsening of 
schizophrenia within 3 months prior to randomization 
o
Psychiatrically stable without symptom exacerbation 
within 3 months prior to randomization
o
PANSS score ≤ 5 on positive items P1, P3-P7 and ≤ 4 on 
positive item P2 at Visit 1, and confirmed at Visit 2
3. Patients must be on stable antipsychotic treatment; also, current 
antipsychotic medications and concomitant anticholinergics, 
antiepileptics, lithium and allowed antidepressants must meet the 
criteria below:
o
Patients must take 1 and may take up to 2 antipsychotics 
(typical and/or atypical), except for clozapine (see Section 
3.3.3)
o
Patients must be stable on current antipsychotics,
anticholinergics, antiepileptics, lithium and allowed
antidepressants for at least 3 months prior to 
randomization and be on current dose for at least 30 days 


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prior to randomization

Patients on long-acting injectable (LAI) 
antipsychotics should be on the same medication 
and dose for at least 3 months prior to 
randomization
4. Patients must demonstrate their ability to properly use the CCT 
device and program, as well as be compliant with CCT run-in
5. Patients must have a study partner who will preferably be 
consistent throughout the study
Main exclusion criteria are as follows:
1. Patients who have a categorical diagnosis of another current major 
psychiatric disorder on the M.I.N.I.
2. Patients with a history of participating in any formal cognitive 
remediation program for 10 or more training sessions
3. Patients who were treated with any of the following medications 
within the last 6 months prior to randomization:
o
Bitopertin, BI 409306, encenicline or other investigational 
drug testing effects on cognition in schizophrenia
o
Clozapine (atypical antipsychotic medication)
o
Sarcosine, cycloserine, serine and glycine
o
Stimulants (e.g. methylphenidate, dextroamphetamine, 
modafinil)
o
Tricyclic antidepressants
4. Patients who have participated in a clinical trial with repeated 
assessments (i.e. a single assessment is not exclusionary) with the 
MCCB within the last 6 months prior to randomization
5. Significant history of drug abuse disorder within the last 6 months 
prior to informed consent, or a positive urine drug screen at Visit 
1
6. Women who are pregnant, nursing, or who plan to become 
pregnant while in the trial
Test product(s)
BI 425809
dose
10 mg q.d.
method and route of 
administration
Tablet, Oral
Comparator product(s)
Matching placebo
dose
Not applicable


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method and route of 
administration
Tablet, Oral
Duration of treatment
12 weeks
Statistical methods
Restricted Maximum Likelihood (REML)-based Mixed-effect Model 
Repeated Measures (MMRM) analysis will be used as the primary 
analysis for the primary efficacy endpoint of change from baseline in
the MCCB neurocognitive composite score after 12 weeks of 
treatment. This model will include fixed effects of treatment, age
stratification factor, visit, as well as the continuous fixed covariates of 
baseline MCCB neurocognitive composite score, change from 
screening to baseline MCCB neurocognitive composite score, 
baseline-by-visit interaction and treatment-by-visit interaction. Patient 
will be treated as random effect. The unstructured variance-
covariance structure will be used to model the within-patient errors. 
For the secondary efficacy endpoint of change from baseline in the 
overall MCCB composite score or PANSS total score after 12 weeks 
of treatment, an MMRM model same as or similar to that used for the 
primary endpoint will be fitted. For change from baseline in SCoRS 
score after 12 weeks of treatment, an ANCOVA model will be fitted. 
Descriptive statistics and exploratory analyses will be provided for 
safety data and other efficacy endpoints.








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TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS .....................................................................2
FLOW CHART........................................................................................................................6
TABLE OF CONTENTS ........................................................................................................9
ABBREVIATIONS................................................................................................................12
1.
INTRODUCTION...............................................................................................14
1.1
MEDICAL BACKGROUND.............................................................................14
1.2
DRUG PROFILE................................................................................................15
1.3
RATIONALE FOR PERFORMING THE TRIAL.........................................17
1.4
BENEFIT - RISK ASSESSMENT.....................................................................18
2.
TRIAL OBJECTIVES AND ENDPOINTS......................................................22
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS........22
2.1.1
Main objectives....................................................................................................22
2.1.2
Primary endpoint(s)............................................................................................22
2.1.3
Secondary endpoint(s) ........................................................................................22
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.........................24
3.1
OVERALL TRIAL DESIGN AND PLAN .......................................................24
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)......................................................................................25
3.3
SELECTION OF TRIAL POPULATION .......................................................25
3.3.1
Main diagnosis for trial entry ............................................................................26
3.3.2
Inclusion criteria .................................................................................................26
3.3.3
Exclusion criteria ................................................................................................27
3.3.4
Withdrawal of patients from therapy or assessments .....................................30
3.3.4.1
Withdrawal from trial treatment ...........................................................................30
3.3.4.2
Withdrawal of consent for trial participation........................................................31
3.3.4.3
Discontinuation of the trial by the sponsor...........................................................31
4.
TREATMENTS...................................................................................................33
4.1
INVESTIGATIONAL TREATMENTS ...........................................................33
4.1.1
Identity of BI investigational product(s) and comparator product(s) ...........33
4.1.2
Selection of doses in the trial and dose modifications......................................34
4.1.3
Method of assigning patients to treatment groups...........................................34
4.1.4
Drug assignment and administration of doses for each patient......................34
4.1.5
Blinding and procedures for unblinding...........................................................35
4.1.5.1
Blinding.................................................................................................................35
4.1.5.2
Unblinding and breaking the code ........................................................................35






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ABBREVIATIONS
AE
Adverse Event
AESI
Adverse Event of Special Interest
ALT
Alanine Aminotransferase
ANCOVA
Analysis of Covariance
AST
Aspartate Transaminase
AUC
Area under the Curve
AUC0-tz
Area under the concentration-time curve of the analyte in plasma over the
time interval from 0 to the last quantifiable data point
BI
Boehringer Ingelheim
CCT
Computerized Cognitive Training
CI
Confidence Interval
CIAS
Cognitive Impairment Associated with Schizophrenia
Cmax
Maximum measured concentration of the analyte in plasma
CNS
Central Nervous System
COVID-19
Coronavirus Disease 2019
CRA
Clinical Research Associate
CRO
Contract Research Organization
CSF
Cerebrospinal Fluid
C-SSRS
Columbia Suicidal Severity Rating Scale
CTL
Clinical Trial Leader
CTM
Clinical Trial Manager
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
DDI
Drug-Drug Interaction
DILI
Drug Induced Liver Injury
DSM-5
Diagnostic and Statistical Manual of Mental Disorders, 5th Edition
ECG
Electrocardiogram
eCRF
Case Report Form, electronic
eDC
Electronic Data Capture
eEoT
Early End of Treatment
EoT
End of Treatment
FAS
Full Analysis Set
GLYT1
Glycine Transporter 1
Hb
Hemoglobin
IB
Investigator’s Brochure
IEC
Independent Ethics Committee
ICH-GCP
ICH Harmonized Tripartite Guideline for Good Clinical Practice
ICH M3 (R2)
Non-Clinical Safety Studies for the Conduct of Human Clinical Trials and 
Marketing Authorization for Pharmaceuticals
IPDs
Important Protocol Deviations
IRB
Institutional Review Board
IRT
Interactive Response Technology
ISF
Investigator Site File


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LAI
Long-Acting Injectable
LPLT
Last Patient Last Treatment
MATRICS
Measurement and Treatment Research to Improve Cognition in 
Schizophrenia
MCCB
MATRICS Consensus Cognitive Battery
MedDRA
Medical Dictionary for Drug Regulatory Activities
MMRM
Mixed-effect Model Repeated Measures
M.I.N.I.
Mini-International Neuropsychiatric Interview
NOAEL
No-observed-adverse-effect level
PANSS
Positive and Negative Syndrome Scale
PK
Pharmacokinetics
PPS
Per-Protocol Set
PoC
Proof of Concept
q.d.
quaque die (once a day)
REML
Restricted Maximum Likelihood
REP
Residual Effect Period
RS
Randomized Set
SAE
Serious Adverse Event
SARS-CoV-2
Severe acute respiratory syndrome coronavirus 2
SCoRS
Schizophrenia Cognition Rating Scale
SmPC
Summary of Product Characteristics
SOPs
Standard Operating Procedures
SUSAR
Suspected Unexpected Serious Adverse Reactions
TS
Treated Set
TSAP
Trial Statistical Analysis Plan
WOCBP
Woman of childbearing potential


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1.
INTRODUCTION
1.1
MEDICAL BACKGROUND
Schizophrenia is a serious mental illness that is chronic and disabling. It has a lifetime 
prevalence of approximately 1%, with almost equal distribution worldwide and comparable 
incidence between men and women.
Schizophrenia is a heterogeneous syndrome and symptoms are clustered into positive, 
negative and cognitive impairments.
Cognitive impairments are a core feature of schizophrenia and have been shown to be a major 
determinant of poor functional outcome. While many neuropsychiatric disorders are 
associated with some degree of cognitive dysfunction, the impairments seen in schizophrenia 
tend to be more severe and more independent of symptomatic state (R10-5111). Meta-
analyses of schizophrenia studies with neurocognitive assessments reported an overall mean 
decrement of at least one standard deviation in cognitive performance compared to 
community controls (R15-3853; R15-3854) and is comparable or greater than the effect sizes 
reported for moderate to severe traumatic brain injury (R15-3852).
Existing treatment options for schizophrenia (i.e. antipsychotics) are primarily efficacious in 
treating positive symptoms, however demonstrated only mild beneficial effects on cognition 
in schizophrenia (R15-5596; R15-5580). Antipsychotics also adversely affect some aspects of 
cognitive function, such as processing speed (R15-5595). So far, no drug has been approved 
for the treatment of Cognitive Impairment Associated with Schizophrenia (CIAS).
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 CIAS.
It has been long hypothesized that deficits in glutamatergic signaling may underlie
schizophrenia, including 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. Targets have 
included NMDA receptor co-factor glycine site, including agonists D-glycine, D-serine, and 
partial agonist D-cycloserine, as well as glycine transporter inhibitors, such as sarcosine and 
bitopertin, however previous studies have 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). Also, 
pharmaceutical industry-sponsored studies with bitopertin (a glycine reuptake inhibitor) 
failed to separate from placebo in the pivotal program to treat negative symptoms of 
schizophrenia (R14-4313; R15-1273) despite a positive signal in Phase II (R15-1266).
BI 425809 works via the same mechanism as bitopertin, therefore hypotheses on bitopertin 
failures have been carefully evaluated in this project. Measures have been taken to address 


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the perceived failures including a different patient group and better control over the 
conduct of cognitive test batteries. One of the hypothesized reasons for bitopertin failure
was lack of environmental cognitive stimulation, which is beneficial to learning as brain 
plasticity is activity-dependent and responds to environmental demands. However, 
cognitive stimulation is often absent in the lives of patients with schizophrenia (R18-1592).
The current trial will test this hypothesis by providing standardized background cognitive 
stimulation via adjunctive Computerized Cognitive Training (CCT).
Therapeutic approaches towards CIAS frequently include various forms of psychotherapy 
and, increasingly, some form of cognitive remediation or cognitive training for which many 
approaches exist, both computerized and non-computerized (R16-2165; R16-2208). 
However, while some meta-analyses suggest that cognitive remediation may be able to 
improve cognitive abilities with a moderate but stable improvement compared to the control 
groups (average effect size 0.45), the studies included in this analyses are highly diverse and 
do not allow a clear conclusion as to what extent of treatment effect was achieved by which 
component of therapy (R16-2166). This is particularly true for cognitive training delivered 
via a computer at home, without an intervention of a therapist. Nevertheless, it is 
hypothesized that cognitive training may lead to a stimulation of the brain, which could result 
in a change in neuroplasticity.
As stated previously, no pharmacological treatment of CIAS exists to date. There has been a 
long-standing debate as to whether a pharmacological treatment may exert its full efficacy 
only when given to a patient who has a low degree of stimulation while receiving 
pharmacological treatment. Cognitive training may provide such stimulation as summarized 
above. In order to reduce bias by cognitive training provided by individuals and to allow for a 
certain level of standardization in the study, computerized cognitive training will be used in 
this study. Provided as training in home settings will make it more easily disseminated to 
special populations that otherwise may have difficulty accessing traditional cognitive training 
programs (R18-1594). At-home adjunctive CCT will be used in this study to provide 
background cognitive stimulation to patients treated with BI 425809.
1.2
DRUG PROFILE
BI 425809 is a potent and selective inhibitor of the Glycine Transporter 1 (GLYT1) and, as 
such, increases the concentration of the NMDA receptor co-activator glycine in the
synaptic cleft. In vivo proof-of-mechanism (i.e. indirect target engagement in the brain) was
demonstrated by a dose-dependent increase of glycine in Cerebrospinal Fluid (CSF), both in 
rats (U13-2547) and humans (c03724403-01).
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 BI 425809 have demonstrated pro-cognitive properties in relevant animal
models of learning and memory. It is therefore expected that treatment with BI 425809 has
the potential to improve CIAS.
A comprehensive package of safety pharmacology, genetic toxicology, fertility and early
embryonic development, embryo-foetal development, and repeat-dose toxicology studies has


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been conducted with BI 425809. The studies support clinical trials of chronic long-term
administration in adults, including women of childbearing potential (WOCBP).
Major human metabolites of BI 425809, M530 (BI 758790) and M232 (BI 761036), do not 
show relevant activity on GLYT1 and Glycine Transporter 2, nor against other off-targets 
tested. M530 and M232 have been evaluated in non-clinical studies with no evidence of 
pharmacological activity, genotoxicity, effects on embryo-foetal development, or adverse 
effects in repeat-dose toxicity.


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For a more detailed description of the BI 425809 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
Intact cognition is essential for everyday living. Cognitive impairment is a core feature of 
schizophrenia (R14-3766). In fact, CIAS has been shown to be a major determinant of poor 
functional outcome (R15-0570, R15-0567). Thus treatment of CIAS is a high unmet medical 
need.
Neuroplasticity, which refers to the brain’s ability to acquire and store new information, is 
activity dependent and responds to environmental demands. Environmental cognitive 
stimulation conducive to learning is often absent in the lives of patients with schizophrenia
(R18-1592). It was hypothesized that efficacy of compounds targeting cognition in patients 
with schizophrenia may be augmented by providing environmental cognitive stimulation
(P17-11122). Cognitive training employing exercises engaging specific cognitive domains is 
an optimal tool to provide environmental cognitive stimulation, with more standardized
delivery than various in-person psychosocial training. Moreover, cognitive training can be 
administered outside of the clinic/hospital in a computerized form known as CCT. This 
training can also be monitored remotely by clinicians to ensure adherence to the training.
As a strategy to enhance neuroplasticity and thereby optimize performance of compromised 
cognitive function in patients with schizophrenia, this study will employ CCT as an 
enrichment strategy adjunctive to the 12-week treatment with BI 425809. The study is 
designed to show superiority of BI 425809 over placebo in patients on a background of CCT.


