Clinical trial NCT02832037
Conditions: Schizophrenia
Sponsor: Boehringer Ingelheim
Start date: 2016-07-25; Completion date: 2020-01-29
Enrollment: 509 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The objective of the study is to investigate the efficacy, safety and pharmacokinetics of four different doses of BI 425809 once daily compared to placebo given for 12 weeks in patients with schizophrenia on stable antipsychotic treatment.

Detailed description:

Arms: arm 1: None arm 2: None arm 3: None arm 4: None arm 5: None
Interventions: intervention 1: BI 425809 dose 1 intervention 2: BI 425809 dose 2 intervention 3: BI 425809 dose 3 intervention 4: BI 425809 dose 4 intervention 5: Placebo
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None intervention 4: None intervention 5: None

Protocol documents:
Prot_000.pdf: 
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
CLINICAL TRIAL PROTOCOL
TITLE PAGE
Document Number:
c03559983-04
EudraCT No.:
2016-000285-28
BI Trial No.:
1346.9
BI Investigational 
Product(s):
BI 425809
Title:
A phase II randomized, double-blinded, placebo-controlled parallel group trial 
to examine the efficacy and safety of 4 oral doses of BI 425809 once daily over 
12 week treatment period in patients with Schizophrenia
Brief Title:
Clinical trial of BI 425809 effect on cognition and functional capacity in 
schizophrenia.
Clinical Phase:
II
Trial Clinical 
Monitor:
Phone: 
 
Fax: 
Coordinating 
Investigator:
Phone: 
Fax: 
Status:
Final Protocol (Revised Protocol (based on global amendment No. 3))
Version and Date:
Version:
Date:
4.0
28 Mar 2019
Page 1 of 116
Proprietary confidential information.
2019 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.


Boehringer Ingelheim                                                                                                      28 Mar 2019
BI Trial No.: 1346.9
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001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
CLINICAL TRIAL PROTOCOL SYNOPSIS
Name of company:
Boehringer Ingelheim 
Name of finished product:
Not applicable
Name of active ingredient:
BI 425809
Protocol date:
24 Feb 2016
Trial number:
1346.9
Revision date:
28 Mar 2019
Title of trial:
A phase II randomized, double-blinded, placebo-controlled parallel group trial to 
examine the efficacy and safety of 4 oral doses of BI 425809 once daily over 12 
week treatment period in patients with Schizophrenia
Coordinating
Investigator:
Phone: 
Fax: 
Trial site(s):
Multi-centre trial
Clinical phase:
II
Objective(s):
The primary objectives of this trial are to provide proof of clinical concept (PoCC) 
and dose finding data in patients with schizophrenia on stable antipsychotic 
treatment who are treated with oral once daily administration of BI 425809 or 
placebo. Other objectives of this trial are to assess the safety 
 
of BI 425809.
Methodology:
Multi-centre, randomized, double-blind, double-dummy, placebo-controlled, 
parallel-group trial
No. of patients: 
720 patients
total entered:
504 patients
each treatment:
84 patients per active treatment arm; 168 patients in placebo arm
Diagnosis :
Patients with established Schizophrenia (as per DSM-5) who are clinically stable


Boehringer Ingelheim                                                                                                      28 Mar 2019
BI Trial No.: 1346.9
Doc. No.: c03559983-04                                  Trial Protocol                                       Page 3 of 116
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001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
Name of company:
Boehringer Ingelheim 
Name of finished product:
Not applicable
Name of active ingredient:
BI 425809
Protocol date:
24 Feb 2016
Trial number:
1346.9
Revision date:
28 Mar 2019
Main criteria
for inclusion:
1.
Patients must be capable of providing signed and dated written informed 
consent by date of Visit 1 in accordance with GCP and the local 
legislation
2.
Men or women who are 18-50 years (inclusively) of age at time of 
consent
3.
Established schizophrenia (as per DSM-5) with the following clinical 
features:

Outpatient, with no hospitalisation for worsening of 
schizophrenia within 3 months (hospitalisation for social 
management and/or day hospital programs within this time are 
acceptable) prior to randomization

Medically stable over the prior 4 weeks and psychiatrically 
stable without symptom exacerbation within 3 months prior to 
randomization

Patients who have no more than a “moderate severe” rating on 
the Positive and Negative Syndrome Scale (PANSS) positive 
items P1, P3-P7 (item score ≤5) and no more than a “moderate” 
rating on the PANSS positive item P2 (item score ≤4)
4.
Current antipsychotic and concomitant psychotropic medications as 
assessed at Visit 1 must meet the criteria below:

Patients may have up to 2 antipsychotics (typical or atypical)

Patients must be maintained on current typical and/or atypical 
antipsychotics other than Clozapine and on current dose for at 
least 4 weeks prior to randomization and/or maintained on 
current long acting injectable antipsychotic and current dose for 
at least 3 months prior to randomization

Patients must be maintained on current concomitant 
psychotropic medications, anticholinergics, antiepileptics and/or 
lithium for at least 3 months prior to randomization and on 
current dose for at least 4 weeks prior to randomization
Test product(s):
BI 425809
dose:
2 mg q.d.


Boehringer Ingelheim                                                                                                      28 Mar 2019
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001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
Name of company:
Boehringer Ingelheim 
Name of finished product:
Not applicable
Name of active ingredient:
BI 425809
Protocol date:
24 Feb 2016
Trial number:
1346.9
Revision date:
28 Mar 2019
5 mg q.d.
10 mg q.d
25 mg q.d.
mode of 
administration:
Tablet, p.o.
Comparator products:
Matching placebo
dose:
Not applicable
mode of 
administration:
Tablet, p.o.
Duration of treatment:
12 weeks
Endpoints
Primary endpoint:

Change from baseline in cognitive function as measured by the composite 
MATRICS consensus cognitive battery (MCCB) score after 12 weeks of 
treatment
Secondary endpoints:

Change from baseline in everyday functional capacity as measured by 
Schizophrenia Cognition Rating Scale (SCoRS) total score after 12 weeks 
of treatment 

Percentage of patients with (serious) adverse events ((S)AEs) (including 
clinically relevant abnormalities of physical examination, vital signs, 
ECG and laboratory tests
Safety criteria:

Occurrence of Protocol-specified AESI (adverse events of special 
interest)

Worsening of disease state as assessed by PANSS

Suicidality as assessed by C-SSRS
Statistical methods:
A multiple comparison procedure with modelling (MCPMod) approach is used in 


Boehringer Ingelheim                                                                                                      28 Mar 2019
BI Trial No.: 1346.9
Doc. No.: c03559983-04                                  Trial Protocol                                       Page 5 of 116
Proprietary confidential information © 2019 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
Name of company:
Boehringer Ingelheim 
Name of finished product:
Not applicable
Name of active ingredient:
BI 425809
Protocol date:
24 Feb 2016
Trial number:
1346.9
Revision date:
28 Mar 2019
this proof of clinical concept (PoCC) and dose finding trial to define one or more 
suitable doses with respect to the efficacy and safety of BI 425809 for further 
testing in pivotal phase III trials in patients with schizophrenia on stable 
antipsychotic treatment. A set of six plausible dose response patterns is considered 
with pre-specified parameters. If the overall MCPMod test is statistically 
significant, rejecting the null hypothesis of a flat dose response relation across 
doses for BI 425809 under study and placebo over 12 weeks for the primary 
endpoint with a contrast test controlled for the family-wise type I error rate at one-
sided alpha=0.05, PoCC is established. After establishing the PoCC, a fitted model 
will be obtained via weighted model averaging across the significant models based 
on the Akaike Information Criterion and the target dose(s) can be determined from 
that model by incorporating information on the minimum clinically relevant effect 
as well as safety information.