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1.4
BENEFIT - RISK ASSESSMENT
This is a Phase II Proof of Concept (PoC) study. In this study, efficacy and safety of the 
potential pro-cognitive medication BI 425809 on a background of cognitive stimulation will 
be tested in patients with CIAS. 
Background cognitive stimulation will be provided using CCT outside of the clinic/hospital. 
A meta-analysis showed that cognitive remediation therapy, including computerized 
interventions in combination with other treatment modalities, such as psychotherapy and 
pharmacological treatment, may have a positive impact on cognition in patients with 
schizophrenia (R16-2166); however, the benefit of CCT alone without involvement of a 
psychotherapist is uncertain. The CCT program will encourage patients to regularly engage in 
exercises that will increase background cognitive stimulation. It is hypothesized that the
beneficial impact on cognition in patients on active treatment with BI 425809 will be further 
enhanced as a result of the increased cognitive activity achieved through CCT.
As in other clinical trials, participation in this study may be associated with potential risks 
derived from administration of an investigational drug and/or from trial-related procedures.
BI 425908 has been tested in 12 Phase I studies assessing safety, tolerability, 
pharmacokinetics (PK) and DDIs in healthy volunteers (male and female) and in two Phase II 
studies in patients. Study 1346-0009 tested 12-week treatment with BI 425809 in patients 
with schizophrenia and study 1346-0023 in patients with Alzheimer’s disease. The potential 
risks and measures to minimize these risks that may potentially arise from administration of 
the study drug and/or from trial-related procedures (e.g. in-/exclusion criteria, restrictions, 
restricted medications, safety monitoring) are described below.
Drug-related risks and safety measures
The overall safety profile of BI 425809 is outlined in the current IB (c02155957).
Based on non-clinical toxicology data, Phase I trials in healthy volunteers and Phase II 
studies in patients with schizophrenia and Alzheimer’s disease, BI 425809 is assessed to be 
generally safe and well-tolerated. The most common AEs reported more frequently for BI 
425809 than placebo were were CNS-related (particularly headache, dizziness and
somnolence) or GI-related (particularly nausea and vomiting), and were typically mild to 
moderate and transient.
Visual disturbances such as flashes of light or blurred vision were reported as adverse events 
in Phase I healthy volunteers studies, but these events were reported infrequently 
(approximately 2% of study participants) in the Phase II study in patients diagnosed with 
schizophrenia (c02155957).  These effects are understood to be mostly mild to moderate and 
transient. Please refer to Section 5.2.6.2 for further details on monitoring, reporting and 
follow-up of any unusual visual perception that patients may experience during this study.
In longer-term studies, BI 425809 was associated with a dose-dependent decrease in Hb: in 
the 12-week Phase II study in patients with schizophrenia administration of the 10 mg dose 
resulted in a decrease of 3.3 g/L (-2.3%) at last value on treatment, while administration of 


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the 25 mg dose resulted in a decrease of 4.5 g/L (-3.2%) (c02155957).  No clear decrease in 
Hb was seen in BI 425809-treated subjects compared to placebo in Phase I trials of short 
treatment duration.  Decreased Hb is also considered to be a potential risk based on 
preclinical data and class effect, as GLYT1 is present on erythrocyte precursors in the bone 
marrow and on circulating reticulocytes and glycine is required for Hb synthesis.
Patients with Hb less than 120 g/L (12g/dL) in men or 115g/L (11.5g/dL) in women will be 
excluded from participation in this study.  Hb will also be monitored through safety 
laboratory tests and additional reflex testing will be done for patients with ≥20g/L (>2g/dL)
decrease in Hb since baseline as described in Table 5.2.3: 1. Patients will be withdrawn from 
the study treatment if: Hb level is <100 g/L (10 g/dL) AND absolute drop of >20 g/L (2 
g/dL) compared to baseline (Visit 2); or if the subject develops anemia with symptoms of 
anemia such as dizziness, fatigue, pallor, shortness of breath, etc as determined by the 
investigator.
Results of DDI studies showed that co-administration with a strong CYP3A inhibitor 
increased the total exposure of BI 425809 significantly, while exposure of BI 425809 was 
decreased in presence of a strong CYP3A4 inducer. Therefore, concomitant use of strong and 
moderate inhibitors or inducers of CYP3A4 should be avoided.
Placebo risks and risks of stopping study drug
There is currently no approved medication indicated for treatment of cognitive impairment in 
schizophrenia. Therefore, a placebo control group is being used in this study design. It should 
be noted that all patients, including those randomized to the placebo group, remain on 
antipsychotic and other psychotropic medications throughout the study. Moreover, all 
patients will complete adjunctive CCT as described above.
According to the medication assignment planned in this trial, 50% of the patients will receive
BI 425809 and 50% of patients will be assigned to placebo. Inclusion criteria imply that 
patients enrolled in this clinical trial should be in stable clinical status and on stable doses of 
antipsychotic and concomitant psychotropic medications. Assignment to the placebo arm or 
stopping the study drug during the treatment period is not associated with a higher risk since 
patients remain on their stable treatment regimen with antipsychotics. Psychiatric events, 
positive and negative symptoms, and suicidality will be monitored throughout the study to 
ensure that worsening of pre-existing conditions or any newly occurring events are detected 
and any necessary actions taken according to stopping criteria.
Although this is an experimental drug at an early stage of clinical development and therefore 
an individual benefit cannot be guaranteed, potential efficacy has been demonstrated by pre-
clinical behavioral cognition models. Given the acceptable safety profile in nonclinical and 
toxicology studies and the good tolerability in clinical studies performed until this 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 further develop treatment 
options to improve cognition as a treatment for an unmet medical need.


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Study procedure risks
The patients may feel discomfort during some of the study procedures, among other study 
procedure risks, such as 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.
We do not anticipate any risks associated with CCT. The weekly training duration is split up 
into short sessions (i.e. it is recommended that patients complete approximately 2.5 hours of 
CCT per week divided into 3-5 sessions of 30-50 minutes duration) to avoid strain caused by 
prolonged use of a personal computer (laptop/desktop) or tablet device.
In summary, results of this study will determine whether benefit of treatment with potential 
pharmacotherapies targeting modulation of neuroplasticity would increase with cognitive 
stimulation through adjunctive CCT in patients with schizophrenia. This is of utmost 
importance as cognitive stimulation is low or even absent in the lives of patients. It was 
indeed hypothesized as one of the reasons for past failures during development of new 
medications to treat CIAS. Since there is currently no approved pharmacotherapy to improve 
CIAS, finding an effective treatment represents a high unmet medical need. Considering the 
chronic and severe disease burden of CIAS, and moreover the potential additional favorable 
effect of adjunctive CCT on cognition in all study patients, the potential therapeutic benefits 
are assessed to outweigh the currently understood potential risks of the treatment and/or trial-
related procedures.
Other risks
Regarding the potential risk while operating machinery, please refer to Section 4.2.2.2.
Consistent with the FDA draft guidance entitled "Suicidal Ideation and Behavior: Prospective
Assessment of Occurrence in Clinical Trials", prospective assessment of suicidal ideation and
behavior is included in this study using the Columbia Suicidal Severity Rating Scale (C-
SSRS). No signal was observed for suicidal ideation or behavior in patient studies of 12 
weeks treatment duration.
Although rare, a potential for drug-induced liver injury (DILI) is under constant surveillance 
by sponsors and regulators. Therefore, this trial requires timely detection, evaluation, and 
follow-up of laboratory alterations in selected liver laboratory parameters to ensure patients´ 
safety, see also Section 5.2.6, adverse events of special interest (AESI).
Overall, the risk for patients with schizophrenia participating in BI 425809 CIAS clinical 
trials is considered increased in light of Coronavirus Disease 2019 (COVID-19), the disease 
caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), 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 and due to potential decrease in Hb after treatment with BI 
425809.


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Therefore, appropriate risk minimization measures will be taken in accordance with the 
public health precautions implemented in the country where the study will be conducted (e.g. 
minimizing time at the clinic, replacement of physical visits with remote visits where 
possible, minimizing the use of public transportation to the site). In the event of restriction to 
visit the investigator site, certain procedures can be done remotely, and local labs can be used 
instead of central lab, as described in Section 10.5. These changes are meant to keep the 
integrity of the trial and they will not affect the benefit-risk of BI 425809. Considering the 
risk, patients with known active SARS-CoV-2 infection within 30 days prior to 
randomization will be excluded from participation in this study. Also, the study drug should 
be discontinued if the patient experiences severe or serious symptomatic infection with 
SARS-CoV-2 (see Section 3.3.4.1).
The investigators will take the totality of information related to each single patient and the 
local COVID-19 situation into consideration when performing the individual benefit-risk 
assessment on a case-by-case basis. Considering all aspects, the investigator will decide upon 
each patient’s (continued) participation in the trial. Boehringer Ingelheim (BI) as the sponsor, 
where required, will support the investigator in their decision making. It is acknowledged that 
the investigator may decide to implement protocol deviations where this protects the safety, 
wellbeing and/or is in the best interest of the patient.


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2.
TRIAL OBJECTIVES AND ENDPOINTS
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS
2.1.1
Main objectives
The primary objective of this Phase II exploratory trial is to provide PoC data to assess the 
effect on cognition of oral once daily administration of BI 425809 given for 12 weeks in 
patients with schizophrenia on stable antipsychotic treatment and adjunctive CCT.
2.1.2
Primary endpoint(s)
Change from baseline in neurocognitive function as measured by the neurocognitive 
composite score of the Measurement and Treatment Research to Improve Cognition in 
Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB) after 12 weeks of 
treatment is the primary efficacy endpoint.
MCCB neurocognitive composite score (including all MCCB domains except Social 
Cognition) was selected because it was found to have greater sensitivity to treatment effect in 
previous studies in the same population (R18-1873).
2.1.3
Secondary endpoint(s)
The secondary endpoints of efficacy and safety are as follows:
∀
Change from baseline in cognitive function as measured by the overall MCCB 
composite score (including social cognition) after 12 weeks of treatment
∀
Change from baseline in the effect of cognitive deficit on day-to-day functioning as 
measured by SCoRS total score after 12 weeks of treatment
∀
Change from baseline in Positive and Negative Syndrome Scale (PANSS) total score 
after 12 weeks of treatment
∀
Percentage of patients with (S)AEs (including clinically relevant abnormalities of 
physical examination, vital signs, ECG test and laboratory tests)
 


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longer time, in the investigator’s opinion, in case of unresolved AEs. Individual patient 
participation is concluded when the patient has completed their last planned visit.
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)
A parallel group design was chosen for this trial to detect the effects of BI 425809 compared
to placebo on cognition in patients with schizophrenia on stable antipsychotic treatment and 
adjunctive CCT. The primary analysis of efficacy is planned after 12 weeks of treatment
(refer to Section 5.7 for appropriateness of treatment duration). The 4 weeks (+7-day 
window) post-treatment Follow-up Visit is considered to be sufficient to evaluate the 
pharmacodynamic effect of BI 425809 after discontinuation and allow for assessment of
reversibility of any unexpected side-effects. Details of the statistical approach and sample 
size justification are given in Section 7.
There is currently no approved medication indicated for treatment of CIAS and therefore, a 
placebo control group is being used in this study design. However, all patients will complete 
adjunctive CCT which has emerged as a non-pharmacological approach to improve cognitive 
impairments in patients with mental illness. It should be noted that all patients, including 
those randomized to the placebo group, are permitted to remain on other antipsychotic and 
psychotropic medications, within the eligibility criteria. The risk to the control group is 
discussed in Section 1.4.
This study includes CCT run-in for two weeks during the screening period.  The intention of 
this CCT run-in is to evaluate patient compliance with an at-home (i.e. completed by the 
patient independently, most likely at home, without clinician intervention) CCT program 
prior to randomization, in order to minimize the number of patients randomized at Visit 2 
who will not be compliant with at-home CCT during the treatment period.  See further 
Section 4.3 and Section 6.2.1.
3.3
SELECTION OF TRIAL POPULATION
It is planned that around 58 trial centres in 6 countries will be participating in this trial and a 
sufficient number of patients will be screened for the trial to ensure that 200 patients are 
randomized to trial treatment.
It is expected that approximately 5 patients will be randomized at each trial center.  If 
enrolment is delayed, additional sites may be recruited. 
To avoid differential center influence on study results, permission to randomize more than 15
patients per site must be obtained from the Clinical Trial Leader (CTL). This will only be 
allowed after a careful review of the enrolment status and of the site.
Screening of patients for this trial is competitive, i.e. screening for the trial will stop at all 
sites once a sufficient number of patients has been screened. Investigators will be notified 


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about screening completion and will then not be allowed to screen additional patients for this 
trial.
A log of all patients enrolled into the trial (i.e. who have signed informed consent) will be 
maintained in the ISF irrespective of whether they have been treated with investigational drug 
or not.
If a patient is enrolled in error (does not meet all inclusion criteria or meets one or more 
exclusion criteria on the day of enrolment), the sponsor should be contacted immediately.
It was decided that patients in this study should be maximum 50 years of age, as 
neuroplasticity (i.e. ability of the brain to change during life by acquiring, storing and re-
using information) declines with age as well as with duration of the illness and treatment with 
antipsychotics. If BI 425809 is shown to be efficacious in this age group, it is planned to 
conduct additional studies to explore efficacy in patients over 50 years of age.
3.3.1
Main diagnosis for trial entry
Only patients with established Schizophrenia (as per Diagnostic and Statistical Manual of 
Mental Disorders, 5th Edition (DSM-5)) who are clinically stable will be screened for 
suitability for the study. Inclusion will be based upon a complete medical history, including 
physical examination, vital signs, 12-lead ECG and clinical laboratory tests.
Please refer to Section 8.3.1 for the documentation requirements pertaining to the in- and 
exclusion criteria.
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.
2. Male or female patients who are 18-50 years (inclusive) of age at time of consent.
3. Established schizophrenia (as per DSM-5) with the following clinical features:
∀
Outpatient, with no hospitalization for worsening of schizophrenia within 3 
months1 prior to randomization 
∀
Psychiatrically stable without symptom exacerbation within 3 months prior to 
randomization
∀
PANSS score ≤ 5 on positive items P1, P3-P7 and ≤ 4 on positive item P2 at Visit 
1, and confirmed at Visit 2
                                                
1 Hospitalization for social management and/or day hospital programs within this time are acceptable.


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4. Patients must be on stable antipsychotic treatment; also, current antipsychotic 
medications and concomitant anticholinergics, antiepileptics, lithium and allowed 
antidepressants must meet the criteria below:
∀
Patients must take 1 and may take up to 2 antipsychotics (typical and/or atypical), 
except for clozapine (see Section 3.3.3)
∀
Patients must be stable on current antipsychotics, anticholinergics, antiepileptics,
lithium and allowed antidepressants for at least 3 months prior to randomization 
and be on current dose for at least 30 days prior to randomization
o
Patients on Long-Acting Injectable (LAI) antipsychotics should be on the 
same medication and dose for at least 3 months prior to randomization
5. Women of childbearing potential (WOCBP)2 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.
6. Patients must demonstrate their ability to properly use the CCT device and program, as 
well as be compliant with CCT run-in (defined as completing at least 2 hours per week 
for two weeks, totalling 4 hours CCT, during the screening period)3.
7. Patients must be able to comply with all protocol procedures, in the investigator’s 
opinion.
8. Patients must have a study partner who will preferably be consistent throughout the study. 
It is recommended that the study partner should interact (in-person or telephone) with the 
subject at least 2 times a week.
3.3.3
Exclusion criteria
1. Patients who have a categorical diagnosis of another current major psychiatric disorder on 
the Mini-International Neuropsychiatric Interview (M.I.N.I.).
2. Diseases of the central nervous system (CNS) that may impact the assessment of the 
cognitive tests as per investigator’s opinion.
                                                
2 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.
3 If target compliance is not met but the investigator believes the patient will be compliant during the treatment period, then 
the investigator should contact the CTM or CTL prior to randomization and a documented discussion should take place to 
determine whether the patient can be randomized (see Section 4.3).


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3. A movement disorder due to antipsychotic treatment not currently controlled with anti-
EPS treatment or another movement disorder (e.g. Parkinson´s disease).
4. Patients with a history of participating in any formal cognitive remediation program for 
10 or more training sessions.
5. Patients who were treated with any of the following medications within the last 6 months 
prior to randomization:
∀
Bitopertin, BI 409306, encenicline or other investigational drug testing effects on
cognition in schizophrenia
∀
Clozapine (atypical antipsychotic medication)
∀
Sarcosine, cycloserine, serine and glycine
∀
Stimulants (e.g. methylphenidate, dextroamphetamine, modafinil)
∀
Tricyclic antidepressants
6. Patients receiving any other investigational drug (other than a potential cognitive 
enhancing drug) within 30 days or 6 half-lives (whichever is longer) prior to 
randomization. For investigational LAI antipsychotics, the last injection must be at least 3 
months or two administration cycles (i.e. 6 months if administration is every 3 months) 
prior to randomization, whichever is longer.
7. Patients who have participated in a clinical trial with repeated assessments (i.e. a single 
assessment is not exclusionary) with the MATRICS Consensus Cognitive Battery 
(MCCB) within the last 6 months prior to randomization.
8. Patients who required a change in ongoing benzodiazepine or sleep medication dose or 
regimen within the last 30 days prior to randomization.
9. Use of systemic steroids within 30 days prior to randomization.
10. Patients taking strong or moderate CYP3A4 inhibitors or inducers within the last 30 days 
prior to randomization. A list of strong or moderate CYP3A4 inhibitors and inducers will 
be provided in the ISF.
11. Patients who must or wish to continue the intake of restricted medications (see Section 
4.2.2.1) or herbal remedies (see Section 4.2.2.2).
12. Patients who received treatment with medical devices (e.g. TMS, neurofeedback) for any 
psychiatric condition within the last 3 months prior to randomization.
13. Patients who have received electroconvulsive therapy (ECT) within 6 months prior to 
randomization or repeated courses of ECT within the past 2 years.
14. Any suicidal behavior in the past 2 years (i.e. actual attempt, interrupted attempt, aborted 
attempt, or preparatory acts or behavior) prior to randomization.


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15. Any suicidal ideation of type 4 or 5 in the C-SSRS in the past 3 months (i.e. active 
suicidal thought with intent but without specific plan, or active suicidal thought with plan 
and intent) prior to randomization.
16. Any of the following, in the judgment of the investigator:
∀
Clinically significant finding of the physical examination, vital signs (including 
blood pressure (BP) and pulse rate (PR)), ECG or laboratory value (as measured 
by the central laboratory) that would jeopardize the patient´s safety while 
participating in the trial or their capability to participate in the trial.
∀
Symptomatic/unstable/uncontrolled or clinically relevant concomitant disease or 
any other clinical condition that would jeopardize the patient´s safety while 
participating in the trial or capability to participate in the trial.
∀
Significant or unstable physical condition that may require change in medication 
or hospitalization that would impact cognitive function, or planned elective 
surgery requiring general anesthesia during the study period.
∀
Patients for which cognitive or other impairment (including severe hearing 
impairment) or symptom severity compromises the ability to perform the CCT or 
assessments related to cognitive outcome measures.
17. Severe renal impairment defined as an eGFR < 30mL/min/1.73m² in the Visit 1 central 
lab report.
18. Indication of liver disease, defined by serum levels of either ALT (SGPT), AST (SGOT), 
or alkaline phosphatase above 3 times upper limit of normal as determined in the Visit 1 
central lab report.
19. Known history of HIV infection based on review of medical history and/or a positive 
result for ongoing Hepatitis B or C infection on the Visit 1 central lab report.
20. 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.
21. Hb less than 120 g/L (12g/dL) in men or 115 g/L (11.5g/dL) in women at Visit 1.
22. History of hemoglobinopathy such as thalassemia major or sickle-cell anemia.
23. Women who are pregnant, nursing, or who plan to become pregnant while in the trial.
24. Significant history of drug abuse disorder within the last 6 months prior to informed 
consent (including alcohol, as defined in DSM-5-substance use disorder or in the opinion 
of the investigator), or a positive urine drug screen at Visit 1. For a list of drugs assessed 
in the urine drug screen, please refer to Table 5.2.3: 1. Note: Patients testing positive for 
cannabis on urine drug screen at Visit 1 may be re-tested once if there is a reasonable 
explanation and expectation that the patient will not test positive again on re-test, and at 
the discretion of the investigator.