Boehringer Ingelheim                                                                                                      28 Mar 2019
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FLOW CHART
Trial Periods
Screening 
Period*
Randomized Treatment Period
End of Trial
Visit
1
27
3
4 7
5
6 
(e)EOT4,7 Follow-
up 14,5
Follow
up 24,5
Weeks
-4 to -1
3
6
9
12
“Days” from date of first 
randomized treatment 
-28 to -7
1 
(***)
22
43
64
85
EOT
+7
EOT
+28
Time window for visits
-28 to -7days
None
±3 
days
±3 
days
±3
days
+3 days
±3 days
±7 days
Informed consent(**)
X
Demographics
X
Medical history
X
Physical examination
X
X
X
X
X
Vital signs
X
X
X
X
X
Height
X
Weight
X
X
X
X
X
Safety Laboratory 
tests(urine/blood)
X
X
X
X
X
Pregnancy test 1
X
X
X
X
X
X
Drug screen test (urine)
X
X
X
X
12 lead-ECG13
  X
X
X
X
X
in-/exclusion criteria
X
X
Contact IRT
X
X
X
X
Randomization
X
Dispense trial drug
X
X
Administer trial drug
X
X
X
X
Termination of trial drug
X
MCCB
X
X
X
X
eC-SSRS
X8
X9
X9
X9
X9
X9
X9
X9
PANSS6
X
X
X
X
ScoRS6
X
X
M.I.N.I.
X
Adverse events
X
X
X
X
X
X
X
X
Compliance check
X
X
X
X
Concomitant therapy
X
X
X
X
X
X
X
X
Completion of patient 
participation (****)
X


Boehringer Ingelheim                                                                                                      28 Mar 2019
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(*) 
The Screening Visit has to be performed from - 28 days to -7 days prior first drug administration
(**)
Re-consenting may become necessary when new relevant information becomes available and should be conducted 
according to the sponsor’s instructions. 
  
Patients who failed screening may repeat the screening phase once after discussion between investigator and sponsor. 
The patient who will be rescreened needs to be re-consented
***)
Day of Randomization / Day of first intake of randomized medication
(****) Completion of patient participation also needs to be completed if the patient withdraws prematurely following 
randomization (see Section 3.3.3)
1 women of childbearing potential must perform urine (dipstick) pregnancy test at Visit 1 (Screening Visit), Visit 2, Visit 3, 
Visit 4, Visit 5, (e)EOT Visit. Urine pregnancy test can be performed more frequently if required by local regulation.
4 An early End of Treatment (eEOT) Visit, as well as a Follow-up Visit 1 and 2, should be performed for any patient who 
discontinues study medication prematurely; the eEOT Visit should be completed as soon as possible after study medication
is stopped.  
5 Follow-up visits are designed to capture withdrawal effects: immediate effects at 1 week after last intake of trial medication 
and based on half-life, again at 4 weeks after last intake of trial medication). Follow-up visit 1 may be conducted as a 
phone visit.
6 Informant ratings are needed for SCoRS and PANSS ratings. In person ratings are preferred whenever possible. However, 
if the informant is not available for in person ratings, telephone interview is acceptable. The informant must be available 
for a telephone interview at the visits indicated in the flowchart.
7 Study procedures of Screening Visit (Visit 1), Visit 2, Visit 4 and (e)EOT Visit can be split into 2 sequential days. If the 
study procedures are split into 2 sequential days, the MCCB,  
 should be 
performed at the first day of the two sequential days (i.e., the day prior to Day 1), and the psychopathologic assessments 
(e.g. SCoRS, PANSS) should be performed on the second day. 
8 Columbia Suicide Severity Rating Scale baseline/screening scale
9 Columbia Suicide Severity Rating Scale since-last-visit scale
13 It is recommended that the 12-lead ECG is performed 3-5 hours after intake of trial drug on visits 4 and (e)EOT.


Boehringer Ingelheim                                                                                                      28 Mar 2019
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TABLE OF CONTENTS
CLINICAL TRIAL PROTOCOL..........................................................................................1
TITLE PAGE ...........................................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS .....................................................................2
FLOW CHART........................................................................................................................6
TABLE OF CONTENTS ........................................................................................................8
ABBREVIATIONS................................................................................................................13
1.
INTRODUCTION...............................................................................................16
MEDICAL BACKGROUND.............................................................................16
1.1
DRUG PROFILE................................................................................................17
1.2
2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK ASSESSMENT .....21
RATIONALE FOR PERFORMING THE TRIAL.........................................21
2.1
TRIAL OBJECTIVES........................................................................................21
2.2
BENEFIT - RISK ASSESSMENT.....................................................................22
2.3
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.........................24
OVERALL TRIAL DESIGN AND PLAN .......................................................24
3.1
3.1.1
Administrative structure of the trial .................................................................25
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
3.2
CONTROL GROUP(S)......................................................................................25
SELECTION OF TRIAL POPULATION .......................................................26
3.3
3.3.1
Main diagnosis for trial entry ............................................................................27
3.3.2
Inclusion criteria .................................................................................................27
3.3.3
Exclusion criteria ................................................................................................28
3.3.4
Removal of patients from therapy or assessments...........................................31
Removal of individual patients .............................................................................31
3.3.4.1
Discontinuation of the trial by the sponsor...........................................................32
3.3.4.2
4.
TREATMENTS...................................................................................................33
TREATMENTS TO BE ADMINISTERED.....................................................33
4.1
4.1.1
Identity of BI investigational product(s) and comparator product(s) ...........33
4.1.2
Method of assigning patients to treatment groups...........................................35
4.1.3
Selection of doses in the trial..............................................................................35
4.1.4
Drug assignment and administration of doses for each patient......................35
4.1.5
Blinding and procedures for unblinding...........................................................36
Blinding.................................................................................................................36
4.1.5.1
Unblinding and breaking the code ........................................................................37
4.1.5.2
4.1.6
Packaging, labelling, and re-supply...................................................................37
4.1.7
Storage conditions...............................................................................................37
4.1.8
Drug accountability.............................................................................................38


Boehringer Ingelheim                                                                                                      28 Mar 2019
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CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE  
4.2
TREATMENT.....................................................................................................38
4.2.1
Rescue medication, emergency procedures, and additional treatment(s) .....38
4.2.2
Restrictions ..........................................................................................................39
Restrictions regarding concomitant treatment ......................................................39
4.2.2.1
Restrictions on diet and life style..........................................................................40
4.2.2.2
TREATMENT COMPLIANCE........................................................................40
4.3
5.
VARIABLES AND THEIR ASSESSMENT ....................................................42
TRIAL ENDPOINTS..........................................................................................42
5.1
5.1.1
Primary Endpoint(s)...........................................................................................42
5.1.2
Secondary Endpoint(s) .......................................................................................43
ASSESSMENT OF EFFICACY........................................................................44
5.2
5.2.1
Assessment of primary and secondary efficacy endpoints..............................44
ASSESSMENT OF SAFETY.............................................................................47
5.3
5.3.1
Physical examination ..........................................................................................47
5.3.2
Vital Signs............................................................................................................47
5.3.3
Safety laboratory parameters ............................................................................48
5.3.4
Electrocardiogram ..............................................................................................50
5.3.5
Other safety parameters.....................................................................................51
Assessment of disease state...................................................................................51
5.3.5.1
Assessment of suicidality......................................................................................51
5.3.5.2
5.3.6
Assessment of adverse events.............................................................................52
Definitions of AEs ................................................................................................52
5.3.6.1
5.3.7
Adverse event collection and reporting.............................................................54
OTHER ASSESSMENTS...................................................................................59
5.6
APPROPRIATENESS OF MEASUREMENTS..............................................59
5.7
6.
INVESTIGATIONAL PLAN.............................................................................60
VISIT SCHEDULE.............................................................................................60
6.1
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS .................60
6.2
6.2.1
Screening and run-in period(s)..........................................................................61
6.2.2
Treatment period(s)............................................................................................62
6.2.3
Follow Up Period and Trial Completion...........................................................64