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25. Patients who are not fluent in the language of the batteries/questionnaires which will be 
used in the country.
26. Patient who did not make an effortful attempt to complete the cognition battery at Visit 1 
in the clinical judgement of the investigator.
27. Patients that previously received treatment in any study with BI 425809.
28. Patients with an allergy to BI 425809 and/or any of the excipients (including lactose) or 
placebo ingredients. A list of BI 425809 and placebo ingredients will be provided in the 
ISF.
29. Patients with known active infection with SARS-CoV-2 within the last 30 days prior to 
randomization.
3.3.4
Withdrawal of patients from therapy or assessments
Every effort should be made to keep the randomized patients in the trial, if possible.
Measures to control the withdrawal rate include careful patient selection, appropriate 
explanation of the trial requirements and procedures prior to randomization, as well as the
explanation of the consequences of withdrawal. 
The decision to discontinue trial treatment or withdraw consent to trial participation and the 
reason must be documented in the patient files and electronic Case Report Form (eCRF). If 
the reason for discontinuation is death, this should be reported on the Serious Adverse Event 
(SAE) form as well, regardless of causal relationship.
3.3.4.1
Withdrawal from trial treatment
An individual patient is to be withdrawn from trial treatment if:
∀
The patient wants to withdraw from trial treatment or study participation, without the 
need to justify the decision
∀
The patient needs to take concomitant drugs that interfere with the investigational 
product or are restricted (see Section 4.2.2.1)
∀
The patient can no longer be treated with trial medication for other medical reasons 
(such as surgery, AEs, other diseases, or pregnancy)
o
If a patient becomes pregnant during the trial the study medication will be 
stopped, the patient will be discontinued from the trial and the patient will be 
followed up until birth or otherwise termination of the pregnancy
o
For further information, including the process for follow-up on the outcome of 
the pregnancy please see Section 5.2.6.2.


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∀
The patient has repeatedly shown to be non-compliant with important trial procedures 
and, in the opinion of both the investigator and sponsor representative, is not willing 
or able to stick to the trial requirements in the future
∀
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)
∀
Hb level <100 g/L (10 g/dL) AND absolute drop of >20 g/L (2 g/dL) since baseline 
(Visit 2); or
The subject develops anemia with symptoms of anemia such as dizziness, fatigue, 
pallor, shortness of breath, etc as determined by the investigator
∀
The patient needs to stop all current antipsychotic medications
∀
The patient’s disease state dramatically worsens, in clinical judgement of investigator
∀
The patient experiences severe or serious symptomatic infection with SARS-CoV-2 
Given the patient’s agreement, the patient will undergo the procedures for early treatment 
discontinuation and follow up as outlined in the Flow Chart and Section 6.2.3.
For all patients the reason for withdrawal from trial treatment (e.g. adverse events) must be 
recorded in the eCRF. These data will be included in the trial database and reported.
Patients who discontinue or withdraw from the study after randomization (Visit 2) will be
considered as “early discontinuations”. The data will be included in the trial database and will 
be reported. Patients who withdraw or discontinue from the trial after randomization will not 
be replaced.
Patients who drop out prior to randomization will be considered Screening Failures. They 
will be recorded as Screening Failures in the eCRF and no further follow-up is required. The 
data will be included in the trial database and will be reported.
3.3.4.2
Withdrawal of consent for trial participation
Patients may withdraw their consent for trial participation at any time without the need to 
justify the decision.
If a patient wants to withdraw consent, the investigator should be involved in the discussion 
with the patient.  See further Section 3.3.4.1 above.
3.3.4.3
Discontinuation of the trial by the sponsor
Boehringer Ingelheim reserves the right to discontinue the trial overall or at a particular trial
site at any time for the following reasons:


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1. Failure to meet expected enrolment goals overall or at a particular trial site
2. Emergence of any efficacy/safety information invalidating the earlier positive benefit-
risk-assessment that could significantly affect the continuation of the trial
3. Violation of ICH-GCP, the trial protocol, or the contract impairing the appropriate 
conduct of the trial
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
BI 425809 tablets have been manufactured by BI Pharma GmbH & Co. KG.
Eligible patients are randomly assigned to one of the double-blind treatment regimens at a 
ratio of 1:1 as follows:
∀
BI 425809 10 mg once daily for 12 weeks
∀
Placebo once daily for 12 weeks
All patients will receive non-pharmacological adjunctive CCT (see further Section 4.2.1).
4.1.1
Identity of BI investigational product(s) and comparator product(s)
The characteristics of the test product are as shown below.
Table 4.1.1: 1
Test product:
Substance:
BI 425809
Pharmaceutical formulation:
Tablet
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
5 mg
Posology
2-0-0 for the dose group of 10 mg
Method and route of administration:
Oral
The characteristics of the reference product are as shown below.
Table 4.1.1: 2
Reference product:
Substance:
Placebo matching BI 425809 5 mg
Pharmaceutical formulation:
Tablet
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
Not applicable


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Posology
2-0-0 for the placebo dose group
Method and route of administration:
Oral
4.1.2
Selection of doses in the trial and dose modifications
According to the result of previous trials, BI 425809 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), please 
refer to Section 1.2 for more details.
Based on preclinical data in animal cognition tasks, BI 425809 shows efficacy at doses which 
correspond to ~50% glycine increase in CSF and CSF levels of the drug in the range of 1x 
GLYT1 IC50 (see chapter 5.1.1.2 of the IB c02155957).
In the Proof of Mechanism trial (c03724403-01) demonstrating functional target engagement 
in healthy volunteers, the target mean increase of 50% in CSF glycine was observed after 
multiple dosing of 10 mg BI 425809 indicating that this dose level generates sufficient drug 
exposure and glycine increases in the brain that are expected to lead to improvement of the 
cognitive abilities in human.
Therefore, based on the preclinical data and data from the Proof of Mechanism Trial, 10 mg 
of BI 425809 was chosen as the dose level to be investigated in the present study.
4.1.3
Method of assigning patients to treatment groups
During Visit 2, eligible patients will be randomized to receive BI 425809 10 mg q.d. or 
placebo in a 1:1 ratio according to a randomization plan. The study drug assignment will 
occur in a blinded fashion via IRT.  All patients will complete adjunctive CCT for the 
duration of the treatment period (see further Section 4.1.1).
4.1.4
Drug assignment and administration of doses for each patient
Dispensing of kits for the double-blind treatment period will begin at Visit 2.  Trial 
medication kits will be provided at Visit 2, Visit 3, Visit 4 and Visit 5.  At each of these 
visits, medication assignment will be provided through IRT.  The assigned medication 
number(s) must be entered in the eCRF, and the corresponding medication kit(s) must be 
given to the patient.  The duration of treatment is 12 weeks.  At Visit 2, Visit 3, Visit 4 and 
Visit 5, patients will receive one treatment kit containing supplies for a total of 28 days (21 
treatment days plus 7 days reserve).
The first dose of study medication will be taken at the end of Visit 2 under supervision of the 
investigator or site staff. For patients that complete the treatment period, 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 (i.e. 2 consecutive calendar days), the last dose of study 




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documented in the source documents and/or appropriate eCRF page along with the date and 
the initials of the person who broke the code.
Due to the requirements to report Suspected Unexpected Serious Adverse Reactions 
(SUSARs), it may be necessary for a representative from BI’s Pharmacovigilance group to 
access the randomization code for individual patients during trial conduct. The access to the 
code will only be given to authorised Pharmacovigilance representatives and not be shared 
further.
4.1.6
Packaging, labelling, and re-supply
The investigational products will be provided by BI or a designated contract research 
organization (CRO). They will be packaged and labelled in accordance with the principles of 
Good Manufacturing Practice. Re-supply to the sites will be managed via an IRT system, 
which will also monitor expiry dates of supplies available at the sites.
For details of packaging and the description of the label, refer to the ISF.
4.1.7
Storage conditions
Drug supplies will be kept in their original packaging and in a secure limited access storage 
area according to the recommended storage conditions on the medication label. A
temperature log must be maintained for documentation.
If the storage conditions are found to be outside the specified range, the Clinical Trial 
Manager (CTM) (as provided in the list of contacts) must be contacted immediately.
4.1.8
Drug accountability
The investigator, pharmacist and/or investigational drug storage manager will receive the 
investigational drugs delivered by the sponsor when the following requirements are fulfilled:
∀
Approval of the clinical trial protocol (CTP) by the Institutional Review Board (IRB) 
Independent Ethics Committee (IEC),
∀
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,
∀
Availability of the curriculum vitae of the Principal Investigator,
∀
Availability of a signed and dated CTP,
∀
Availability of the proof of a medical license for the Principal Investigator (if 
applicable),
∀
Availability of FDA Form 1572 (if applicable).


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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, and/or pharmacist and/or investigational drug storage manager must 
maintain records of the product’s delivery to the trial site, the inventory at the site, the use by 
each patient, and the return to the sponsor or warehouse / drug distribution centre or 
alternative disposal of unused products. If applicable, the sponsor or warehouse / drug 
distribution centre will maintain records of the disposal.
These records will include dates, quantities, batch / serial numbers, expiry (‘use- by’) dates, 
and the unique code numbers assigned to the investigational product and trial patients. The 
investigator / pharmacist / investigational drug storage manager will maintain records that 
document adequately that the patients were provided the doses specified by the CTP and 
reconcile all investigational products received from the sponsor. At the time of return to the 
sponsor and/or appointed CRO, the investigator / pharmacist / investigational drug storage 
manager 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
Emergency treatments and procedures
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 deemed necessary per clinical judgment 
can be given.
Other treatments
Throughout the duration of the trial patients should continue to take only their current 
antipsychotic and concomitant psychotropic medications, the dose of which should remain 
unchanged if at all possible.  These medications will not be provided as part of the clinical 
trial supplies, unless required by local laws and regulations.
Any change in dose of antipsychotic and concomitant psychotropic medications should be 
recorded in the source documentation and on the appropriate pages of the eCRF.
Any additional treatment that is considered necessary for the patient’s welfare may be given 
at the discretion of the investigator.


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Adjunctive Computerized Cognitive Training (CCT)
All patients in the study will complete adjunctive CCT for the duration of the 12-week 
treatment period (and additional CCT run-in during the screening period).
Total CCT will be approximately 30 hours spread over the 12-week treatment period. It is 
recommended that patients complete approximately 2.5 hours of CCT per week divided into 
3-5 sessions of 30-50 minutes duration.  Patients can split assigned training sessions into 
shorter segments, instead of completing the session as one continuous workout, however 
patients should be instructed that the training done during a session or segment thereof should 
preferably be minimum 10 minutes duration. Sessions should not exceed 1 hour of 
continuous training to patient fatigue.
The same program will be used to deliver CCT during both the screening and treatment 
period.  The CCT exercises completed during the screening period (CCT run-in) will match 
the CCT exercises completed during the treatment period in order to most effectively serve 
the intention of the CCT run-in, which is to identify and exclude patients who will not be 
compliant with completing at-home CCT exercises.  It is recognized that patients may gain 
some benefit from completion of CCT during the run-in period. To minimize the effect of 
CCT during run-in, a large variety of exercises will be delivered so that patient will have 
limited exposure to any one particular exercise, and all exercises will start at the lowest level 
of difficulty. In addition, once eligibility based on CCT run-in is established, patients should 
be advised to not complete any further CCT until they are randomized to the treatment 
period.
Selection of CCT target duration
The CCT target duration of total approximately 30 hours divided into 3-5 sessions per week 
is based on a meta-analysis published in 2011 (R16-2166) of cognitive remediation therapy 
for schizophrenia. This review examined 2,104 patients who participated in 40 different 
studies.  The average length of administration (CCT use) was 32.2 hours over an average of
16.7 weeks. Results showed a statistically significant improvement in global cognition of 
moderate effect size (average 0.45).  The meta-analysis included studies that used both 
computerized and non-computerized methods, with no difference between the two 
approaches.
Our goal for the CCT component of this study is not to improve cognition but to provide a 
moderate level of background cognitive stimulation.  Based on the above-mentioned meta-
analysis, it was determined that total approximately 30 hours of CCT over 12 weeks with a 
recommendation for 3-5 sessions per week should allow for the desired moderate level of 
background cognitive stimulation from the adjunctive CCT.


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4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
Medications listed under the inclusion criteria (Section 3.3.2) and exclusion criteria (Section 
3.3.3) are restricted during the trial period as well.
In addition, the following concomitant medication and treatment restrictions apply for the 
duration of the trial:
∀
Patients should not be on maintenance therapy with opioids (e.g. methadone, 
suboxone) during the trial period
∀
If given, olanzapine daily dose per label should not be exceeded
∀
Patients taking anticholinergic and antihistaminic medication should be on a stable 
dose not exceeding daily recommended dose per label in the country
o
Particular caution regarding the total dose should be taken for patients that are 
being treated with anticholinergics for various indications
∀
Patients should take the last dose of antihistaminic, benzodiazepine or other sedative
medication no less than 8 hours before MCCB during the trial period; in case this 
cannot be done at a scheduled visit, then the visit should preferably (if possible) be 
rescheduled within the allowed visit window
∀
New or changes in dose and frequency of psychosocial treatments (including social 
skills treatment or vocational treatment, and not including cognitive remediation 
therapy) is not permitted during the trial period; if patients are on these treatments at 
randomization, this should not have been started or changed in the prior three months
∀
Additional (i.e. non-study) cognitive remediation therapy, cognitive behavioural 
therapy or cognitive training is not permitted during the study period
∀
Any medication that may interfere with the pro-cognitive action of BI 425809 is not 
permitted during the treatment period and the 4-week follow-up period, in the clinical 
judgment of the investigator
∀
Patient will not receive electroconvulsive therapy nor begin any type of 
traditional/complementary therapies for cognition
∀
CYP3A4 sensitive drugs with narrow therapeutic range (such as cyclosporine or 
fentanyl) are not permitted during the trial period
o
A list of CYP3A4 sensitive drugs with narrow therapeutic range will be 
provided in the ISF
Further notes regarding concomitant medication and treatment restrictions:
∀
Non-systemic use (topical, inhalation or nasal administration) of corticosteroids, 
antihistaminics and anticholinergics is allowed.
∀
The allowed CYP3A4 sensitive drugs and CYP2B6 sensitive drugs may have 
decreased levels of exposure when given concomitantly with BI 425809; investigators 
should assess if dose adjustments and/or monitoring of the underlying disease is 
clinically required for patients who are taking such drugs (for a list of CYP3A4 and 
CYP2B6 sensitive drugs please refer to the ISF)


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4.2.2.2
Restrictions on diet and life style
The following are not permitted starting 7 days before the first administration of trial 
medication until the (e)EoT Visit:
∀
Grapefruit
∀
St. John's wort (Hypericum perforatum)
∀
Dietary supplements and herbal remedies that may impact cognition, in the 
investigator´s judgement
As a general precaution for CNS-active drugs, it is recommended that subjects should 
exercise caution when driving or operating machinery after drug administration. 
Patients should not abuse alcohol or use drugs of abuse during the study. A urine drug screen
will be performed at selected study visits (see Flow Chart). For a list of drugs assessed by the 
urine drug screen please refer to Table 5.2.3: 1.
Patients should not enter or modify a smoking-cessation program during the conduct of the 
trial.
Patients should keep their usual habits throughout the study for diet and exercise, as well as 
nicotine, alcohol and caffeine intake.
Patients do not have to come fasted to any trial visit.
4.2.2.3
Contraception requirements
WOCBP (for the definition please refer to Section 3.3.2) must use highly effective methods
of birth control per ICH M3 (R2) that results in a low failure rate of less than 1% per year 
when used consistently and correctly. Such methods should be used throughout the trial, and 
for a period of at least 35 days after last trial drug intake.
Acceptable methods of birth control for this trial include:
∀
Combined (estrogen and progestogen containing) hormonal birth control that prevents 
ovulation (oral, intravaginal, transdermal)
∀
Progestogen-only hormonal birth control that prevents ovulation (oral, injectable, 
implantable)
∀
Intrauterine device or intrauterine hormone-releasing system
∀
Bilateral tubal occlusion
∀
Vasectomised sexual partner with documented absence of sperm
∀
Complete sexual abstinence when this is in line with the preferred and usual lifestyle 
of the patient (note: periodic abstinence such as calendar, ovulation, symptothermal, 
post-ovulation methods and withdrawal are not acceptable methods of contraception)


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4.3
TREATMENT COMPLIANCE
Study medication will be dispensed to the patient at the study site by responsible site
personnel. Details regarding dispensing of the study medication to each participating patient,
including patient identification, the amount of study drug dispensed, the date the drug was
dispensed, and the numbers of tablets returned to the site will be recorded in the drug
accountability log. All dispensed study drug should be recorded in the drug accountability log
of the ISF.
Patients are requested to bring all remaining trial medication including empty package 
material with them when attending visits.
Based on tablet counts, treatment compliance will be calculated as shown in the formula 
below. Compliance will be verified by the Clinical Research Associate (CRA) authorised by 
the sponsor.
Treatment compliance (%) =
Number of tablets actually taken # 100
     Number of tablets which should have been taken
as directed by the investigator
If the number of doses taken is not between 80-120%, site staff will re-train the patient and
explain the importance of treatment compliance.  The site should also discuss with the patient 
if the number of doses taken is greater than 100%, to determine the reason.
Compliance with adjunctive CCT
Total CCT will be approximately 30 hours spread over the 12-week treatment period.
Optimally, patients should complete approximately 2.5 hours of CCT per week divided into 
3-5 sessions of 30-50 minutes duration.  Patients can split the training sessions into shorter 
segments during the day and throughout the week, however the training done during a session 
or segment thereof should preferably be minimum 10 minutes duration.
CCT compliance will be monitored on an ongoing basis by site staff (CCT coach) that should 
follow up with patients to discuss compliance status and provide advice and motivation as 
necessary. See Section 6.2 for further description of the role and responsibilities of the CCT 
coach.
CCT compliance during run-in (screening period)
The CCT run-in will be completed by the patient during the screening period. Patients that 
comply with CCT run-in will be eligible for randomization. Preferably within 7 days after 
written informed consent signed (enrolment), the CCT run-in will begin. The baseline MCCB
assessment at Visit 2 should be done within 7 days after patient completes the CCT run-in
whenever possible. This allows sufficient time for patients to complete the CCT run-in (two
weeks) and for sites to receive/review the compliance results prior to Visit 2.