Boehringer Ingelheim                                                                                                      28 Mar 2019
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7.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE
...............................................................................................................................65
STATISTICAL DESIGN - MODEL.................................................................65
7.1
NULL AND ALTERNATIVE HYPOTHESES ...............................................65
7.2
PLANNED ANALYSES.....................................................................................65
7.3
7.3.1
Primary endpoint analyses.................................................................................66
Primary analysis of the primary endpoint.............................................................66
7.3.1.1
7.3.2
Secondary endpoint analyses .............................................................................68
7.3.4
Safety analyses.....................................................................................................68
INTERIM ANALYSES ......................................................................................70
7.4
HANDLING OF MISSING DATA ...................................................................70
7.5
RANDOMIZATION...........................................................................................70
7.6
DETERMINATION OF SAMPLE SIZE .........................................................71
7.7
8.
INFORMED CONSENT, DATA PROTECTION, TRIAL RECORDS........73
TRIAL APPROVAL, PATIENT INFORMATION, AND INFORMED 
8.1
CONSENT ...........................................................................................................73
DATA QUALITY ASSURANCE ......................................................................74
8.2
RECORDS...........................................................................................................74
8.3
8.3.1
Source documents ...............................................................................................74
8.3.2
Direct access to source data and documents.....................................................74
8.3.3
Storage period of records ...................................................................................75
LISTEDNESS AND EXPEDITED REPORTING OF ADVERSE EVENTS75
8.4
8.4.1
Listedness.............................................................................................................75
8.4.2
Expedited reporting to health authorities and IEC / IRB...............................75
STATEMENT OF CONFIDENTIALITY........................................................75
8.5
END OF TRIAL..................................................................................................76
8.6
PROTOCOL VIOLATIONS .............................................................................76
8.7
COMPENSATION AVAILABLE TO THE PATIENT IN THE EVENT OF 
8.8
TRIAL RELATED INJURY..............................................................................76
9.
REFERENCES....................................................................................................77
PUBLISHED REFERENCES............................................................................77
9.1
UNPUBLISHED REFERENCES......................................................................87
9.2
10.
APPENDICES.....................................................................................................88
INSTRUCTIONS FOR USE..............................................................................88
10.1
10.1.1
Batteries and questionnaires..............................................................................88
10.1.2
Definition of positive Reports of Suicidal Ideation and Behavior ..................88


Boehringer Ingelheim                                                                                                      28 Mar 2019
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OPHTHALMOLOGIC SUBSTUDY..............................................................103
10.8
10.8.1
Flowchart...........................................................................................................103
10.8.2
Objective ............................................................................................................103
10.8.3
Selection of Study Population ..........................................................................104
Inclusion Criteria.................................................................................................104
10.8.3.1
Exclusion Criteria ...............................................................................................104
10.8.3.2
10.8.4
Sub-study Design...............................................................................................104


Boehringer Ingelheim                                                                                                      28 Mar 2019
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10.8.5
Ophthalmological examinations ......................................................................105
10.8.6
Endpoints...........................................................................................................107
10.8.7
Planned Analyses Determination of Sample Size...........................................107
Planned Analyses ................................................................................................107
10.8.7.1
Sample Size.........................................................................................................107
10.8.7.2
11.
DESCRIPTION OF GLOBAL AMENDMENT(S) .......................................108
GLOBAL AMENDMENT 1 ............................................................................108
11.1
GLOBAL AMENDMENT 2 ............................................................................110
11.2
GLOBAL AMENDMENT 3 ............................................................................116
11.3


Boehringer Ingelheim                                                                                                      28 Mar 2019
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ABBREVIATIONS
AE
Adverse Event
AESI
Adverse Event of Special Interest
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
BDNF
Brain-Derived Neurotrophic Factor
BI 
Boehringer Ingelheim
BP
Blood pressure
CIAS
Cognitive Impairment Associated with Schizophrenia
CML
Local Clinical Monitor 
CNS
Central Nervous System
CRA
Clinical Research Associate
CRF
Case Report Form
CRO
Contract Research Organisation
C-SSRS
Columbia Suicide Severity Rating Scale
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
CYP
Cytochrome P450
DILI
Drug Induced Liver Injury
DNA
Deoxyribonucleic Acid
DSM - 5
Diagnostic and Statistical Manual of Mental Disorders 5th Edition
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
EMA
European Medicinal Agency
(e) EOT
(early) End of Treatment
EPS
Extrapyramidal symptoms
ERG
Electroretinogram
EudraCT
European Clinical Trials Database
FAS
Full Analysis Set


Boehringer Ingelheim                                                                                                      28 Mar 2019
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FC
Flow Chart
FDA
Food and Drug Administration
GCP
Good Clinical Practice
eGFR
Estimated glomerular filtration rate
GLYT 1
Glycine Transporter 1
HA
Health Authorities
Hb
Hemoglobin
Hct
Hematocrit
HIV
Human Immunodeficiency Virus
IB
Investigator’s Brochure
ICH
International Conference on Harmonization
IEC
Independent Ethics Committee
IRB
Institutional Review Board
IRT
Interactive Response Technology
ISF
MATRICS
Investigator Site File
Measurement and Treatment Research to Improve Cognition in 
Schizophrenia
MCCB
MATRICS consensus cognitive battery
MCH
Mean cell hemoglobin
MCHC
Mean corpuscular hemoglobin concentration
MCPMod
Multiple Comparison Procedure with Modelling techniques
MCV
Mean corpuscular volume
MedDRA
Medical Dictionary for Drug Regulatory Activities
M.I.N.I
Mini International Neuropsychiatric Interview
MMRM
Mixed effects Model Repeated Measures
MRD
Multiple-rising dose
MST
Medical Sub team
NMDA
N-methyl-D-aspartate
NMDA-R
N-methyl-D-aspartate receptor
NOAEL
No-observed-adverse-effect level
PANSS
Positive and Negative Syndrome Scale
PCP
Phencyclidine
PI
Principal Investigator
p.o.
per os (oral)
PoCC
Proof of Clinical Concept
PoM
Proof of Mechanism
PR
Pulse rate


Boehringer Ingelheim                                                                                                      28 Mar 2019
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q.d.
quaque die (once a day)
RBC
Red blood cell
RDC
Remote Data Capture
RDW
Red blood cell distribution width
REP
Residual effect period, after the last dose of medication with measureable 
drug levels or pharmacodynamic effects still likely to be present
SAE
Serious Adverse Event
SCoRS
Schizophrenia Cognition Rating Scale
SOP
Standard Operating Procedure
SRD
SUSAR
TCM 
TIBC
TMS
TSAP
TSH
VAS
Single-rising dose
Suspected Unexpected Serious Adverse Reaction
Trial Clinical Monitor
Total Iron Binding Capacity
Transcranial Magnetic Stimulation
Trial Statistical Analysis Plan
Thyroid-stimulating hormone
Visual Analogue Scale
WBC
White blood cell
WoCBP
Women of child-bearing Potential