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Target compliance for the CCT run-in is at least 2 hours per week for two weeks, totalling 4 
hours, during the screening period. If target compliance is not met but the investigator 
believes the patient will be compliant during the treatment period, then the investigator 
should contact the CTM or CTL prior to randomization and a documented discussion should 
take place to determine whether the patient can be randomized. See further Section 6.2.1.
During the screening period, once eligibility based on CCT run-in is established, the patient 
should not complete any further CCT until they are randomized to the treatment period.
CCT compliance during treatment period
CCT compliance during the treatment period should also be maintained at 2-3 hours (i.e. 
approximately 2.5 hours) per week across 3-5 sessions. Additionally, the CCT coach will 
discuss compliance during regular contact (at least weekly) with patients (see further 
description of CCT coach role and responsibilities in Section 6.2).
Minimum compliance expectation is at least 1 hour per week throughout the trial.  Any 
instance in which a patient completes less than 1 hour of CCT in any given week will be 
recorded as a protocol deviation (i.e. CCT low compliance).
Patients that do not complete any of the assigned CCT (i.e. zero sessions started) for 3 
consecutive weeks or more will be recorded as a protocol deviation (i.e. CCT non-
compliance).


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5.
ASSESSMENTS
5.1
ASSESSMENT OF EFFICACY
Change in cognitive function, everyday living skills, motivation and disease state will be 
measured by the batteries, scales and questionnaires listed below.
During the scheduled visits, the investigator or site staff will perform the evaluations by
asking subjects questions or help subjects to complete the evaluations which have to be done 
by themselves at sites.
In some cases the investigator or site staff will ask the study partner questions in order to 
complete evaluations. A study partner is defined as any person who has been capable of 
interacting with the patient over the past week. It is recommended that the study partner
should interact (in person or telephone) with the subject at least 2 times a week. If the study 
partner is not available for in person interview at the scheduled visit, telephone interview is 
acceptable. The study partner should preferably be the same person throughout the study. 
However, in the event that the identified study partner becomes unavailable or unwilling to 
provide input during the study, the patient should contact the investigator and identify a new 
study partner.
MATRICS Consensus Cognitive Battery (MCCB) will be used at screening (Visit 1), 
randomization (Visit 2/baseline), Visit 4 and (e)EoT Visit to evaluate the effects of BI 
425809 on cognitive functions.
MCCB comprises 10 tests, which assess 7 cognitive domains, including speed of processing, 
attention vigilance, working memory, verbal learning, visual learning, reasoning and problem 
solving, and social cognition (R13-2347; R13-2373).
The 10 tests of the MCCB with corresponding cognitive domains are listed in Table 5.1: 1
below:
Table 5.1: 1 MCCB tests and cognitive domains (R13-2373)
Test
Domain
Trail Making Test, Part A (TMT)
Speed of Processing
Brief Assessment of Cognition in 
Schizophrenia, symbol coding subtest 
(BACS SC)
Speed of Processing
Hopkins Verbal Learning Test – Revised 
(HVLT-R), immediate recall
Verbal Learning
Wechsler Memory Scale, 3rd ed. Spatial 
span subtest (WMS-III SS) 
Working Memory (nonverbal)




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Positive and Negative Syndrome Scale (PANSS) will be used to evaluate broad 
psychopathology associated with schizophrenia disease state at screening (Visit 1), 
randomization (Visit 2), Visit 4 and (e)EoT Visit.
The PANSS has 30 items. Each is rated from 1 to 7 points. The total factor score is the 
summation of the actual points for each item, leading the total score ranging from 30 to 210. 
(R13-5061).


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5.2
ASSESSMENT OF SAFETY
5.2.1
Physical examination
A complete physical examination will be performed at the time points specified in the Flow 
Chart.  It includes at a minimum general appearance, neck, lungs, cardiovascular system, 
abdomen, extremities, skin, eyes and nervous system. The physical examination will include 
examination of known and suspected sites of disease. A complete physical exam is also 
required at eEoT Visit.
Clinically relevant abnormal findings noticed from physical examination after Visit 1
assessment will be reported as (S)AEs.
Body weight and height will be measured as indicated in the Flow Chart.
5.2.2
Vital signs
Vital signs will be evaluated at the time points specified in the Flow Chart, prior to blood 
sampling, including the (e)EoT Visit and the Follow-up Visit (4 weeks after (e)EoT). This 
includes temperature, 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.
BP measurement can be done manually or electronically (preferably with the same device at 
every visit). The BP measurement can be repeated after 10 minutes rest at the discretion of 
the investigator (e.g. if there is reason to think the patient was anxious or under stress at the 
time of first measurement), in which case the second measurement should be recorded in the 
eCRF.
Clinically relevant abnormal findings from vital signs evaluation noticed after Visit 1 will be 
reported as (S)AEs.


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5.2.3
Safety laboratory parameters
Safety laboratory parameters to be assessed are listed in Table 5.2.3: 1. For the sampling time 
points please see the Flow Chart.
Patients do not have to be fasted for the blood sampling for the safety laboratory.
All analyses will be performed by a central laboratory, the respective reference ranges will be 
provided in the ISF. 
Instructions regarding sample collection, sample handling/ processing and sample shipping 
are provided in the Laboratory Manual in the ISF. 
The central laboratory will send reports to the investigator. It is the responsibility of the 
investigator to evaluate the laboratory reports. Clinically relevant abnormal findings on lab 
results after baseline safety laboratory parameters are assessed, as judged by the investigator,
will be reported as AEs (please refer to Section 5.2.6).
Laboratory results of the patients will be available to the respective investigator and to the 
sponsor, and abnormal laboratory alerts will be sent automatically to the sites and to the 
sponsor within 24 hours.
In case the criteria for hepatic injury are fulfilled, a number of additional measures will be 
performed (please see Section 5.2.6.1 and the DILI Checklist provided in the eDC system.
The amount of blood taken from the patient concerned will be increased due to this additional 
sampling.
The central laboratory will transfer the results of the analysis to the sponsor.
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 must be confirmed using an unscheduled visit lab kit and should be repeated until 
normalization or stabilization or until an alternative explanation has been found.
Clinically significant abnormal laboratory results should be reported by the investigators in 
the eCRF either on baseline condition (from Visit 1 test) or on AE page (from subsequent 
visits test). The following lab parameters will not be determined at each study visit:
∀
Vitamin B12 and folate – only at Visit 1
∀
TSH – only at Visit 1
∀
Infections screen – only at Visit 1
∀
Prolactin – only at Visit 2 and (e)EoT


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Table 5.2.3: 1
Safety laboratory tests
Category
Test name
Haematology
Hematocrit (Hct)
Hemoglobin (Hb)*
Red Blood Cell Count/ Erythrocytes
Reticulocyte Count
White Blood Cells / Leukocytes
Platelet Count/ Thrombocytes
MCV, MCH, RDW, MCHC
Diff. Automatic (manual if 
diff. automatic is abnormal)
- Neutrophils 
- Eosinophils 
- Basophils
- Monocytes
- Lymphocytes
Chemistry
AST(GOT)
ALT(GPT)
Alkaline Phosphatase (AP)
Creatine Kinase (CK)
CK-MB – only if CK is elevated
Gamma-Glutamyl Transferase (GGT/γ-GT)
Lactic Dehydrogenase (LDH)
Lipase
Amylase
Calcium
Sodium
Urea (BUN)
Potassium
Glucose
Creatinine
Vitamine B12
Bilirubin Total, fractionated if increased
Protein, Total
C-Reactive Protein
Cholesterol, total
Triglycerides
TSH
Folate
Estimated Glomerular filtration rate (eGFR) – using the CKD-EPI 
equation
Prolactin
Pregnancy test 
(females only)
Human urine chorionic gonadotropin
Serum Beta hCG, Qualitative – only if human urine chorionic 
gonadotropin is positive


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Category
Test name
Urinalysis
Urine Nitrite
Urine Protein
Urine Glucose
Urine Ketone
Urobilinogen
Urine Bilirubin
Urine RBC/ Erythrocytes
Urine WBC/ Leukocytes
Urine pH
Urine creatinine
Drug screen (urine) Cannabis
Barbiturates
Opiates
Cocaine
Amphetamines
Methadone
PCP
Infections screen 
(only at Visit 1)
Hepatitis B Surface antigen (qualitative)
Hepatitis C antibodies (qualitative)
Hepatitis C Vaccine (HCV) RNA – only if Hepatitis C antibodies 
(qualitative) is positive
*For patients with >2g/dL decrease in Hb since baseline (Visit 2), the following tests will be 
added: serum ferritin, serum iron, TIBC, reticulocyte index.
5.2.4
Electrocardiogram
The 12-lead ECGs will be performed as scheduled in the Flow Chart. Twelve-lead ECGs (I, 
II, III, aVR, aVL, aVF, V1 – V6) will be recorded using equipment provided by a central 
ECG vendor. The ECGs will be recorded for at least 10-second duration after the subjects 
have rested for at least 5 minutes in a supine position and prior to lab sampling. Electrode 
placement will be performed according to the method of Einthoven/Goldberger (ankles and 
wrists). At all time points indicated in the Flow Chart, single ECGs will be recorded. ECG 
recordings at planned time points may be repeated for quality reasons like alternating current 
artefacts, muscle movements and electrode dislocation. In this case the repeated ECG 
recordings will be used if quality was better.
The investigator or a designee will evaluate whether the ECG is normal or abnormal and 
whether it is clinically significant, if abnormal. The electronic version of the ECG is regarded 
as source data. Dated and signed printouts will be stored in the patient’s medical file if there 
is no validated and certified e-medical record for ECG data.
Additional ECGs may be collected by the investigator for safety reasons. Clinically relevant 
findings noticed at baseline assessment (Visit 1) should be reported as baseline condition.


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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. Abnormalities detected during this centralized ECG 
evaluation will not necessarily qualify as AE.
Central evaluation on individual ECG level will be performed by the vendor and a report will 
be provided to the site. Decisions on eligibility for the trial and treatment or further follow-up 
of any findings are in the responsibility of the investigator.
5.2.5
Other safety parameters
5.2.5.1
Assessment of disease state
PANSS will be used to evaluate the disease state. It contains seven positive symptom items, 
seven negative symptom items and 16 general psychopathology symptom items. Fourteen of 
the PANSS items require input from a study partner. A trained rater interviews the patient 
and the study partner, estimated to take 30-40 minutes for evaluating the subjects’ disease 
state.
5.2.5.2
Assessment of suicidality
Suicidal risk assessed by the eC-SSRS (electronic version):
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 eC-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 eC-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).
The C-SSRS / eC-SSRS has been widely used in large multinational clinical trials. The eC-
SSRS will be administered first at screening (Visit 1) (using the ‘Baseline / Screening’
version) with the aim to exclude subjects with active moderate or severe symptomatology 
within a specified time prior to screening. The life time history of suicidal ideation and 
behavior will also be recorded.


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After screening (Visit 1) the assessment ‘since last visit’ will be performed at each clinic visit
(‘Since Last Visit version’). The investigator is to review/consider the eC-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. If 
the positive report is confirmed, appropriate actions for the subject’s safety have to be 
initiated.
All C-SSRS reports of suicidal ideation type 4 or 5 and all reports of suicidal behavior must 
be reported as separate SAEs by the investigator.
For ‘Self-injurious behaviour, no suicidal intent’ (Type 11) standard AE / SAE reporting 
rules are to be applied.
For each negative report (suicidal ideation type 1, 2 or 3) after start of the trial, the
investigator is to decide based on clinical judgment whether it represents an AE as defined in 
the protocol, and if it is considered an AE then it must be reported accordingly.
5.2.6
Assessment of adverse events
5.2.6.1
Definitions of AEs 
Adverse event
An AE is defined as any untoward medical occurrence in a patient or clinical investigation 
subject administered a medicinal product and which does not necessarily have to have a 
causal relationship with this treatment.
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product.
The following should also be recorded as an AE in the eCRF and BI SAE form (if 
applicable):
∀Worsening of the underlying disease or of other pre-existing conditions
∀Changes in vital signs, ECG, physical examination and laboratory test results, if they 
are judged clinically relevant by the investigator*
*Note: If such abnormalities already exist prior to trial inclusion, they will be considered as 
baseline conditions and should be collected in the eCRF only.
Regarding AEs in the context of suicidal risk assessment by C-SSRS, Section 5.2.5.2 should 
be adhered.


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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 hospitalization or 
-
requires prolongation of existing hospitalization,
-
results in persistent or significant disability or incapacity, or
-
is a congenital anomaly / birth defect,
or
-
is deemed serious for any other reason if it is an important medical event when based 
on appropriate medical judgement which may jeopardise the patient and may require 
medical or surgical intervention to prevent one of the other outcomes listed in the 
above definitions. Examples of such events are intensive treatment in an emergency 
room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do 
not result in hospitalization or development of dependency or abuse. 
Regarding SAEs in the context of suicidal risk assessment by C-SSRS, Section 5.2.5.2 should 
be adhered.
AEs considered “Always Serious”
Cancers of new histology and exacerbations of existing cancer must be classified as a serious 
event regardless of the time since discontinuation of the drug and must be reported as 
described in Section 5.2.6.2, sub-sections “AE Collection” and “AE reporting to sponsor and 
timelines”.
In accordance with the European Medicines Agency initiative on Important Medical Events, 
Boehringer Ingelheim has set up a list of further AEs, which by their nature, can always be 
considered to be “serious” even though they may not have met the criteria of an SAE as 
defined above.
The latest list of “Always Serious AEs” can be found in the eDC system. These events should 
always be reported as SAEs as described above.
Adverse events of special interest (AESIs)
The term AESI relates to any specific AE that has been identified at the project level as being 
of particular concern for prospective safety monitoring and safety assessment within this trial, 
e.g. the potential for AEs based on knowledge from other compounds in the same class. 
AESIs need to be reported to the sponsor’s Pharmacovigilance Department within the same 
timeframe that applies to SAEs, please see above.
The following are considered as AESIs:


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Hepatic injury
A hepatic injury is defined by the following alterations of hepatic laboratory parameters: 
∀
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
∀
aminotransferase (ALT, and/or AST) elevations ≥10 fold ULN
These lab findings constitute a hepatic injury alert and the patients showing these lab 
abnormalities need to be followed up according to the “DILI checklist” provided in the eDC 
system.
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.
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
Causal relationship of AEs
Medical judgement should be used to determine the relationship, considering all relevant 
factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge, 
confounding factors such as concomitant medication, concomitant diseases and relevant 
history. 
Arguments that may suggest that there is a reasonable possibility of a causal relationship 
could be:
∀
The event is consistent with the known pharmacology of the drug
∀
The event is known to be caused by or attributed to the drug class
∀
A plausible time to onset of the event relative to the time of drug exposure
∀
Evidence that the event is reproducible when the drug is re-introduced
∀
No medically sound alternative aetiologies that could explain the event (e.g. pre-
existing or concomitant diseases, or co-medications)
∀
The event is typically drug-related and infrequent in the general population not 
exposed to drugs (e.g. Stevens-Johnson syndrome)
∀
An indication of dose-response (i.e. greater effect size if the dose is increased, smaller 
effect size if dose is diminished)


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Arguments that may suggest that there is no reasonable possibility of a causal relationship 
could be:
∀
No plausible time to onset of the event relative to the time of drug exposure is evident 
(e.g. pre-treatment cases, diagnosis of cancer or chronic disease within days / weeks 
of drug administration; an allergic reaction weeks after discontinuation of the drug 
concerned)
∀
Continuation of the event despite the withdrawal of the medication, taking into 
account the pharmacological properties of the compound (e.g. after 5 half-lives); of 
note, this criterion may not be applicable to events whose time course is prolonged 
despite removing the original trigger
∀
Additional arguments amongst those stated before, like alternative explanation (e.g. 
situations where other drugs or underlying diseases appear to provide a more likely 
explanation for the observed event than the drug concerned)
∀
Disappearance of the event even though the trial drug treatment continues or remains 
unchanged


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6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
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 randomization (Visit 2). The trial medication kits contain sufficient 
medication to allow for these time windows.
The end of the trial is defined as “last patient out” (i.e. last visit completed by the last 
patient).
If the reason for removal of a patient from the treatment is an AE or an abnormal laboratory 
test result, the patient must be followed until they are resolved, or deemed reasonably 
followed up by the investigator on consultation with BI.
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
Patients do not have to come fasted for any trial visits.
The following guidance pertains to conduct of the neuropsychological assessments:
∀
Each assessment of the rating scales (MCCB, SCoRS, PANSS, 
) should 
preferentially be done by the same members of the site staff for a given patient 
throughout the study period
o
Note: MCCB and SCoRS should not be administered to a patient by the same 
rater at the same visit to prevent bias on the SCoRS ratings
∀
The MCCB assessments at Visit 4 and (e)EoT Visit must be started at the same 
time of the day as at Visit 2 (+/- 60 minutes); in case this cannot be done at a 
scheduled visit, then the visit should be rescheduled within the allowed visit window
∀
The MCCB assessment should preferably be done in the morning
∀
The screening MCCB assessment must be done before start of CCT run-in and at least 
12 days prior to the baseline MCCB assessment at Visit 2
∀
Visit 2 should be done within 7 days after patient completes the CCT run-in whenever 
possible
o
During the screening period, once eligibility based on CCT run-in is 
established, the patient should not complete any further CCT until they are 
randomized to the treatment period.
∀
The neuropsychological assessments should be conducted in the following order:
o
Screening (Visit 1) and Visit 4: The MCCB is done first before other 
neuropsychological assessments
o
Visit 2 and (e)EoT Visit: The 
 MCCB is done 
before other neuropsychological assessments


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∀
Study procedures for Visit 2 and (e)EoT Visit can be split into 2 sequential days (i.e. 2 
consecutive calendar days), in which case: the 
, MCCB 
 
 should be performed on the first day (for Visit 2, this should
preferably be done within 7 days after patient completes the CCT run-in); the other 
neuropsychological assessments (i.e. PANSS, SCoRS, 
) should 
be performed on the second day (for Visit 2, this would be day of first study drug 
intake).
∀
During the neuropsychological testing, patients are allowed to take short breaks as 
needed, in the judgement of the rater/investigator
∀
The site staff must be properly trained on all trial procedures and training 
documentation has to be filed in the ISF; the training standards and standards for the 
conduct of the assessments will be defined for each assessment individually and can 
be found in the ISF; it is the responsibility of the Principal Investigator at the site to 
ensure proper training of all members of the site staff involved in the 
neuropsychological assessments
o
In addition, the site staff that will be administering the neuropsychological 
performance and clinical rating scales may require certification
The following information applies to the CCT and related activities:
∀
The CCT exercises will come from the CR-Psychiatry program provided via the 
 
∀
Patients will use a personal computer (laptop/desktop) or tablet device with web 
browser to access the CCT exercises through the internet; each patient will need to log 
into their own account within the 
 in order to access and 
complete their CCT exercises
∀
All CCT training data is saved on a secure server by the CCT vendor; data can then be 
viewed by sponsor and site staff through a secure, password-protected and HIPAA-
compliant clinician server (CCT “portal”)
o
Note: These data will only be used to ensure compliance with the use of CCT;
they will not be used to display or analyze medical information about a 
patient, they will not be used to support or provide recommendations about 
prevention, diagnosis or treatment, and they will not be used to enable review 
the basis for such recommendations with the intent of making treatment 
decisions
∀
Each participating site will identify a CCT “coach” who will supervise use of the CCT 
program by study participants; the CCT coach performs various functions including:
o
Creates patient accounts within the 
o
Manages allocation and return of CCT devices 
o
Provides training/re-training as necessary on the proper use of the CCT 
program
o
Proactively contacts patients at least weekly during the treatment period (more 
frequent contacts may be warranted during the CCT run-in) to provide 
guidance and encouragement to complete assigned CCT exercises, and to 
ensure that the CCT program is problem-free
o
Monitors CCT compliance remotely via CCT portal on an ongoing basis (at 
least weekly although more frequent checks are encouraged during the CCT 


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run-in) and follows up with patients as necessary to discuss compliance status 
and encourage them to complete CCT to target (i.e. 2.5 hours per week 
divided into 3-5 sessions of 30-50 minutes duration)
o
Is available to remotely assist study patients in case of technical difficulties or 
questions regarding the CCT program
∀
All sites will receive a CCT Manual (available in the ISF) containing further details 
regarding the CCT program and CCT coach role and responsibilities
∀
Patients should try to avoid antihistaminic, benzodiazepine or other sedative 
medication within 8 hours before CCT training sessions, if possible
Study procedures to be performed at each visit are listed in the Flow Chart. Additional details
regarding visit procedures are provided below.
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 Section 10.5.
6.2.1
Screening and run-in period(s)
After patients have been informed about the trial, written informed consent in accordance 
with ICH-GCP and the local legislation must be obtained prior to any study related 
procedures taking place. Once consented, the patient is considered enrolled in the trial and 
starts the screening period. The patient is recorded on the enrolment log and registered in the 
IRT system as a screened patient.
All procedures for screening (Visit 1) as listed in the Flow Chart have to be performed within
28 days (or within 38 days if cannabis re-testing is performed) prior to Visit 2 (date of first 
drug administration) and can occur on more than one day. It is recommended that Visit 1 
laboratory samples are collected as early as possible in the screening period.
Baseline conditions and medical history will be recorded, including but not limited to:
∀
Demographics such as gender, age, ethnicity, smoking and alcohol history
∀
All concomitant medications.
∀
Psychiatric and relevant non-psychiatric history
o
Baseline disease state will be assessed by PANSS
The following assessments will be completed to assess eligibility:
∀
PANSS Positive scale item P1-P7 will be used for confirming eligibility at Visit 1 and 
Visit 2
∀
The M.I.N.I. and the ‘Baseline / Screening’ version of the C-SSRS will be 
administered for eligibility confirmation


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The SCoRS assessment will be done during screening (Visit 1).
BP should always be measured before any blood samples are taken. For details regarding the 
correct method for measuring BP, see Section 5.3.2.
A 12-lead ECG will be taken.
Any abnormal condition of clinical significance identified during physical examination, vital 
signs, 12 lead ECG and/or laboratory assessment should be recorded as a baseline condition.
All women of childbearing potential must perform urine (dipstick) pregnancy test at 
screening (Visit 1). The urine dipstick test will be completed locally on-site using kits 
provided by central lab. In the event of a positive urine pregnancy test, a serum pregnancy 
test will be performed by the central lab for confirmation.
During screening, the investigator should highlight to patients the importance of not taking 
drugs of abuse during the study, and that the urine drug screen will be repeated periodically 
throughout the trial. Patients should also be informed that they cannot participate in the trial if 
they have a positive urine drug screen (see further the relevant exclusion criterion in Section 
3.3.3).
The screening MCCB assessment must be done before start of CCT run-in and it is 
recommended that as many of the other screening procedures as possible also should be 
assessed prior to start of CCT run-in. The process for completion of CCT run-in includes the 
following:
∀
Preferably within 7 days after written informed consent signed (enrolment), patients 
that still meet eligibility criteria (according to available information) will begin the 
CCT run-in; this will be considered day 1 of the CCT run-in
∀
On day 1 of the CCT run-in, the following will be completed by the CCT coach:
o
Provide initial training to patient on use of the CCT program; patients with 
little or no experience using a personal computer (laptop/desktop) or tablet 
device may require additional training from the CCT coach on how to properly 
use the CCT device
o
Supervise the first CCT session at the clinic to ensure the patient is able to 
demonstrate proper use of the CCT device and program
o
Allocate a CCT device to the patient, if needed (i.e. if patient does not have or 
is not willing to use their own device or does not have reliable internet access)
∀
During the CCT run-in (2 weeks), the CCT coach will:
o
Proactively contact patient at least weekly (although more frequent contacts 
may be warranted) to provide guidance and coaching about their progress, and 
ensure that the CCT program is problem-free
o
Monitor CCT compliance remotely via CCT portal on an ongoing basis (at 
least weekly although more frequent checks are recommended) and follow up 
with patients as necessary to discuss compliance status and encourage them to 
complete CCT exercises to target








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All patients with Hb drop below 100 g/L (10 g/dL) or absolute decrease >20 g/L (2 g/dL) 
since baseline (Visit 2) will need to be followed up post-end of study until value returns to 
baseline/normal value, or resolution (per investigator’s judgment).






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For the definition of MCCB neurocognitive composite score, please refer to Section 7.1.
7.3.2
Secondary endpoint analyses
A specification of secondary endpoints is provided in Section 2.1.3.
The analyses of efficacy-related secondary endpoints will be performed in FAS. The same 
model utilized for the primary endpoint will be fitted for change from baseline in the overall 
MCCB composite score. For change from baseline in PANSS total score after 12 weeks of 
treatment, an MMRM model that includes treatment, age and visit as factors, the 
corresponding baseline value as a covariate, as well as treatment-by-visit and baseline-by-
visit interactions will be fitted. For change from baseline in SCoRS score after 12 weeks of 
treatment, an ANCOVA model that includes treatment and age as factors, and its 
corresponding score at baseline as a covariate will be fitted. The adjusted mean values as well 
as the treatment group contrasts at week 12 will be presented together with the 95% 
confidence intervals (CI). All p-values will be considered descriptive.
For the percentage of patients with (S)AEs (including clinically relevant abnormalities of 
physical examination, vital signs, ECG and laboratory tests), comparison will be made for (BI 
424809 + CCT) group vs. (placebo + CCT) group on TS together with descriptive statistics.
For other secondary endpoints, only descriptive statistics and exploratory analyses will be 
provided.
Other analyses may be considered if deemed necessary and the details will be provided in the 
TSAP.
7.3.4
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 the end of the REP, a period of 11 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 


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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 the 
database lock.
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. Treatment 
groups will be compared descriptively with regard to distribution parameters as well as with 
regard to frequency and percentage of patients with abnormal values or clinically relevant 
abnormal values.
Vital signs, physical examinations, or other safety-relevant data observed at screening (Visit 
1), baseline (Visit 2), 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.
7.5
HANDLING OF MISSING DATA
Every effort will be made to collect complete data at the pre-planned time points. Handling of 
missing data in MCCB tests will follow the MCCB Manual (available in the ISF). In general, 
for completely missing visit missing data will not be imputed and will be handled through the 
MMRM under the “missing at random” assumption. BI standards will be used for missing 
data in AE, safety lab, 
. The missing data handling rules will be further 
specified in details in the TSAP.


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7.6
RANDOMIZATION
Eligible patients will be stratified by age (age 18-40 and age 41-50) and will be randomized 
with 1:1 ratio to the BI 425809 10 mg + CCT and placebo + CCT arms. The randomization 
will be implemented in blocks to achieve balanced allocation to each of the two treatment 
arms. The block size will be documented in the clinical trial report (CTR).  
The randomization will be conducted via an IRT. BI will arrange for the randomization and 
the packaging and labelling of trial medication. The randomization list will be generated by a 
validated system, which utilizes a pseudo-random number generator to make the resulting 
treatment sequence both reproducible and non-predictable. Access to the randomization 
codes will be controlled and documented.
7.7
DETERMINATION OF SAMPLE SIZE
It is planned to randomize a total of 200 subjects in the trial, because this sample size is
considered sufficient to achieve the aims of this exploratory trial.
Based on this sample size, the probabilities for observing a mean difference < 0.3, 0.3 - 0.4, 
or > 0.4 between the treatment arm and the placebo arm on the change from baseline MCCB
neurocognitive composite score after 12 weeks of treatment are displayed in Table 7.7: 1. 
For these calculations, the following assumptions are made. A total of 200 patients are
randomized. Assuming a10% dropout rate this leads to a total of 180 evaluable subjects. 
Table 7.7: 1 
Probabilities of observing a mean difference in the primary endpoint 
< 0.3, 0.3 – 0.4, or > 0.4 for treatment relative to placebo arm under 
different scenarios (90 evaluable patients per arm).
True effect size relative 
to placebo
Probability to observe a mean difference
of
(BI 425809 vs. Placebo)
BI 425809
< 0.3
0.3 – 0.4
> 0.4.
0.5
0.092
0.159
0.749
0.45
0.158
0.204
0.638
0.4
0.251
0.242
    0.507
0.35
0.362
0.270
0.368
0.3
0.493
0.255
0.252
                 0.25
      0.632
0.211
0.157
0.2
0.748
0.163
0.089
The calculation was performed using R version 3.3.2, based on 10000 simulations.


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Hence, assuming the true effect size is 0.45, there is a 64% probability to observe a mean 
difference between the treatment and placebo arms greater than 0.4, and an 84% probability 
to observe a mean difference of at least 0.3. On the other hand, assuming the true effect size 
is only 0.2, there is a 75% probability of observing a mean difference less than 0.3, and a 
91% probability of observing a mean difference of at most 0.4.


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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), and other current relevant regulations. Investigators and site 
staff must adhere to these principles.
Standard medical care (prophylactic, diagnostic and therapeutic procedures) remains the 
responsibility of the treating physician of the patient.
The investigator will inform the sponsor immediately of any urgent safety measures taken to 
protect the trial patients against any immediate hazard, as well as of any serious breaches of 
the protocol or of ICH-GCP.
The Boehringer Ingelheim transparency and publication policy can be found on the following 
web page: trials.boehringer-ingelheim.com. The rights of the investigator and of the sponsor
with regard to publication of the results of this trial are described in the investigator contract. 
As a rule, no trial results should be published prior to finalization of the CTR.
The certificate of insurance cover is made available to the investigator and the patients, and is
stored in the ISF.
8.1
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.


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8.2
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED CONSENT
This trial will be initiated only after all required legal documentation has been reviewed and 
approved by the respective IRB / IEC and Competent Authority (CA) according to national 
and international regulations. The same applies for the implementation of changes introduced 
by amendments.
Prior to patient participation in the trial, written informed consent must be obtained from each 
patient (or the patient’s legally accepted representative) according to ICH-GCP and to the 
regulatory and legal requirements of the participating country. Each signature must be 
personally dated by each signatory and the informed consent and any additional patient-
information form retained by the investigator as part of the trial records. A signed copy of the 
informed consent and any additional patient information must be given to each patient or the 
patient’s legally accepted representative.
Re-consenting may become necessary when new relevant information becomes available and 
should be conducted according to the sponsor’s instructions.
If study conduct may need to be adjusted during the COVID-19 pandemic (see Section 6.2
and Section 10.5), the patient must be made aware of any modifications and provide their 
agreement to the modifications prior to them being implemented.
The consent and re-consenting process should be properly documented in the source 
documentation.
8.3
RECORDS
CRFs for individual patients will be provided by the sponsor. See Section 4.1.5.2 for rules 
about emergency code breaks. For drug accountability, refer to Section 4.1.8.
8.3.1
Source documents
In accordance with regulatory requirements, the investigator should prepare and maintain 
adequate and accurate source documents and trial records that include all observations and 
other data pertinent to the investigation on each trial patient. Source data as well as reported 
data should follow the “ALCOA principles” and be attributable, legible, contemporaneous, 
original and accurate. Changes to the data should be traceable (audit trail).
Data reported on the eCRF must be consistent with the source data or the discrepancies must 
be explained.
The current medical history of the patient may not be sufficient to confirm eligibility for the 
trial and the investigator may need to request previous medical histories and evidence of any 
diagnostic tests. If medical records cannot be obtained prior to randomization, a phone call 
with the treating physician(s) detailing eligibility information must be conducted and 
documented, and the documentation filed with the subject’s source records. If medical 
records cannot be obtained and a phone call with the treating physician(s) cannot be 
conducted, the CTM or CTL should be contacted for further discussion.


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8.3.2
Direct access to source data and documents
The sponsor will monitor the conduct of the trial by regular on-site monitoring visits and in-
house data quality review. The frequency of site monitoring will be determined by assessing 
all characteristics of the trial, including its nature, objective, methodology and the degree of 
any deviations of the intervention from normal clinical practice.
The investigator /institution will allow site trial-related monitoring, audits, IRB / IEC review 
and regulatory inspections. Direct access must be provided to the eCRF and all source 
documents/data, including progress notes, copies of laboratory and medical test results, which 
must be available at all times for review by the CRA, auditor and regulatory inspector (e.g.
United States Food and Drug Administration). They may review all eCRFs and informed 
consents. The accuracy of the data will be verified by direct comparison with the source 
documents described in Section 8.3.1. The sponsor will also monitor compliance with the 
protocol and ICH-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
Individual patient data obtained as a result of this trial is considered confidential and 
disclosure to third parties is prohibited with the exceptions noted below. Patient privacy will 
be ensured by using patient identification code numbers.
Data protection and data security measures are implemented for the collection, storage and 
processing of patient data in accordance with the principles 6 and 12 of the World Health 
Organization Good Clinical Practices handbook and the EU General Data Protection 
Regulation.


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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 
Not applicable
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 SUSARs occurring with 
the trial medication until 30 days after LPLT at their site.
Early termination of the trial is defined as the premature termination of the trial due to any 
reason before the end of the trial as specified in this protocol.
Temporary halt of the trial is defined as any unplanned interruption of the trial by the 
sponsor with the intention to resume it.
Suspension of the trial is defined as an interruption of the trial based on a Health Authority 
request.
The IEC / CA in each participating EU member state will be notified about the trial
milestones according to the respective laws.
A final report of the clinical trial data will be written only after all patients have completed 
the trial in all countries (EU or non-EU) to incorporate and consider all data in the report. The 
sponsor will submit to the EU database a summary of the final trial results within one year 
from the end of a clinical trial as a whole, regardless of the country of the last patient (EU or 
non-EU).
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL
The trial is sponsored by Boehringer Ingelheim (BI).