Boehringer Ingelheim                                                                                                      28 Mar 2019
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1.
INTRODUCTION
MEDICAL BACKGROUND
1.1
Schizophrenia is a serious mental illness that is chronic and disabling in its clinical course. It 
has been long hypothesized that deficits in glutamatergic signaling may underlie
schizophrenia, including negative and cognitive symptoms (R13-4521). Existing treatment 
options for schizophrenia (i.e. first- and second-generation antipsychotics) are primarily 
efficacious in treating positive symptoms and have limited efficacy for treating the cognitive 
and negative symptoms. Inhibition of GLYT 1 aims at improving NMDA receptor 
hypoactivation in patients with schizophrenia by increasing the concentration of the NMDA 
receptor co-activator glycine in the synaptic cleft, thereby leading to improvement of 
negative and cognitive symptoms in patients with schizophrenia (as add-on therapy to 
antipsychotics). 
Schizophrenia has a life-time prevalence of approximately 1%, with almost equal distribution 
worldwide and comparable incidence between men and women.
Schizophrenia is a heterogenous syndrome defined by hallucinations, delusions, social 
withdrawal, restricted emotional experiences and expressions, and disorganized behavior. 
Although the current diagnostic systems emphasize positive and negative symptoms of the 
illness, early descriptions of schizophrenia viewed cognitive impairment as a core feature. 
Kraepelin described a wide range of cognitive deficits in characterizing the illness, including 
attention, memory, retention, association, mental efficiency, judgment, syntax, as well as 
processes and fluidity in thoughts (Ref: Kraepelin 1919 Dementia Praecox and paraphrenia).  
Bleuer described deficits in associative thinking as a core feature of schizophrenia and 
viewed hallucinations as rather accessory (Ref: Bleuler 1950 Dementia Praecox or the group 
of schizophrenias).
Cognitive impairments are a core feature of schizophrenia and have been shown to be a major 
determinant of poor functional outcome. As a group, patients with schizophrenia perform 
significantly worse than controls on almost all neuropsychological tests. 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).
A meta-analysis of more than 200 studies in Schizophrenia which included neurocognitive 
assessments between 1980 and 1997 reported an overall mean of about one standard 
deviation in cognitive performance compared to community controls (R15-3853). Another 
meta-analysis of studies in the following decade produced similar magnitude of deviation 
from population norms (R15-3854). The magnitude of difference in composite cognition 
measures from healthy volunteers is comparable or greater than the effect sizes reported for 
moderate to severe traumatic brain injury (R15-3852).
Around 20-60% of the variance in functional outcome in schizophrenia is explained by 
cognitive performance (R10-5094; R10-5096; R10-5100; R10-5104).


Boehringer Ingelheim                                                                                                      28 Mar 2019
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As of yet, no drug has been approved for the treatment of cognitive impairment in
schizophrenia. Antipsychotics have demonstrated mild beneficial effects on cognition in 
schizophrenia (R15-5596; R15-5580). However, antipsychotics also adversely affect some 
aspects of cognitive function, such as processing speed (R15-5595).
Various glutamatergic agents have been tested for the treatment of schizophrenia. Targets 
include NMDA receptor co-factor glycine site, including agonists D-gycine, D-serine, and 
partial agonist D-cycloserine, as well as glycine transporters, such as sarcosine and bitopertin.
D-cylcoserine has shown modest reductions in negative symptom scores (R15-5877), but in 
another study, it did not differentiate from placebo (R15-5838). In the latter study, D-
cycloserine separated from placebo in improvement in cognitive function, driven by outlier 
responders. When d-cycloserine was dosed once a week, there was significant improvement 
in negative symptoms, most pronounced in affective flattening and anhedonia (R15-5584). D-
serine has also produced inconsistent results on positive, negative and cognitive symptoms of 
schizophrenia (R15-5615; R15-5578; R15-5639). Inconsistent results were seen from 
sarcosine trials as well (R13-4524; R13-4448; R15-5616).
Conventional antipsychotics (including both first- and second generation antipsychotics) have 
only modest effects on cognitive performance (and also negative symptoms) and no drugs 
have yet been approved for the treatment of CIAS or negative symptoms.
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 
motivation for developing novel treatments for CIAS.
DRUG PROFILE
1.2
 In addition, the GLYT1 
inhibitor prototype sarcosine has shown to improve positive, negative, and cognitive 
symptoms in patients with schizophrenia (R13-4447; R13-4524). It is therefore thought that
treatment with BI 425809 has the potential to improve cognitive functioning in patients with
schizophrenia. 
In a proof of clinical concept trial of another GLYT1 inhibitor, bitopertin, efficacy signals 
were observed in negative symptoms of schizophrenia (R13-4509), but not replicated in 
phase III trials (R14-4313; R15-1273). 


Boehringer Ingelheim                                                                                                      28 Mar 2019
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The safety observations from clinical trials have replicated findings from other compounds 
with the same mode of action (R13-4450; R13-4451; R13-4508). Potential risks associated 
with BI 425809 are transient visual disturbances, and somnolence. Based on class-effect, BI 
425809 may have the potential to be associated with hemoglobin decrease (R15-1266; R15-
1273; R15-1270). 


Boehringer Ingelheim                                                                                                      28 Mar 2019
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Boehringer Ingelheim                                                                                                      28 Mar 2019
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Clinical experience in humans
At the time of preparation of this clinical trial protocol, BI 425809 has been used in seven
phase I trials: 

1346.1 Single rising dose (SRD) trial: completed, report archived

1346.2 Multiple rising dose (MRD) trial: completed, preliminary data available

1346.3 Proof of mechanism trial: completed, report archived

1346.4 Single rising dose (SRD) in Japanese and Chinese trial: completed, preliminary 
data available

1346.10 Itraconazole-interaction trial: completed, report archived

1346.22 interaction with cytochrome P450 and  P-glycoprotein substrates trial: 
completed, report archived

1346.18 DDI strong CYP3A4 inducer, completed
For a more detailed description of the drug profile refer to the current Investigator’s Brochure
(IB) which is included in the Investigator Site File (ISF).


Boehringer Ingelheim                                                                                                      28 Mar 2019
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2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT
RATIONALE FOR PERFORMING THE TRIAL
2.1
This trial is designed to investigate whether BI 425809 as an add-on therapy to antipsychotics 
can improve cognitive symptoms in patients with schizophrenia. 
Ophthalmological sub-study:
This trial will further characterize the ocular safety of BI 425809 and effects on 
ophthalmologic physiology in patients with CIAS. Therefore, a sub-set of patients will 
undergo special ocular safety assessments. 
The sub-studies are described in detail in 
 Appendix 10.8 
of this protocol and implemented in the country(ies) planned to participate in this sub-study.
TRIAL OBJECTIVES
2.2
The primary objectives of this trial are to provide proof of clinical concept (PoCC) and dose 
finding data in patients with schizophrenia on stable antipsychotic treatment who are treated 
with oral once daily administration of BI 425809 or placebo. Other objectives of this trial are 
to assess the safety 
The PoCC and dose finding are achieved through the primary endpoint comparison (mean 
change from baseline in composite MCCB score at Week 12) of the four BI 425809 doses (2 
mg q.d., 5 mg q.d., 10 mg q.d. and 25 mg q.d.) and placebo. A non-flat dose response 
relationship between the BI 425809 doses and placebo is tested using the multiple 
comparison procedures and modelling (MCPMod) approach (R10-1424; R15-1961).