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A Coordinating Investigator is responsible to coordinate investigators at the different sites 
participating in this trial. Tasks and responsibilities are defined in a contract. 
Relevant documentation on the participating (Principal) Investigators (e.g. their curricula 
vitae) will be filed in the ISF.
The investigators will have access to the BI clinical trial portal Clinergize to access 
documents provided by the sponsor. 
BI has appointed a CTL, responsible for coordinating all required activities, in order to 
-
manage the trial in accordance with applicable regulations and internal SOPs,
-
direct the clinical trial team in the preparation, conduct, and reporting of the trial,
-
ensure appropriate training and information of CTMs, CRAs, and investigators of 
participating countries.
The organisation of the trial in the participating countries will be performed by the respective 
local or regional BI-organisation (Operating Unit, OPU) in accordance with applicable 
regulations and BI SOPs, or by a Contract Research Organisation (CRO) with which the 
responsibilities and tasks will have been agreed and a written contract filed before initiation 
of the clinical trial.
Data Management and Statistical Evaluation will be done by BI according to BI SOPs.
Tasks and functions assigned in order to organise, manage, and evaluate the trial are defined 
according to BI SOPs. A list of responsible persons and relevant local information can be 
found in the ISF.
A central laboratory service, a central images service for ECG, an IRT vendor and a vendor 
for delivery of the CCT exercises will be used in this trial. Details will be provided in the 
Central Laboratory Manual, ECG Manual, IRT Manual and CCT Manual, respectively, 
available in the ISF.




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9.2
UNPUBLISHED REFERENCES
U13-2547
Nonclinical Report 1310-e. Increase of glycine in rat CSF by BI 425809.


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Investigator Brochure BI 425809, 1346.P1, 1346.P2.
c02820512-01
Final Clinical Trial Report (1346.1).  Safety, tolerability, and 
pharmacokinetics of single rising oral doses of BI 425809 in healthy male 
subjects (partially randomised, single-blind, placebo-controlled) and 
investigation of relative bioavailability and food effect of BI 425809 (open-
label, randomised, three-way cross-over) The single rising dose (SRD) part 
of this study was prematurely discontinued because the maximum tolerated 
dose was reached.  05 May 2015
c03355329-01
Final Clinical Trial Document (1346.10). Relative bioavailability of single 
oral dose of BI 425809 when administered alone or in combination with 
multiple oral doses of itraconazole in healthy male subjects (an openlabel, 
two-period, fixed-sequence trial). 03 Dec 2015
c03559983-04
Final Protocol (1346.9)  A phase II randomzed, double-blinded, placebo-
controlled parallel group trial to examine the efficacy and sfety of 4 oral 
doses of BI 425809 once daily over 12 week treatment period in patients 
with Schizophrenia (28 Mar 2019)
c03572014-01
Final Clinical Trial Report (1346.2). Safety, tolerability, and 
pharmacokinetics of multiple rising doses of BI 425809 tablets given orally 
once or twice daily for 12 days to young and elderly healthy male and 
female volunteers (randomised, double-blind, placebo-controlled within 
dose groups Phase I study) (Part 1) and comparison of pharmacokinetics of 
a single oral dose of BI 425809 after oral administration in the morning 
versus oral administration in the evening in young healthy male and female 
volunteers (randomised, two-sequence, open, two period, two-way cross 
over) (Part 2). 04 Jul 2016.
c03724403-01     Final Clinical Trial Report (1346.3).  Non-randomised, open label, 
sequential-group study to assess the pharmacokinetics and 
pharmacodynamic effect of different multiple oral doses of BI 425809 in 
healthy male volunteers.  01 Feb 2016.
c03760676-01
Final Clinical Trial Report (1346.4).  Safety, tolerability and 
pharmacokinetics of single rising oral doses of BI 425809 in healthy 
Japanese and Chinese male subjects (randomised, doubleblind, placebo-
controlled design within dose groups). 17 Mar 2016.
c08949593-01
Final Clinical Trial Report (1346.22). A study to investigate the effects of 
multiple doses of BI 425809 on the single dose pharmacokinetics of 
cytochrome P450 substrates (midazolam, warfarin and omeprazole) and a 
P-glycoprotein substrate (digoxin) administered orally in an open-label, 
one-sequence trial in healthy male subjects. 01 Aug 2016.


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Final Clinical Trial Report (1346.18). Effects of rifampicin on the 
pharmacokinetics of BI 425809 following oral administration in healthy 
male subjects (an open-label, two-period, fixedsequence trial). 09 Jan 2018.
001-MCS-36-472 Boehringer Ingelheim SOP: „Standart Operation Procedure“, current 
version, IDEA for CON


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10.
APPENDICES
10.1
INSTRUCTIONS FOR USE
Further instructions for use of the CCT program will be described in the CCT Manual 
available in the ISF.
Additionally, instructions for use of the central laboratory service, central images service for 
ECG and IRT system will be described in the Central Laboratory Manual, ECG Manual and 
IRT Manual, respectively, available in the ISF.


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10.5
POTENTIAL MODIFICATION OF TRIAL CONDUCT IN CASE OF 
RESTRICTIONS DUE TO COVID-19
As mentioned in Section 6.2, in case of any new restrictions during the COVID-19 pandemic
and for patients already in the study, study conduct may need to be adjusted based on the 
investigator’s discretion (and agreed with the sponsor). 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 cases, when it is impossible to conduct the visits at the trial site, visits may be 
performed at the patient’s home or remotely (via telephone and/or internet based means of 
communication). The visits may also be performed as a combination of home and remote 
visits. Based on a thorough benefit-risk assessment (see Section 1.4), the visit procedures 
may be adjusted for the purpose of particular visits, whereby critical safety measures will 
remain in place. All home/remote visits need to be discussed with and approved by the 
sponsor.
Local regulatory and legal requirements of the participating country need to be respected for 
all modifications. Patients need to be informed about the modifications and agree to them 
before implementation (see Section 8.2).
Under these circumstances, the below modifications can be considered. 
Remote visit
If a patient is not able to come to the site for an in-clinic trial visit, a remote visit (by phone) 
should be performed instead and all assessments that can be done by phone performed.


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The following study data may be collected/reported during phone contacts: Adverse events, 
concomitant therapies, C-SSRS, birth control check (for women of childbearing potential), 
SCoRS and PANSS, 
, and study medication and CCT compliance checks. Patients can 
report and/or send photos of study medication kit used to their site staff, if needed and 
possible.
Additional guidance for assessing specific symptoms as part of adverse event check during 
phone contacts is available to investigators and should be followed.
MCCB cannot be done via phone, but in certain situations it may be possible to complete 
some MCCB sub-tests (enough to derive a composite score) via videoconference between the 
rater and the patient, if agreed with sponsor. If necessary during COVID-19 pandemic, based 
on the REP for BI 425809 (as defined in Section 1.2), Visit 6/(e)EoT Visit may be delayed up 
to 10 days following the last dose of trial medication, in case this helps to facilitate an in-
clinic trial visit with MCCB assessment.
Safety and other laboratory tests, vital signs, ECG
If blood sampling for central lab at the trial site is not possible, safety lab analyses can be 
performed at a local laboratory. The results of the lab tests must be transferred to the 
investigator who ensures medical review and proper documentation in the eCRF.
Recommended minimum safety lab parameters are: Hematology, Urea (BUN), Creatinine, 
eGFR, liver enzymes, pregnancy test (for WOCBP).
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).
Direct-to-patient shipment of trial medication
If a patient is not able to come to Visit 3, Visit 4 or Visit 5 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. Investigators should conduct phone visits first to discuss adverse events, 
concomitant therapies, C-SSRS, birth control check, and assess study medication and CCT 
compliance. If possible and as per investigator’s clinical judgement, safety laboratory tests 
should be done at a local laboratory.


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
11.1
GLOBAL AMENDMENT 1
Date of amendment
21 DECEMBER 2018
EudraCT number
EU number
2018-002740-82
BI Trial number
1346-0038
BI Investigational Product(s)
BI 425809
Title of protocol
A phase II randomized, double-blinded, placebo-
controlled parallel group trial to examine the
efficacy and safety of BI 425809 once daily with 
adjunctive Computerized Cognitive Training over 
12 week treatment period in patients with 
schizophrenia
To be implemented only after approval of the IRB / IEC / Competent 
Authorities
X
To be implemented immediately in order to eliminate hazard –
IRB / IEC / Competent Authority to be notified of change with request for 
approval
Can be implemented without IRB / IEC / Competent Authority approval as 
changes involve logistical or administrative aspects only
Section to be changed
Lay Title
Description of change
“combined with” changed to “together with”
Rationale for change
To simplify language and better describe intended 
use of Computerized Cognitive Training for this 
study
Section to be changed
CLINICAL TRIAL PROTOCOL SYNOPSIS
Description of change
“proof of clinical concept (PoCC)” changed to 
“proof of concept (PoC)” 
Rationale for change
To reflect exploratory nature of the study
Section to be changed
Flow Chart
Description of change
“Days” from first randomized treatment amended 
for visits during the treatment period
Rationale for change
Visit 2 (randomization) is more accurately zero (0) 
days from first randomized treatment, rather than 1 
day from first randomized treatment; number of 
days from first randomized treatment was revised 
accordingly for Visit 3, Visit 4, Visit 5 and Visit 
6/EoT
Section to be changed
Flow Chart
Description of change
Addition to footnote 9 describing audio recording 
of patient and study partner interviews for SCoRS 
and PANSS assessments
Rationale for change
To explain that interviews will be audio recorded 


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for Quality Control purposes
Section to be changed
ABBREVIATIONS
Description of change
Proof of Clinical Concept (PoCC) changed to 
Proof of Concept (PoC)
Rationale for change
PoCC will no longer be referenced in the protocol, 
replaced with PoC
Section to be changed
1.1
Description of change
Revised background information on cognitive 
training
Rationale for change
To highlight that cognitive training will be used in 
this study only as background cognitive stimulation
Section to be changed
1.3
Description of change
Revised points regarding cognitive training
Rationale for change
To highlight that cognitive training will be used in 
this study only as background cognitive stimulation
Section to be changed
1.4
Description of change
PoCC changed to PoC
Rationale for change
Clarification
Section to be changed
1.4
Description of change
Revised description of cognitive training
Rationale for change
To highlight that cognitive training will be used in 
this study only as background cognitive stimulation
Section to be changed
2.1.1
Description of change
PoCC changed to PoC and explanatory text added
Rationale for change
To reflect the exploratory nature of the study
Section to be changed
3.3.3
Description of change
Exclusion criterion no. 24 was amended to remove 
exception for Benzodiazepines
Rationale for change
Benzodiazepines are not included in the urine drug 
screen
Section to be changed
3.3.3
Description of change
New exclusion criterion no. 28 added to exclude 
patients with an allergy to BI 425809 and/or any of 
the excipients (including lactose) or placebo 
ingredients
Rationale for change
Additional safety consideration
Section to be changed
4.2.1
Description of change
Revised wording regarding decision for CCT 
schedule
Rationale for change
To better explain choice of CCT schedule for the 
study
Section to be changed
4.3
Description of change
Removed wording regarding the planned 
automated notifications and reminders
Rationale for change
Automated notifications and reminders will not be 
used


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Section to be changed
7.1
Description of change
PoCC changed to PoC
Rationale for change
Clarification
Section to be changed
8
Description of change
Removal of reference to medical device regulations
Rationale for change
Previous text does not apply to this study
11.2
GLOBAL AMENDMENT 2
Date of amendment
02 OCTOBER 2019
EudraCT number
EU number
2018-002740-82
BI Trial number
1346-0038
BI Investigational Medicinal 
Product(s)
BI 425809
Title of protocol
A phase II randomized, double-blinded, placebo-
controlled parallel group trial to examine the
efficacy and safety of BI 425809 once daily with 
adjunctive Computerized Cognitive Training over 
12 week treatment period in patients with 
schizophrenia
Global Amendment due to urgent safety reasons
Global Amendment
X
Section to be changed
Clinical Trial Protocol Synopsis
Description of change
Revision to Statistical Methods section to indicate 
change from screening to baseline MCCB 
neurocognitive composite score, rather than 
baseline to screening
Rationale for change
To correct typo
Section to be changed
Flow Chart
Description of change
CCT compliance check and CCT progress 
reviewed and re-training/reminders to patients as 
needed added during Screening Period
Rationale for change
To align with Section 6.2
Section to be changed
Flow Chart, footnote (*)
Description of change
Recommendation for screening laboratory samples 
be collected as soon as possible following 
enrolment
Rationale for change
To encourage assessment of laboratory results prior 
to start of CCT run-in
Section to be changed
Flow Chart, footnote (*)
Description of change
Allowance for an extension of the Screening 
Period of up to 10 days (for total 38 days) in case 
cannabis re-testing per exclusion criterion 24 is 
performed


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Rationale for change
Logistical, to allow for some time to pass (per 
investigator discretion) between initial urine drug 
screen and cannabis re-test
Section to be changed
Flow Chart, footnotes 1 and 12
Description of change
Addition of word “preferably” to describe timing 
of procedures in relation to CCT run-in
Rationale for change
To clarify that defined overall screening window 
from Visit 1 to first drug administration should be 
the priority consideration
Section to be changed
Flow Chart, footnote 3
Description of change
Clarification that a serum pregnancy test will be 
performed by central lab if urine test positive, 
independent of Investigator discretion
Rationale for change
To align with central laboratory manual
Section to be changed
Flow Chart, footnote 12
Description of change
Clarify that once CCT run-in compliance is 
established, no further CCT should be completed 
until patient is randomized, and that CCT run-in 
should not be repeated for re-screened patients if 
already confirmed before screening failure
Rationale for change
To minimize CCT exposure prior to randomization
Section to be changed
3.3.3
Description of change
Addition to Exclusion criterion 19 to exclude 
patients with known history of HIV infection 
“based on review of medical history”
Rationale for change
Clarification that active HIV testing at Visit 1 is 
not intended
Section to be changed
3.3.3
Description of change
Revision of Exclusion criterion 24 to remove 
timeframe for cannabis re-testing
Rationale for change
Timeframe for re-testing should be at the 
investigator’s discretion and based on when the 
patient last used cannabis
Section to be changed
4.2.1
Description of change
Removal of statement that CCT sessions must be 
minimum 10 consecutive minutes to be included in 
weekly accrual time
Rationale for change
CCT program does not identify short 
training segments for site users 
Section to be changed
4.3
Description of change
Add that site should discuss with patient to 
determine reason if the number of doses taken is 
greater than 100%
Rationale for change
Comment required in eCRF if the number of doses 
taken is greater than 100%, per FDA request for all 
CNS active medication


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Section to be changed
4.3
Description of change
Replacement of statement that CCT sessions must 
be minimum 10 consecutive minutes to be included 
in weekly accrual time with preference for training 
to be done for a minimum of 10 minutes
Rationale for change
CCT program does not identify short 
training segments for users
Section to be changed
4.3
Description of change
Addition of word “preferably” to describe timing 
of procedures in relation to CCT run-in
Rationale for change
To clarify that defined overall screening window 
from Visit 1 to first drug administration should be 
the priority consideration
Section to be changed
4.3 and 6.2
Description of change
Clarify that once CCT run-in compliance is 
established, no further CCT should be completed 
until patient is randomized
Rationale for change
To minimize CCT exposure prior to randomization
Section to be changed
4.3
Description of change
Revision of description of protocol deviation for 
CCT non-compliance
Rationale for change
Clarification
Section to be changed
5.2.6.2
Description of change
To provide clarification regarding the process for 
AE collection
Rationale for change
Clarification
Section to be changed
6.2
Description of change
The MCCB assessments at Visit 4 and (e)EoT Visit 
must be started at the same time of the day as at 
Visit 2 (+/- 60 minutes)
Rationale for change
The Visit 2 MCCB assessment (not the Visit 1 
MCCB assessment) should be considered as 
baseline for start time of subsequent MCCB 
assessments
Section to be changed
6.2, 6.2.1, 6.2.2
Description of change
Addition of word “preferably” to describe timing 
of procedures in relation to CCT run-in
Rationale for change
To clarify that defined overall screening window 
from Visit 1 to first drug administration is the 
priority consideration
Section to be changed
6.2.1
Description of change
Addition of recommendation to collect Visit 1 
laboratory samples as early as possible in the 
screening period
Rationale for change
To encourage assessment of laboratory results prior 
to start of CCT run-in