Boehringer Ingelheim                                                                                                      28 Mar 2019
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BENEFIT - RISK ASSESSMENT
2.3
The overall safety profile of BI 425809 is outlined in the current IB c02156531
Drug-related risks and safety measures
Considering the chronic and severe disease burden of CIAS, the potential therapeutic benefits 
are assessed to outweigh the currently understood potential risks of the treatment.
Based on non-clinical toxicology data, clinical data from other compounds in the same class, 
and subjects exposed in phase I trials, BI 425809 is assessed to be generally safe and well-
tolerated. Most common AEs were CNS related, headache being the most frequent. There is 
potential for BI 425809 to be associated with transient visual disturbances, and somnolence.  
These effects are understood to be mostly mild to moderate and transient. 
Decreased hemoglobin is also considered to be a potential risk based on preclinical data and 
class effect; however, no clear decrease in hemoglobin was seen in BI 425809-treated 
subjects compared to placebo in phase I trials so far (of up to 14 days duration). Patients with 
hemoglobin less than 120 g/L (12g/dL) in men or 115g/L (11.5g/dL) in women will be 
excluded from participation.
Administration with strong CYP3A inhibitor/ inducers did significantly impact the total 
exposure of BI 425809. As BI 425809 is a sensitive substrate of CYP3A4, co-administration 
of moderate to strong CYP3A4 inhibitors and inducers are excluded during the participation 
in this trial. Furthermore, as data of the DDI cocktail study 1346.22 suggest that BI 425809 is 
a mild CYP3A4 inducer, clinical monitoring is considered necessary when co-administering 
sensitive substrates of CYP3A4 at least to the highest tested dose of 25 mg BI 425809. 
Sensitive CYP3A4 substrates with a narrow therapeutic index are excluded during this trial.
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 C-SSRS.
Although rare, a potential for drug-induced liver injury 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 5.3.6.1.
Placebo Risks and Risks of stopping study drug
There is currently no approved medication indicated for treatment of cognitive impairment in 
schizophrenia. Since an approved, effective comparator is not available for this study, 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, are permitted to remain on other
antipsychotic and psychotropic medications. 


Boehringer Ingelheim                                                                                                      28 Mar 2019
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According to the medication assignment planned in this trial, 67% of the patients will receive
BI 425809 and 33% of patients will be assigned to placebo. Patients treated in this clinical 
trial should be in stable clinical status and on stable doses of antipsychotic and concomitant 
psychotropic medications. Participation will not alter current disease treatment. Assignment 
to the placebo arm or stopping the study drug during the treatment period is not associated 
with a higher risk since patients should remain on their stable treatment regimen. 
Additionally, BI 425809 targets the cognitive symptoms in schizophrenia and there is no 
preclinical evidence suggesting an effect on positive or negative symptoms of schizophrenia. 
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 actions taken according to stopping criteria.
This is an experimental drug at an early stage of testing 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.


Boehringer Ingelheim                                                                                                      28 Mar 2019
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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
OVERALL TRIAL DESIGN AND PLAN
3.1
Figure 3.1:1
Trial design
This is a 12-week, multi-center, multi-national, randomized, double-blind, double dummy, 
placebo controlled parallel group trial in patients with schizophrenia. In total, 504 patients 
with schizophrenia on stable antipsychotic treatment and meet the entrance criteria are
planned to be randomized into this trial.
Patients are enrolled in the trial once informed consent has been signed. Patients suitable after
screening will be randomized to the 12 week treatment period assigned at a ratio of 1:1:1:1:2
to one of five arms:
-
2 mg BI 425809 
-
5 mg BI 425809 
-
10 mg BI 425809 
-
25 mg BI 425809
-
placebo 
The randomized treatment will be double blind.
After completion of the 12-week double-blind treatment period, or following early 
discontinuation of trial medication at any time point, patients will complete the 4 week 
follow-up period, with two follow up visits to capture immediate effects at 1 week after last 


Boehringer Ingelheim                                                                                                      28 Mar 2019
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intake of trial medication and again at 4 weeks after last intake of trial medication. Safety 
will be formally evaluated at each visit until end of the observational period which is 28 days 
after end of treatment or for an appropriately longer time in case of unresolved adverse 
events. Individual patient participation is concluded when the patient has completed their last 
planned visit.
3.1.1
Administrative structure of the trial
Boehringer Ingelheim has appointed a Trial Clinical Monitor, 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,
-
order the materials as needed for the trial, 
-
ensure appropriate training and information of local clinical monitors (CML), 
Clinical Research Associates (CRAs), and Investigators of participating countries.
 has been selected as service provider to support the following tasks
related to the neuropsychological assessments: necessary rater prequalification, rater training,
provision of rater materials and central review of assessments (details will be provided in the 
ISF).
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 will be 
defined according to BI SOPs. 
A list of responsible persons and relevant local information (as protocol reference, if 
applicable) can be found in the ISF.
A Coordinating Investigator is nominated and will be responsible to coordinate Investigators 
at different centres participating in this multicentre trial. Tasks and responsibilities will be 
defined in a contract. Relevant documentation on the participating (Principal) Investigators 
and other important participants, including their curricula vitae, will be filed in ISF.
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
3.2
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. The 
primary analysis of efficacy is planned for 12 weeks of treatment. The 1 and 4 weeks post-
treatment follow-up visits is considered to be sufficient to evaluate the pharmacodynamic 
effect of BI 425809 after discontinuation, to capture withdrawal effects and allow for 
assessment of reversibility of any unexpected side-effects.


Boehringer Ingelheim                                                                                                      28 Mar 2019
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Proof of clinical concept and dose finding are combined within this single phase II trial. In 
order to achieve both aims in an efficient way, i.e., with a comparably large success 
probability, the generalized MCPMod approach (R10-1424) has been implemented as the 
statistical design. This approach is able to incorporate potential relationships between the 
different doses into the evaluations via optimal test contrasts which increases the probability 
of success compared with clinical multiple comparison procedures. MCPMod has been 
evaluated by the EMA recently and is considered to be an efficient statistical methodology 
for model-based design and analysis of phase II dose finding studies under model uncertainty 
(EMA qualification opinion). As a second step for designing the trial efficiently the allocation 
ratio has been chosen to be 1:1:1:1:2 for the treatment groups compared with the placebo. 
Thereby the success probability of the trial is increased further compared to a balanced 
allocation ratio whilst keeping the risk of a false positive outcome at the same level. A 
sufficiently broad set of candidate shapes for the dose-response relationship has been chosen 
including monotonic and non-monotonic options. Details of the statistical approach including 
the set of candidate models as well as a sample size justification are given in Section 7.
SELECTION OF TRIAL POPULATION
3.3
It is planned that around 80 trial centres in 11 countries will be participating in this trial and
a sufficient number of patients will be screened for the trial to ensure that 504 patients are 
randomized to trial treatment.
It is expected that approximately 5-10 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 20 
patients per site must be obtained from the TCM. 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 
centers when such a number of patients has been screened that it is anticipated that a 
sufficient number of patients will be randomized to trial treatment. Investigators will be 
notified when the appropriate number of patients has been screened and screening is 
complete, and will not be allowed to recruit additional patients for this trial. Patients who 
have completed Visit 1 procedures prior to notification of the termination of recruitment will 
be allowed to continue in the trial, if they meet all entry criteria and they are able to follow 
the visit schedule specified in the protocol.
A log of all patients enrolled into the trial (i.e. who have signed informed consent) will be 
maintained in the ISF at the investigational site irrespective of whether they have been treated 
with investigational drug or not.


Boehringer Ingelheim                                                                                                      28 Mar 2019
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3.3.1
Main diagnosis for trial entry
Only patients with established Schizophrenia (as per 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 (Source Documents) for the documentation requirements 
pertaining to the in- and exclusion criteria.
3.3.2
Inclusion criteria
1)
Patients must be capable of providing signed and dated written informed consent 
by date of Visit 1 in accordance with GCP and the local legislation.
2)
Men or women 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 
months (hospitalization for social management and/or day hospital 
programs within this time are acceptable) prior to randomization
Medically stable over the prior 4 weeks and psychiatrically stable without 
symptom exacerbation within 3 months prior to randomization
patients who have no more than a “moderate severe”  rating on  the PANSS 
positive items P1, P3-P7 (item score ≤ 5) and no more than a “moderate” 
rating on the PANSS positive item P2 (item score ≤ 4)  
4)
Current antipsychotic and concomitant psychotropic medications as assessed at 
Visit 1 must meet the criteria below: 
patients may have up to 2 antipsychotics (typical and/or atypical)
patients must be maintained on current typical and/or atypical 
antipsychotics other than Clozapine and on current dose for at least 4 weeks 
prior to randomization and/or maintained on current long acting injectable 
antipsychotics and current dose for at least 3 months prior to randomization
patients must be maintained on current concomitant psychotropic 
medications, anticholinergics, antiepileptics and/or lithium for at least 3 
months prior to randomization and on current dose for at least 4 weeks prior 
to randomization.


Boehringer Ingelheim                                                                                                      28 Mar 2019
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5)
Women of child-bearing potential* must be ready and able to use highly effective
methods of birth control per ICH M3 (R2) that result in a low failure rate of less 
than 1% per year when used consistently and correctly. Such methods should be 
used throughout the study and the patient must agree to periodic pregnancy 
testing during participation in the trial. A list of contraceptive methods meeting 
these criteria will be provided in the patient information
*Women of childbearing potential are defined as:
Any female who has experienced menarche and does not meet the criteria for 
“women not of childbearing potential” as describe below. 
Women not of childbearing potential are defined as: Women who are 
postmenopausal (12 months with no menses without an alternative medical cause) 
or who are permanently sterilized (e.g. hysterectomy, bilateral oophorectomy or 
bilateral salpingectomy. 
6)
Patients must exhibit reliability, physiologic capability, and an educational level
sufficient to comply with all protocol procedures, in the investigator’s opinion
7)
Patients must have an identified informant who will be consistent throughout the 
study. It is recommended that the informant should interact with the subject at 
least 2 times a week.
3.3.3
Exclusion criteria
1)
Patients who on the Mini-international neuropsychiatric Interview (M.I.N.I) have 
a categorical diagnosis of another current major psychiatric disorder
2)
Diseases of the central nervous system that may impact the assessment of the 
cognitive tests as per investigator’s opinion
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 receiving another investigational drug or procedure within 30 days or 6 
half-lives (whichever is longer) or participation in another trial with any cognitive 
enhancing therapy or procedure within the last 6 months prior to randomization
5)
Patients participating in any formal cognitive remediation programme for at least 
4 sessions within the last 4 weeks prior to randomization
6)
Patients who have received electroconvulsive therapy within 6 months prior to 
randomization


Boehringer Ingelheim                                                                                                      28 Mar 2019
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7)
Patients who have been on BI 409306, encenicline or other investigational drug 
testing effects on cognition in schizophrenia within the last 6 months prior to 
randomization or who have previously been on bitopertin 
8)
Patients who have participated in a clinical trial with repeated MATRICS 
Consensus Cognitive Battery (MCCB) assessments within the last 6 months prior 
to randomization
9)
Patients who required change in ongoing stable benzodiazepine or sleep 
medication regimen within the last 4 weeks prior to randomization
10) Patients who have been treated with Clozapine within 6 months prior to 
randomization
11) Patients who received treatment with medical devices (e.g. TMS, neurofeedback)
for any psychiatric condition within the last 3 months prior to randomization
12) 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.)
13) 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)
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
15) Any suicidal ideation of type 4 or 5 in the Columbia Suicidal Severity Rating 
Scale (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) In the judgment of the investigator any clinically significant finding of the 
physical examination (including BP, PR and ECG) or laboratory value (as 
measured by the central laboratory at visit 1) that would jeopardize the patient´s 
safety while participating in the trial and their capability to participate
17) Any 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 and capability to participate in the trial as per 
investigator´s opinion.
18) Severe renal impairment defined as an eGFR < 30mL/min/1.73m² in the 
screening central lab report 


Boehringer Ingelheim                                                                                                      28 Mar 2019
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19) Indication of liver disease, defined by serum levels of either ALT (SGPT), AST 
(SGOT), or alkaline phosphatase above 3 times upper limit of normal (ULN) as 
determined in the screening central lab report 
20) Known history of HIV infectionand/or a positive result for ongoing Hepatitis B or 
C infection on the Visit 1 central lab report
21) Medical history of primary or recurrent malignant disease with the exception of 
resected cutaneous squamous cell carcinoma in situ, basal cell carcinoma, 
cervical carcinoma in situ or in situ prostate cancer with a normal prostate 
specific antigen (PSA) post treatment  
22) Significant or unstable physical condition that in the investigator´s judgement 
may require change in medication or hospitalisation that would impact cognitive 
function, or planned elective surgery requiring general anesthesia during the 
study period
23) Hemoglobin less than 120 g/L (12g/dL) in men or 115 g/L (11.5g/dL) in women
24) History of hemoglobinopathy such as thalassemia major or sickle-cell anemia
25) Women who are pregnant, nursing, or who plan to become pregnant while in the 
trial or
Men who are able to father a child, unwilling to be abstinent or use adequate
contraception for the duration of study participation and for at least 28 days after 
treatment has ended
26) Significant history of drug abuse disorder (including alcohol, as defined in DSM-
5-substance use disorder or in the opinion of the investigator) within the last 6 
months prior to informed consent, or a positive urine drug screen at screening
(except for Benzodiazepines taken according to prescription and as an ongoing, 
stable regimen )(for a list of drugs assessed in the urine drug screen, please refer 
to Table 5.3.3:1). 
27) Patients who are not fluent in the language of the batteries/questionnaires which 
will be used in the country
28) Patients for which cognitive impairment or symptom severity compromises the 
validity of the cognitive outcome measures, in the clinical judgement of the 
investigator
29) Patient who did not make an effortful attempt to complete the cognition battery at 
screening in the clinical judgement of the investigator


Boehringer Ingelheim                                                                                                      28 Mar 2019
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3.3.4
Removal of patients from therapy or assessments
Removal of individual patients
3.3.4.1
An individual patient is to be withdrawn from trial treatment if:

The patient withdraws consent for study treatment or study participation, without the need 
to justify the decision

The patient needs to take concomitant drugs that interfere with the investigational 
product(s) in the clinical judgement of the investigator´s (please refer to Section 4.2.2).

The patient can no longer be treated with trial medication for other medical reasons (such 
as surgery, adverse events, other diseases, or pregnancy)

The patient exhibits suicidality, in the clinical judgement of the investigator or       
according to criteria below:
•
Any suicidal behavior (i.e. actual attempt, interrupted attempt, aborted attempt or 
preparatory acts or behavior)
•
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)

The patient needs to stop all current antipsychotic or concomitant psychotropic
medications.

The patient’s disease state dramatically worsens, in clinical judgement of investigator
If a patient becomes pregnant during the trial the study medication will be stopped, the
patient will be discontinued from the trial and the patient will be followed up until birth or
otherwise termination of the pregnancy. For further information, including the process for 
follow-up on the outcome of the pregnancy please see Section 5.3.7.
A patient can be discontinued after discussion between Sponsor and Investigator if eligibility
criteria are being violated, or if the patient fails to comply with the protocol (e.g. 
nonattendance at study assessments).
Patients who discontinue or withdraw from the study after randomization (Visit 2) will be
considered as “early discontinuations” and the reason for premature discontinuation must be
recorded in the eCRFs and in the source documents. 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.
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 (e.g. adverse events) must be recorded in the 
(e)CRF. These data will be included in the trial database and reported.
Patients who drop out prior to randomization will be considered screening failures. They will 
be recorded as screening failures in the Electronic Case Report Form (eCRF) and no further 
follow-up is required. The data will be included in the trial database and will be reported.