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Section to be changed
6.2, 6.2.1 and 6.2.2
Description of change
Deletion of statements indicating provision of 
related CCT device equipment
Rationale for change
No related equipment to be provided
Section to be changed
6.2 and 6.2.1
Description of change
Addition of encouragement for more frequent 
checks of CCT compliance during run-in
Rationale for change
To allow more timely patient follow-up if 
compliance not meeting eligibility requirements
Section to be changed
6.2.1 and 6.2.2
Description of change
Clarification at all relevant visits that a serum 
pregnancy test will be performed by central lab if 
urine test positive, independent of Investigator 
discretion
Rationale for change
To align with central laboratory manual
Section to be changed
6.2.1
Description of change
Addition of reason for CCT device allocation 
Rationale for change
To avoid CCT compliance issues due to patient’s 
lack of internet availability
Section to be changed
6.2.1
Description of change
Clarify that CCT run-in should not be repeated for 
re-screened patients if already confirmed before 
screening failure
Rationale for change
To minimize CCT exposure prior to randomization
Section to be changed
6.2.2
Description of change
Clarification that EoT visit cannot be done before 
Day 84, rather than Day 85
Rationale for change
To align with changes to Flow Chart in Global 
Amendment 1
Section to be changed
6.2.2
Description of change
Deletion of instructions at EoT relating to 
procedures in the event of positive pregnancy test
Rationale for change
To correct error
Section to be changed
7
Description of change
Slight changes to wording (grammatical)
Rationale for change
For clarity and to correct typo
Section to be changed
7.3.1
Description of change
Revision to indicate change from screening to 
baseline MCCB neurocognitive composite score, 
rather than baseline to screening
Rationale for change
To correct typo
Section to be changed
8
Description of change
Addition of statement that the trial will be carried 
out in accordance with the Medical Devices 
Directive and the harmonised standards for 
Medical Devices


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Rationale for change
Sponsor to provide ECGs as loaned equipment, 
which would be considered a medical device
Section to be changed
8.1
Description of change
Deletion of reference to Clinergize as an electronic 
ISF
Rationale for change
To reflect the requirement for all original records 
generated at a site to be retained within the local 
ISF on-site 
Section to be changed
10.4
Description of change
Revision of Day numbers in Table 10.4.1: 1
Rationale for change
To align with changes to Flow Chart in Global 
Amendment 1
Section to be changed
11.1
Description of change
For previous Global Amendment 1, “X” placed in 
tick box associated with implementation 
instruction “To be implemented only after approval 
of the IRB / IEC / Competent Authorities”
Rationale for change
Tick box previously not filled
11.3
GLOBAL AMENDMENT 3
Date of amendment
21 Jul 2020
EudraCT number
EU number
2018-002740-82
BI Trial number
1346-0038
BI Investigational Medicinal 
Product(s)
BI 425809
Title of protocol
A phase II randomized, double-blinded, placebo-
controlled parallel group trial to examine the
efficacy and safety of BI 425809 once daily with 
adjunctive Computerized Cognitive Training over 
12 week treatment period in patients with 
schizophrenia
Global Amendment due to urgent safety reasons
Global Amendment
X
Section to be changed
CLINICAL TRIAL PROTOCOL SYNOPSIS 
Main in- and exclusion criteria
Description of change
Remove reference to psychotropic medications in 
general with examples
Rationale for change
Alignment with change to section 3.3.2 inclusion 
criterion 4 
Section to be changed
FLOW CHART
Description of change
For the Trial Period corresponding to the Follow-
up Visit, change name from “End of Trial” to “End 
of Study”


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Rationale for change
Avoid any confusion with the End of Trial (EoT) 
Visit
Section to be changed
FLOW CHART
Description of change
Add SCoRS assessment to Visit 1 (Screening)
Rationale for change
Pre-exposure to SCoRS at Visit 1 will allow Study 
Partners to anticipate the questions that will be 
asked at the baseline SCoRS assessment at Visit 2 
and observe the patient more closely leading up to 
the baseline assessment, thereby allowing for 
enhanced quality of the Study Partner contribution 
to the baseline SCoRS assessment
Section to be changed
FLOW CHART footnote (*****)
Description of change
Instruction that, following patient’s trial 
participation, only any cancers of new histology 
and exacerbations of existing cancer, trial treatment 
related SAEs and trial treatment related AESIs of 
which the investigator may become aware of
should be reported and only via the BI SAE form, 
in alignment with wording in Section.5.2.6.2
Rationale for change
Additional reminder to investigator
Section to be changed
FLOW CHART footnotes 1, 5 and 6
Description of change
Added clarification that split visits are to be done 
on 2 consecutive calendar days
Rationale for change
Avoid the possible misinterpretation of the word 
“sequential” that could lead to a split visit being 
done a Friday and the following Monday
Section to be changed
FLOW CHART footnote 13
Description of change
Additional note that any hemoglobin decrease >20 
g/L (2 g/dL) since baseline (Visit 2) or leading to 
symptoms of anemia (e.g. dyspnea, dizziness, etc) 
will require safety follow-up with safety lab at the 
next visit(s), or earlier if considered necessary by 
the investigator
Rationale for change
Reminder for investigators, in alignment with new 
text in Section 5.2.6.2
Section to be changed
FLOW CHART footnote 14
Description of change
Additional note that all patients with hemoglobin 
drop below 100 g/L (10 g/dL) or absolute decrease 
>20 g/L (2 g/dL) since baseline (Visit 2) will need 
to be followed up post-end of study until value 
returns to baseline/normal value, or resolution (per 
investigator’s judgment)
Rationale for change
Reminder for investigators, in alignment with new 
text in Section 6.2.3
Section to be changed
1.2
Description of change
Various changes to Drug Profile wording based on 
updated IB


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Rationale for change
Alignment with updated Investigator’s Brochure
Section to be changed
1.4
Description of change
Various changes to Benefit-Risk Assessment 
wording based on updated IB
Rationale for change
Alignment with updated Investigator’s Brochure
Section to be changed
3.3
Description of change
Updated planned number of trial centres and 
countries participating in the trial, indicated as 
range
Rationale for change
To reflect current planned number of trial centres 
and countries participating in the trial
Section to be changed
3.3.2 inclusion criterion 4
Description of change
Remove reference to psychotripic medications in 
general with examples
Rationale for change
Greater clarity regarding the medications that 
pertain to this inclusion criterion
Section to be changed
3.3.2 inclusion criterion 6
Description of change
Clarification as a footnote to the inclusion criterion 
itself that if the CCT run-in compliance threshold 
(i.e. at least 2 hours per week for two weeks, 
totalling 4 hours CCT) is not met, then the patient 
may still be randomized pending a documented 
discussion between the investigator and the CTM 
or CTL
Rationale for change
Alignment with existing wording in Section 4.3
Section to be changed
3.3.2 inclusion criterion 7
Description of change
Remove specific mention of at-home CCT 
exercises
Rationale for change
Overlap with inclusion criterion 6 which pertains 
to patient’s ability to comply with at-home CCT 
exercises
Section to be changed
3.3.3
Description of change
New exclusion criterion 29 for patients with known 
active infection with SARS-CoV-2 within the last 
30 days prior to randomization
Rationale for change
Due to COVID-19 increased risk for study patients
Section to be changed
3.3.4.1
Description of change
Addition of additional criterion for discontinuation 
of trial treatment for patients that experience severe 
of serious symptomatic infection with SARS-CoV-
2
Rationale for change
Due to possible increased risk of COVID-19 
complications for patients taking BI 425809
Section to be changed
4.1.4
Description of change
Adjustment to repeated text in same section
Rationale for change
Remove unnecessary (repeated) text


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Section to be changed
4.1.4
Description of change
Added clarification that split visits are to be done 
on 2 consecutive calendar days
Rationale for change
Avoid the possible misinterpretation of the word 
“sequential” that could lead to a split visit being 
done a Friday and the following Monday
Section to be changed
4.1.4
Description of change
Including the possibility for trial medication to be 
shipped from the site to the patient if necessary due 
to the COVID-19 pandemic
Rationale for change
Allow patients that cannot visit the site due to 
COVID-19 to continue on trial medication if 
judged favourable and safe by the investigator
Section to be changed
4.2.1
Description of change
Added the word “only” when describing patient’s 
use of their current antipsychotic and concomitant 
psychotropic medications during the trial
Rationale for change
Additional clarity that new antipsychotic and 
psychotropic medications are discouraged during 
the treatment period
Section to be changed
4.2.1
Description of change
Added instructions that CCT run-in during 
screening period should stop once eligibility is 
confirmed
Rationale for change
Limit CCT exposure prior to baseline (Visit 2)
Section to be changed
4.2.2.1
Description of change
Added text that if patients take antihistaminic, 
benzodiazepine or other sedative medication less 
than 8 hours before MCCB, then the visit should 
preferably (if possible) be rescheduled within the 
allowed visit window
Rationale for change
Suggested process to avoid patients completing 
MCCB within 8 hours of taking antihistaminic, 
benzodiazepine or other sedative medication
Section to be changed
5.1
Description of change
Add that SCoRS will be done at screening (Visit 1)
Rationale for change
Alignment with FLOW CHART
Section to be changed
Table 5.2.3: 1
Description of change
Remove (Stix) from Urinalysis category
Rationale for change
Correction; on-site dipstick (stix) is not being used 
for the indicated urinalysis tests
Section to be changed
5.2.6.2
Description of change
Define the individual patient´s end of study as the 
Follow-up Visit
Rationale for change
Clarification, in alignment with FLOW CHART 
footnote (*****)


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Section to be changed
5.2.6.2
Description of change
Remove the requirement to use fax when sending 
BI SAE form
Rationale for change
Some sites may not have access to fax and can use 
another method to send SAE form to BI
Section to be changed
5.2.6.2
Description of change
Additional note that any hemoglobin decrease >20 
g/L (2 g/dL) since baseline (Visit 2) or leading to 
symptoms of anemia (e.g. dyspnea, dizziness, etc) 
will require safety follow-up with safety lab at the 
next visit(s), or earlier if considered necessary by 
the investigator
Rationale for change
New safety information regarding risk of 
hemoglobin decrease
Section to be changed
6.2
Description of change
Change to more generic introductory wording for 
the various guidance points pertaining to conduct 
of the neuropsychological assessments
Rationale for change
Some points are required while others are 
preferred, so not accurate to characterize all points 
as requirements that need to be followed
Section to be changed
6.2
Description of change
Added clarification that split visits are to be done 
on 2 consecutive calendar days
Rationale for change
Avoid the possible misinterpretation of the word 
“sequential” that could lead to a split visit being 
done a Friday and the following Monday
Section to be changed
6.2
Description of change
Clarify that the CCT “coach”, not the patient, will 
need to create patient accounts within the 
Rationale for change
Only the CCT “coach”, and not the patient, is able 
to create patient accounts within the 
 
Section to be changed
6.2
Description of change
Mention potential modifications for trial conduct 
related in situations when patients might not be 
able to come to the site for the scheduled visit 
during the COVID-19 pandemic
Rationale for change
Adding reference to modifications described in 
Section 10.5
Section to be changed
6.2.1
Description of change
Add SCoRS as an assessment to be done during the 
screening period
Rationale for change
Alignment with FLOW CHART
Section to be changed
6.2.1


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Description of change
Added instructions that re-screening must be 
registered in IRT
Rationale for change
To align with established procedures for registering 
re-screened patients in IRT
Section to be changed
6.2.2
Description of change
Added reminder (applicable to Visit 2 and as 
needed throughout the treatment period) that 
patients should avoid taking antihistaminic, 
benzodiazepine or other sedative medication within 
8 hours of MCCB visits, if applicable
Rationale for change
Avoid patients completing MCCB within 8 hours 
of taking antihistaminic, benzodiazepine or other 
sedative medication
Section to be changed
6.2.2
Description of change
Added clarification that split visits are to be done 
on 2 consecutive calendar days
Rationale for change
Avoid the possible misinterpretation of the word 
“sequential” that could lead to a split visit being 
done a Friday and the following Monday
Section to be changed
6.2.3
Description of change
Additional note that all patients with hemoglobin 
drop below 100 g/L (10 g/dL) or absolute decrease 
>20 g/L (2 g/dL) since baseline (Visit 2) will need 
to be followed up post-end of study until value 
returns to baseline/normal value, or resolution (per 
investigator’s judgment)
Rationale for change
New safety information regarding risk of 
hemoglobin decrease
Section to be changed
7.3.5
Description of change
Clarification that samples of patients who receive 
placebo treatment will not be analysed
Rationale for change
Bioanalysis of placebo samples is not necessary
Section to be changed
8.2
Description of change
Add text regarding the need for patients to provide 
consent to any modifications to trial conduct that 
may be required during the COVID-19 pandemic
Rationale for change
Ensure patient is made aware of and provides 
agreement for any modifications due to COVID-19
Section to be changed
10.5
Description of change
New section added describing potential 
modification of trial conduct in case of restrictions 
due to COVID-19, such as remote visits (by phone) 
and direct-to-patient trial medication shipment
Rationale for change
Guidelines for modifications to trial visits to be 
considered during COVID-19


 
 
 
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SAP_001.pdf: 
001-MCS-50-415_RD-01 (3.0) / Saved on: 18 Jan 2021
 
TRIAL STATISTICAL ANALYSIS PLAN
c36448622-01
BI Trial No.:
1346-0038
Title:
A phase II randomized, double-blinded, placebo-controlled 
parallel group trial to examine the efficacy and safety of BI 
425809 once daily with adjunctive Computerized Cognitive 
Training over 12 week treatment period in patients with 
schizophrenia
Clinical Trial Protocol (c20831949-05), including Global 
Protocol Amendment 1.0 (21 Dec 2018), Global Protocol 
Amendment 2.0 (02 Oct 2019), Global Protocol Amendment 3.0
(21 Jul 2020)
Investigational
Product(s):
BI 425809
Responsible trial 
statistician(s):
Phone: 
 
Fax: 
Date of statistical 
analysis plan:
10 OCT 2022 SIGNED
Version:
Final
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reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.


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1.
TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
1.
TABLE OF CONTENTS......................................................................................2
LIST OF TABLES...................................................................................................................4
2.
LIST OF ABBREVIATIONS ..............................................................................5
3.
INTRODUCTION.................................................................................................7
5.
ENDPOINTS(S) ....................................................................................................9
5.1
PRIMARY ENDPOINT(S) ..................................................................................9
5.2
SECONDARY ENDPOINT(S) ..........................................................................10
5.2.1
Key secondary endpoint(s).................................................................................10
5.2.2
Secondary endpoint(s) ........................................................................................10
6.
GENERAL ANALYSIS DEFINITIONS ..........................................................16
6.1
TREATMENT(S)................................................................................................16
6.2
IMPORTANT PROTOCOL DEVIATIONS....................................................16
6.3
SUBJECT SETS ANALYSED...........................................................................16
6.5
POOLING OF CENTRES .................................................................................19
6.6
HANDLING OF MISSING DATA AND OUTLIERS....................................19
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS ...................21
7.
PLANNED ANALYSIS......................................................................................22
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS.........22
7.2
CONCOMITANT DISEASES AND MEDICATION .....................................22
7.3
TREATMENT COMPLIANCE........................................................................22
7.4
PRIMARY ENDPOINT(S) ................................................................................23
7.4.1
Primary analysis of the primary endpoint(s) ...................................................23
7.5
SECONDARY ENDPOINT(S) ..........................................................................25
7.5.1
Key secondary endpoint(s).................................................................................25
7.5.2
(Other) Secondary endpoint(s) ..........................................................................25
7.5.2.1
Primary analysis of the secondary endpoints........................................................25
7.7
EXTENT OF EXPOSURE.................................................................................27
7.8
SAFETY ANALYSIS..........................................................................................27
7.8.1
Adverse Events ....................................................................................................28
7.8.2
Laboratory data ..................................................................................................30
7.8.3
Vital signs.............................................................................................................31


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7.8.4
ECG......................................................................................................................31
7.8.5
Others...................................................................................................................31
8.
TIMEPOINT OF RELEASE OF TREATMENT INFORMATION.............32
9. 
REFERENCES....................................................................................................33
11.
HISTORY TABLE..............................................................................................36




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2.
LIST OF ABBREVIATIONS
Term
Definition / description
AE
Adverse Event
AESI
Adverse Event of Special Interest
ALT
Alanine Aminotransferase
ANCOVA
Analysis of Covariance
AST
Aspartate Transaminase
ATC
Anatomical Therapeutic Chemical
AUC
Area under the curve
AUC0-tz
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to the last quantifiable data point
CCT
Computerized Cognitive Training
CI
Confidence Interval
Cmax
Maximum measured concentration of the analyte in plasma
COVID-19
Coronavirus Disease 2019
C-SSRS
Columbia Suicidal Severity Rating Scale
DILI
Drug Induced Liver Injury
GlyT1
Glycine Transporter 1
gMean
Geometric Mean
IPD
Important Protocol Deviation
MATRICS
Measurement and Treatment Research to Improve Cognition in 
Schizophrenia
MCCB
MATRICS Consensus Cognitive Battery
MedDRA
Medical Dictionary for Drug Regulatory Activities
M.I.N.I.
Mini-International Neuropsychiatric Interview
MMRM
Mixed-effect Model Repeated Measures
PANSS
Positive and Negative Syndrome Scale
PoC
Proof-of-concept
PT
Preferred Term
REML
Restricted Maximum Likelihood


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Term
Definition / description
REP
Residual Effect Period
SARS-CoV-2
Severe acute respiratory syndrome coronavirus 2
SCoRS
Schizophrenia Cognition Rating Scale
SOC
System Organ Class
WHO DD
World Health Organization Drug Dictionary




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5.2
SECONDARY ENDPOINT(S)
5.2.1
Key secondary endpoint(s)
Not applicable. No key secondary endpoints in this trial.
5.2.2
Secondary endpoint(s)
The secondary efficacy endpoints are:
∀
Change from baseline in MCCB overall composite T-score after 12 weeks of  
treatment
∀
Change from baseline in SCoRS total score after 12 weeks of treatment
∀
Change from baseline in PANSS total score after 12 weeks of treatment
The secondary safety endpoints is:
∀
Percentage of patients with (S)AEs
Unless otherwise specified, the secondary endpoints will be used as defined in CTP Section 5.
MCCB
MCCB overall composite T-score is derived from all 7 domains: 1) Speed of Processing, 2) 
Verbal Learning, 3) Working Memory, 4) Reasoning and Problem Solving, 5) Visual 
Learning, 6) Attention/Vigilance, and 7) Social Cognition.
SCoRS
SCoRS interviewer total score will be used for secondary endpoint analysis.
PANSS
PANSS has 30 items, each rated from 1 to 7 points. The PANSS total score will be calculated 
as the summation of the item scores, leading to a total score ranging from 30 to 210.
The PANSS total score is calculated only if the number of missing item scores is ≤6 (i.e. 
≤20% of the 30 items). Otherwise, the total score will be left as missing. See Section 6.6 for
imputation and derivation rules.