Boehringer Ingelheim                                                                                                      28 Mar 2019
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Discontinuation of the trial by the sponsor
3.3.4.2
Boehringer Ingelheim reserves the right to discontinue the trial overall or at a particular trial 
site at any time for the following reasons:
1. Failure to meet expected enrolment goals overall or at a particular trial site
2. 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 GCP, the CTP, or the contract disturbing 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).


Boehringer Ingelheim                                                                                                      28 Mar 2019
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4.
TREATMENTS
TREATMENTS TO BE ADMINISTERED
4.1
BI 425809 tablets have been manufactured by BI Pharma GmbH & Co. KG
4.1.1
Identity of BI investigational product(s) and comparator product(s)
The characteristics of the test products are as shown below.
Table 4.1.1: 1
Test product 1:
Substance:
BI 425809
Pharmaceutical formulation:
Tablet
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
1mg
Posology
2-0-0 for the dose group of 2mg
Route of administration:
oral
Table 4.1.1: 2
Test product 2:
Substance:
BI 425809
Pharmaceutical formulation:
Tablet
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
5 mg
Posology
1-0-0 for the dose group of 5mg
2-0-0 for the dose group of 10mg
Route of administration:
oral


Boehringer Ingelheim                                                                                                      28 Mar 2019
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Table 4.1.1: 3
Test product 3:
Substance:
BI 425809
Pharmaceutical formulation:
Tablet
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
25 mg 
Posology
1-0-0 for the dose group of 25mg
Route of administration:
oral
The characteristics of the reference products are as shown below.
Table 4.1.1: 4
Reference product 1:
Substance:
Placebo matching BI 425809 1mg and 5mg
Pharmaceutical formulation:
Tablet
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
-
Posology
1-0-0 for the dose group of 5mg
2-0-0 for the dose group of 25mg and the placebo 
dose group
Route of administration:
oral
Table 4.1.1: 5
Reference product 2
Substance:
Placebo matching BI 425809 25 mg
Pharmaceutical formulation:
Tablet
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
-
Substance:
Placebo matching BI 425809 25 mg
Posology
1-0-0 for the dose group of 2mg, 5mg, 10mg and the 
placebo dose group
Route of administration:
oral


Boehringer Ingelheim                                                                                                      28 Mar 2019
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4.1.2
Method of assigning patients to treatment groups
During Visit 2 and after the patient’s eligibility has been confirmed, the treatment will be 
assigned via Interactive Response Technology (IRT). To facilitate the use of the IRT, the 
Investigator will receive all necessary instructions. A copy of the IRT manual will be 
available in the ISF.
Patients will be randomly assigned, in a 1:1:1:1:2 ratio to either
i.
2mg BI 425809
ii.
5mg BI 425809
iii.
10mg BI 425809
iv.
25mg BI 425809
v.
Placebo
Details on randomization are provided in Section 7.6.
Patient assignment to the treatment groups will be determined by a computer generated
random sequence. Access to the randomization code will be controlled and documented. For
further details please refer to Sections 4.1.5.1 and 4.1.5.2.
The kit(s) corresponding to the assigned medication number(s) should be given to the patient
and the number of the kit(s) that was/were dispensed will be entered in the eCRF. 
Using this procedure, relevant parties will be blinded to the treatment group assignment.
4.1.3
Selection of doses in the trial
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 (150mg per day).
The doses selected for this trial cover the estimated therapeutic range and include a safety
margin (Please refer to Section 1.2 for more details).
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 and Visit 4. 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 both Visit 2 and Visit 4 patients will receive one 
treatment kit containing supplies for 42 treatment days (plus 7 day reserve).
Following the screening period, patients who qualify according to entry criteria will be
randomized to one of the five treatment groups of the treatment period to be evaluated as 
outlined in Table 4.1.4: 1.


Boehringer Ingelheim                                                                                                      28 Mar 2019
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Since the tablet size of 1mg and 5 mg is smaller than the tablets size of 25mg, the number of
tablets per day will be 3 for all treatments (once daily) to maintain blinding.
Table 4.1.4: 1
Treatment administration per dose group and day (first treatment 
period)
Treatment group
Dose
Total units per daily dose
BI 425809 2mg
BI 1mg/BI 1mg /placebo 2**
3
BI 425809 5mg
BI 5mg/placebo 1*/placebo 2**
3
BI 425809 10mg
BI 5mg/BI 5mg/placebo 2**
3
BI 425809 25mg
Placebo 1*/placebo 1*/BI 25mg
3
Placebo
Placebo 1*/placebo 1*/placebo 2**
3
*placebo 1 matching BI 425809 1mg and 5mg tablets
**placebo 2 matching BI 425809 25mg tablets
Patients should be instructed to take three tablets orally with water and with or without food 
in the morning, except for visit days where patients will be given their daily dose at the trial 
site. If a dose is missed by more than 12 hours, that dose should be skipped and the next dose
should be taken as scheduled. On days prior to a visit, the dose should be taken
approximately 24 hours before the planned dose at the visit. 
The first dose of study medication will be taken at the end of Visit 2 under supervision of the 
investigator or site staff. The last dose of study medication should be taken on the day before 
the End of Treatment visit.
Patients should be instructed not to take their trial medication in the morning before visit
days, as they will be dosed at the site. Patients who fail to do so should have the visit 
rescheduled as soon as possible, ideally on the following day.
A dose reduction of BI 425809 is not possible.
4.1.5
Blinding and procedures for unblinding
Blinding
4.1.5.1
Patients, Investigators and everyone involved in trial conduct or analysis or with any other
interest in this double-blind trial will remain blinded with regard to the randomized treatment 
assignments until after database lock. However, due to the requirements to report
Suspected Unexpected Serious Adverse Reactions (SUSARs), it may be necessary for a
representative from BI’s drug safety group to access the randomization code for individual
patients during study conduct. In such cases, access to the code will only be permitted by
authorized drug safety representatives. Access to the code will be via the IRT system.
The randomization code will be kept blinded by Clinical Trial Support up to database lock.
Please refer to Section 4.1.5.2 for the rules regarding breaking the code for an individual or 
for all patients in emergency situations.


Boehringer Ingelheim                                                                                                      28 Mar 2019
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Unblinding and breaking the code
4.1.5.2
Emergency unblinding will be available to the Investigator / Pharmacist / investigational drug 
storage manager via IRT. It must only be used in an emergency situation when the identity of 
the trial drug must be known to the Investigator in order to provide appropriate medical 
treatment or otherwise assure safety of trial participants. 
However, due to the requirements to report Suspected Unexpected Serious Adverse Reactions 
(SUSARs), it may be necessary for a representative from BI’s drug safety group to access the 
randomization code for individual patients during study conduct.
Each site receives a manual from the IRT provider that contains instructions on how to 
unblind the treatment of a patient via the IRT (via 24-hour Emergency helpline). If the code 
break for a patient is accessed, the Sponsor must be informed immediately. The reason for 
accessing the code break, together with the date, must be documented on the appropriate 
eCRF page and in the source documents. In case third party needs to break the code, 
however, when the Investigator cannot be reached, the code can be opened by calling 
emergency code manager.
4.1.6
Packaging, labelling, and re-supply
Trial medication will be labelled with the trial identification and medication code number. It
will be dispensed as indicated in the Flow Chart. At each dispensing, supplies for 42 
treatment days (plus 7 day reserve) will be given to the patient. 
Supply and re-supply will be managed by the IRT according to the IRT Manual.
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 local clinical monitor 
(as provided in the list of contacts) must be contacted immediately.