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENT(S)
For basic study information on treatments to be administered, assignment of treatment groups, 
selection of doses, refer to CTP Section 4. 
Table 6.1: 1 lists the two treatment arms in this study. Table 6.1: 2 defines the analysing 
treatment period for safety analysis. For this study, the residual effect period (REP) is defined 
as 11 days after the last dose of trial medication.
Table 6.1: 1
Treatment descriptions
Long Name
Short Name
Placebo + Computerized 
Cognitive Training
Placebo + CCT
BI 425809 10 mg + Computerized 
Cognitive Training
BI 10 mg + CCT
Table 6.1: 2
Analysing treatment periods (same for all treatment groups)
Analysing Treatment 
Period
Start Date
End Date (inclusive)
Screening
Date of informed consent
Date of the first treatment 
administration – 1 day
On-Treatment
Date of the first treatment 
administration
Date of the last treatment 
administration + REP
Follow-up
Date of the last treatment 
administration + REP + 1 day
Date of the last per protocol 
visit
Residual effect period (REP) is defined as 11 days after the last dose of study medication.
6.2
IMPORTANT PROTOCOL DEVIATIONS
Handling of iPDs in analysis is included in the DV domain specifications and stored within 
the TMF in EDMS. 
Identification of iPD will be finalized at database lock (DBL). For iPDs identifiable only from 
unblinded data, rules are pre-specified in the DV domain specification.
6.3
SUBJECT SETS ANALYSED
The following patient analysis sets are defined:
∀
Randomized Set (RS): includes all patients who signed informed consent and were 
randomized to receive either BI 425809 + CCT or placebo + CCT. Patients will be 
analysed as randomized.


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∀
Treated Set (TS): includes all patients in RS who were treated with at least one dose 
of the trial regimen (including both drug and CCT). TS will be used for safety 
analyses as well as demographics and baseline characteristics and treatment regimen 
exposure. Patients will be analysed under the actual trial regimen received at
randomization.
∀
Full Analysis Set (FAS): includes all patients in TS who had non-missing baseline 
and at least one non-missing post-baseline on-treatment measurement of the primary 
efficacy endpoint. FAS will be used for efficacy analyses. Patients will be analysed as 
randomized.




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6.5
POOLING OF CENTRES
This section is not applicable because centre/country is not included in the statistical model.
6.6
HANDLING OF MISSING DATA AND OUTLIERS
Unless otherwise specified, missing data will not be imputed and will remain missing. 
Potential outliers will be reported and analysed as observed.
MCCB
Handling of missing data in MCCB tests will follow the MCCB Manual (available in the 
ISF). See Section 10.1 for detailed descriptions and imputation rules.
EoT measurement of MCCB endpoints which were collected >12 days after the last study
medication intake date will not be included in the analysis.
SCoRS
For the 20-item SCoRS assessment, if six or more of the 20 items have missing response, 
which includes the response of “N/A”, for a subject at a visit, then the SCoRS total score for 
that subject at that visit is missing. If five or less of the 20 items have missing response, which 
includes the response of “N/A”, for a subject at a visit, then the item with missing response 
will be imputed first with the average of the non-missing item values for the subject at the 
visit, and then SCoRS total score for the subject at the visit will be derived as the sum of the 
non-missing item values and the imputed item values.


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PANSS
PANSS total and subscale scores will be calculated as sums of their constituting item scores.
If ≤20% of the items are missing in the calculation of the total or subscale scores, the missing 
items will be temporarily imputed with the mean of the non-missing item scores. The total or 
subscale score will then be calculated as the sum of the non-missing and imputed item scores.
For calculation of PANSS total score and the subscale scores, the maximum numbers of 
missing items allowed are:
PANSS total score:
6 out of 30
Positive Symptom:
1 out of 7
Negative Symptom:
1 out of 7
General Psychopathology:
3 out of 16
Emotional Expression:
0 out of 4
Emotional Experience:
0 out of 3
Marder Negative Factor:
1 out of 7
If more than the maximum allowed number of items are missing, the score will not be 
calculated.


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6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
In general, baseline value will be the measurement taken on the day of randomization (Visit 
2), and prior to the first study medication administration. If this value is not available, the 
measurement at the screening visit (Visit 1) will be used, except for MCCB assessments.
Baseline for MCCB neurocognitive composite score and related endpoints is defined as the 
measurements taken at randomization (Visit 2), and prior to the first administration of the 
study medication.
Analysis visit will be used for by-visit summaries and analysis of efficacy endpoints. Study 
day windows for mapping to analysis visits are presented in Table 6.7: 1. Actual study day 
will be calculated starting with day of randomization as Day 1. If more than one assessment is 
mapped to the same post-baseline analysis visit, the closest assessment to the planned study 
day will be used. In case of a tie, the earlier assessment will be used.
Table 6.7: 1
Analysis visit windows
Analysis 
visit
Nominal 
Timepoint
Planned 
study 
day
Actual study day window
MCCB*, 
PANSS
Other efficacy 
assessments
2
Baseline
1
≤1
≤1
4
Week 6
43
2 – 60
6/EoT
Week 12
85
≥61
≥2
*MCCB assessments taken >12 days after the last study medication intake will not be included in the analysis.
Safety endpoints will be summarized based on nominal visits as reported in the CRFs. No re-
labelling to analysis visits will be performed. 
In subject data listings, all data at scheduled or unscheduled timepoints will be presented.


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7.
PLANNED ANALYSIS
For End-Of-Text (EoT) tables of parameters 
, the set of summary statistics 
is: N / Mean / Standard Deviation SD / Min / Median / Max.
For tables that are provided for endpoints with some extreme data, median, quartiles and 
percentiles should be preferred to mean, standard deviation, minimum and maximum.
In general, means, medians, and quantiles are presented to one more decimal place than the 
raw data, whereas SDs are presented to two more decimal places than the raw data. Minima 
and maxima are presented to the same number of decimal places as the raw data.
Tabulations of frequencies for categorical data will include all possible categories (including 
categories with zero count) and will display the number of observations in a category as well 
as the percentage (%) relative to the respective treatment group (unless otherwise specified, 
all subjects in the respective subject set whether they have non-missing values or not). 
The precision for percentages should be one decimal point. The category missing will be 
displayed only if there are actual missing values.
If applicable, conversion from days to weeks, months and years follows the rules below:
∀
weeks = days ÷ 7
∀
months = 12 × days ÷ 365.25
∀
years = days ÷ 365.25
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Only descriptive statistics are planned for this section of the report.
7.2
CONCOMITANT DISEASES AND MEDICATION
Only descriptive statistics are planned for this section of the report.
Concomitant diseases will be coded based on the most current version of MedDRA. A 
summary of concomitant diseases will be provided by treatment group, system organ class 
(SOC), and preferred term (PT).
Concomitant medication will be coded according to WHO DD and classified by the 
Anatomical, Therapeutic, Chemical (ATC) classification system. Concomitant medication 
will be summarized separately for psychoactive medications.
7.3
TREATMENT COMPLIANCE
Only descriptive statistics are planned for this section of the report. See Section 5.4 for 
definitions of treatment compliance and CCT compliance/exposure.


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7.4
PRIMARY ENDPOINT(S)
7.4.1
Primary analysis of the primary endpoint(s)
The primary analysis is a restricted maximum likelihood (REML) based approach using the 
following mixed model with repeated measurements (MMRM) comparing the change from 
baseline in MCCB neurocognitive composite T-score after 12 weeks of treatment:
 =  +  +  +  ! + "
" ∼$(%, ')
where

= response variable for subject 8 in age stratum ; at visit < receiving treatment =,

= coefficient of baseline effect at visit <,

= baseline MCCB neurocognitive composite T-score of subject 8,

= effect of treatment = at visit <,

= effect of age stratum ;
 
= coefficient of change from screening to baseline effect,
!
= change from screening to baseline in MCCB neurocognitive composite T-score
"
= random error associated with visit < of subject 8,  independently distributed
      across subjects,
Σ
= unstructured variance-coviarance matrix.
The model will include fixed, categorical effects of treatment at each visit, fixed continuous 
effect of baseline at each visit, fixed effects of age strata (≤40 vs. >40), and fixed continuous 
effect of change in MCCB neurocognitive composite score from screening to baseline. Visit 
will be treated as the repeated measure with an unstructured variance-covariance matrix used 
to model the within-patient measurements.
Denominator degrees of freedom will be calculated using Kenward-Roger approximation. The 
primary treatment comparison will be the contrast between the two treatments at the endpoint 
visit, i.e. Week 12.
The primary analysis will be performed on FAS. Patients will be analysed according to the 
actual age stratum they belong to, regardless of any treatment mis-assignment due to wrong 
stratum identification because such an error would have occurred before randomization and is 
therefore consistent with regulatory guidance.
In the event of non-convergence, the following methods will be attempted in order:
1. Add the ‘singular=1e-10’ option in the model statement, to raise the threshold at 
which columns are declared linearly dependent from the default value of 1e-12.
2. Set ‘maxiter=100’ in PROC MIXED statement, to increase the number of convergence 
interactions from a default of 50.
3. Set ‘scoring=4’ to specify the use of Fisher scoring algorithm in the first 4 iterations.


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4. Include the statement ‘performance nothread’ to remove multi-threading from 
calculations.


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7.5
SECONDARY ENDPOINT(S)
7.5.1
Key secondary endpoint(s)
This section is not applicable as no key secondary endpoint has been specified in the protocol.
7.5.2
(Other) Secondary endpoint(s)
7.5.2.1
Primary analysis of the secondary endpoints
Primary analysis of the secondary endpoints will be conducted on FAS. Estimated least 
squares mean difference between the two treatment arms will be provided together with 95% 
confidence intervals. Statistical model and estimation method for each secondary endpoint are 
described below.
MCCB overall composite T-score
The primary analysis of change from baseline in MCCB overall composite T-score after 12 
weeks of treatment will be a REML based approach using the same MMRM as in Section 
7.4.1. The baseline and change-from-screening-to-baseline covariates,  and !, will be 
replaced by their overall composite T-score version.
SCoRS interviewer total score
The primary analysis of change from baseline in SCoRS interviewer total score after 12 
weeks of treatment will be an ANCOVA based approach using the following model:
 =  +  +  + "
" ∼$(0, IJ)
where


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
= response variable for subject 8 in age stratum ; receiving treatment =,

= coefficient of baseline effect,

= baseline value of subject 8,

= effect of treatment =,

= effect of age stratum ;
"
= random error associated with subject 8, independently distributed ,
across subjects
PANSS total score
The primary analysis of change from baseline in PANSS total score after 12 weeks of 
treatment will be a REML based approach using the following simplified MMRM from that 
in Section 7.4.1:
 =  +  +  + "
where  = baseline score of subject 8, while the other covariates and parameters are same as 
defined in Section 7.4.1.


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7.7
EXTENT OF EXPOSURE
Extent of exposure will be summarized for the treated set using descriptive statistics for days 
on treatment as well as frequency and percentage of subjects in the following categories: <30 
days, 30 – 41 days, 42 – 59 days, 60 – 89 days, ≥ 90 days.
Exposure to CCT will be summarized using descriptive statistics as described in Section 5.4.
7.8
SAFETY ANALYSIS
All safety analyses will be performed on the treated set.


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7.8.1
Adverse Events
Unless otherwise specified, the analyses of AEs will be descriptive in nature. All analyses of 
AEs will be based on the number of subjects with AEs and not on the number of AEs. The 
reporting and analysis of AEs will follow the BI guideline (2). AEs will be coded with the 
latest version of MedDRA.
The analysis of AEs will be based on the concept of treatment emergent AEs. For this study, 
the residual effect period (REP) is defined as 11 days after the last dose of trial medication.
That means that all AEs occurring between first drug intake till 11 days after last drug intake 
will be assigned to the “on-treatment” period. All AEs occurring before first drug intake will 
be assigned to ‘screening’ and all AEs occurring after last drug intake + 11 days will be 
assigned to ‘follow-up’ (for listings only). For details on the treatment definition, see Section 
6.1.
Adverse events of special interest (AESIs)
As defined in CTP Section 5.2.6.1, AESI includes hepatic injury defined by the following 
alterations of hepatic laboratory parameters:
∀
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
∀
aminotransferase (ALT, and/or AST) elevations ≥10-fold ULN.
Other significant AE (according to ICH E3)
According to ICH E3 (6), AEs classified as "other significant" needs to be reported and will 
include those non-serious and non-significant AEs with
1. ‘action taken = discontinuation’ or ‘action taken = reduced’; or
2. marked haematological and other lab abnormalities or lead to significant concomitant 
therapy as identified by the Clinical Monitor / Investigator during medical quality 
review at a trial oversight meeting (TOM).


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An overall summary of AEs will be presented.
The frequency of subjects with AEs will be summarised by treatment, primary system organ 
class and PT. Separate tables will be provided for subjects with SAEs, AEs leading to 
treatment discontinuation, AEs of at least moderate severity and related AEs. 
The system organ classes will be sorted by default alphabetically, PTs will be sorted by 
frequency (within SOC). Customized sorting orders may also be used based on trial needs, 
e.g. SOC sorted by frequency.
Separate tables will be provided for the following AEs:
∀
drug-related AEs
∀
serious AEs (SAEs)
∀
drug-related SAEs
∀
AESIs
∀
Other significant AE (according to ICH E3)
∀
AEs leading to death
∀
AEs leading to discontinuation of trial medication
∀
AEs occurred with >2% incidence in the preferred term
∀
AEs by intensity
∀
AEs occurred during the follow-up period.
∀
AEs related to COVID-19
7.8.2
Laboratory data
The analyses of laboratory data will be descriptive in nature and will be based on BI standards
(5).
Descriptive statistics for laboratory values will be derived and displayed visit-by-visit using 
converted values. Shift tables of change in laboratory parameters between baseline and worst 
value on treatment, between baseline and last value on treatment, and between worst and last 
value on treatment will also be presented.
In addition, the following will be presented for haemoglobin (Hb):
∀
shift tables of change in Hb between last value on treatment and last value post-treatment,
∀
spaghetti plots of change in Hb from baseline across time with time trend of mean and 
standard error, 


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7.8.3
Vital signs
Only descriptive statistics are planned for this section of the report.
7.8.4
ECG
Clinically relevant abnormal ECG findings will be reported and analysed as AEs.
7.8.5
Others
Worsening Disease State as assessed by PANSS
Change in PANSS from baseline to each post-baseline visit will be presented in a data listing. 
Increases greater than or equal to 5 will be flagged.
Suicidality as assessed by the C-SSRS
C-SSRS will be summarized by counts and percentages per treatment group. The number of 
patients with suicidal ideation (for each type of 1 to 5 separately), suicidal behaviour (type 6 –
10), and with self-injurious behaviour without suicidal intent will be presented, overall and 
within subcategories. A summary will also be presented for lifetime experience. Shift table 
and listings will be provided.


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8.
TIMEPOINT OF RELEASE OF TREATMENT 
INFORMATION
The treatment information will be released to unblind the trial database after the last patient 
has completed their End-of-Study/Follow-up visit and all data has been entered and cleaned as 
defined in the “Data Ready to be Unblinded and/or Final Trial Closure Notification” (RUN) 
form.


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9.
REFERENCES
1.
CPMP/ICH/363/96: "Statistical Principles for Clinical Trials", ICH Guideline Topic E9, 
Note For Guidance on Statistical Principles for Clinical Trials, current version.
2.
BI-KMED-BDS-HTG-0066: “Analysis and Presentation of Adverse Event Data from 
Clinical Trials”, KMed.
3.
BI-KMED-BDS-HTG-0035: “Handling of Missing and Incomplete AE Dates”, KMed.
4.
BI-KMED-TMCP-MAN-0012: “Standards and processes for analyses performed within 
Clinical Pharmacokinetics/Pharmacodynamics”, KMed.
5.
BI-KMED-BDS-HTG-0042: “Handling, Display and Analysis of Laboratory Data”, 
KMed.
6.
CPMP/ICH/137/95: “Structure and Content of Clinical Study Reports”, ICH Guideline 
Topic E3; Note For Guidance on Structure and Content of Clinical Study Reports,
current version, EMA webpage.
7.
Little, R. J. & Rubin, D. B. (2002). Statistical Analysis with Missing Data (2nd ed). New 
York: John Wiley & Sons.


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11.
HISTORY TABLE
Table 11: 1
History table
Version
Date
Author
Sections changed
Brief description of change
1
10-OCT-2022
None
This is the final TSAP 


 
 
 
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