Boehringer Ingelheim                                                                                                      28 Mar 2019
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4.1.8
Drug accountability
The Investigator < and/or > 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 trial protocol by the IRB / ethics committee, 

Availability of a signed and dated clinical trial contract between the Sponsor and the head 
of the investigational site,

Approval/notification of the regulatory authority, e.g. competent authority,

Availability of the curriculum vitae of the principal Investigator,

Availability of a signed and dated clinical trial protocol

Availability of the proof of a medical license for the principal Investigator

For US: Availability of Form 1572
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 alternative disposal of unused products. 
These records will include dates, quantities, batch / serial numbers, expiry (‘use- by’) dates, 
and the unique code numbers assigned to the investigational 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.
CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE 
4.2
TREATMENT
4.2.1
Rescue medication, emergency procedures, and additional treatment(s)
No rescue medication, emergency procedure or additional treatments are foreseen for this 
trial.
Throughout the duration of the trial patients should continue to take their current 
antipsychotic and concomitant psychotropic medications, the dose of which should remain 
unchanged if at all possible.  These medications will not be provided as part of the clinical 
trial supplies, unless required by local laws and regulations.
Any change in dose of antipsychotic and concomitant psychotropic medications should be 
recorded in the source documentation and on the appropriate pages of the eCRF.
Any additional treatment that is considered necessary for the patient’s welfare may be given 
at the discretion of the Investigator.


Boehringer Ingelheim                                                                                                      28 Mar 2019
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4.2.2
Restrictions
Restrictions regarding concomitant treatment
4.2.2.1
The following drugs are prohibited for 6 months prior to randomization and during the trial 
period:
Clozapine (atypical antipsychotic medication), 
Sarcosine, cycloserine, serine and glycine, 
stimulants (e.g. methylphenidate, dextroamphetamine) and modafinil
tricyclic antidepressants
In addition, the following drugs are restricted for the timeframes specified below:
Patients should not be on maintenance therapy with opioids (e.g. methadone, suboxone) 
during the trial period.
Systemic steroids should be discontinued more than 30 days prior to randomization.
Use of Olanzapine is permitted but should be limited to a maximum daily dose of 25mg
during the trial period.
patients must be maintained on current concomitant psychotropic medications, 
anticholinergics, antiepileptics and/or lithium for at least 3 months prior to 
randomization and on current dose for at least 4 weeks prior to randomization and 
during the trial period.
Patients should not receive more than 4mg benztropine or no more than 50mg 
diphenhydramine (or equivalent doses of other anticholinergic or antihistaminic
medication) and should receive the last dose at least 8hrs before cognitive testing
during the trial period.
New or changes in dose and frequency of psychosocial treatments, including but not 
limited to social skills treatment or vocational treatment is not permitted during the trial
period. If patients are on these treatments, this should have not been started or changed 
in the past three months prior to randomization.
Patients participating in any formal cognitive remediation program for at least 4 
sessions within the last month prior to randomization are excluded. 
Use of moderate or strong CYP3A4 inhibitors or inducers is not permitted within the 
last 30 days prior to randomization and during the trial participation. (For a list of 
moderate or strong CYP3A4 inhibitors and inducers, see Investigator Site File).
CYP3A4 sensitive drugs with narrow therapeutic index (such as cyclosporine or 
fentanyl, refer to list in ISF) are not permitted during the trial period.
Please note: CYP3A4 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.
Any medication that may interfere with the action of BI 425809 or whose action may 
be altered by concomitant administration of BI 425809 during the treatment period and 


Boehringer Ingelheim                                                                                                      28 Mar 2019
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the 4-week follow-up period, in the clinical judgment of the investigator, is not 
permitted.
No entering or modification of smoking-cessation programs may occur during the 
conduct of the trial.
Patient will not begin or increase frequency/duration of psychotherapy during the trial 
period, receive electroconvulsive therapy, nor begin any type of 
traditional/complementary therapies. Use of hypnotics and anxiolytics is not prohibited; 
however, there should be no change in benzodiazepine or sleep medication regimen 
within the last 4 weeks prior to randomization. Last intake before cognitive testing 
should be at least 8 hours.
Restrictions on diet and life style
4.2.2.2
Dietary supplements and products including St. John's wort (Hypericum perforatum) and 
herbal remedies that may impact the assessment of cognitive tests in the investigator´s 
judgement are not permitted starting 7 days before the first administration of trial medication 
until the end of treatment.
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 of alcohol or drugs during study as defined in the fifth edition of
the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) or in the opinion of the
investigator, or as indicated by a positive urine drug screen. For a list of drugs assessed by the 
urine drug screen please refer to Table 5.3.3:1.
There are no other restrictions on diet, exercise, or smoking except that the patient’s usual
habits, including nicotine and caffeine intake, should not be significantly changed.
Patients do not have to come fasted to any trial visit.
TREATMENT COMPLIANCE
4.3
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 investigator site file.
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 the number of tablets
taken, divided by the number of tablets which should have been taken according to the 


Boehringer Ingelheim                                                                                                      28 Mar 2019
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scheduled period, multiplied by 100. Compliance will be verified by the on-site monitor 
authorized by the Sponsor.
Treatment compliance (%) =
Number of tablets actually taken 100
Number of tablets which should have been taken
If the number of doses taken is not between 80-120%, site staff will explain the patient the 
importance of treatment compliance.


Boehringer Ingelheim                                                                                                      28 Mar 2019
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5.
VARIABLES AND THEIR ASSESSMENT 
TRIAL ENDPOINTS
5.1
5.1.1
Primary Endpoint(s)
Change from baseline in cognitive function as measured by the composite MCCB score after 
12 weeks of treatment is the primary efficacy endpoint.
The 10 tests of the MCCB with corresponding cognitive domains are listed in Table 5.1.1: 1 
below:
Table 5.1.1: 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)
Letter-Number Span test (LNS)
Working Memory (verbal)
Neuropsychological Assessment Battery, mazes 
subtest (NAB mazes)
Reasoning and Problem Solving
Brief Visuospatial Memory Test- Revised (BVMT-R)
Visual Learning
Category Fluency test, animal naming
Speed of Processing
Mayer-Salovey-Caruso Emotional Intelligence Test, 
managing emotions branch (MSCEITTM ME) 
Social Cognition
Continous Performance Test, Identical Pairs version 
(CPT-IP)
Attention/ Vigilance


Boehringer Ingelheim                                                                                                      28 Mar 2019
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5.1.2
Secondary Endpoint(s)
Change from baseline in everyday functional capacity as measured by Schizophrenia 
Cognition Rating Scale (SCoRS) total score after 12 weeks of treatment is the 
secondary efficacy endpoint.
The 20 items of the SCoRS specifically assess cognitive functioning in each of the 
seven MCCB cognitive domains:
-
Memory: 4 items
-
Learning: 2 items
-
Attention: 3 items
-
Working Memory: 2 items
-
Problem Solving 3 items
-
Processing/Motor speed: 2 items
-
Social Cognition: 3 items
-
Language: 1 item
Percentage of patients with (S)AEs (including clinically relevant abnormalities of 
physical examination, vital signs, ECG test and laboratory tests)


Boehringer Ingelheim                                                                                                      28 Mar 2019
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Further safety endpoints: 
Further exploratory endpoints to assess safety are as shown below:
Occurrence of Protocol-specified AESI (adverse events of special interest)
Worsening of disease state as assessed by PANSS
Suicidality as assessed by C-SSRS
ASSESSMENT OF EFFICACY
5.2
5.2.1
Assessment of primary and secondary efficacy endpoints
Change in cognitive function, everyday living skills and disease state will be measured by the 
batteries, scales and questionnaires listed below.
MATRICS Consensus Cognitive Battery (MCCB) will be used to evaluate the effects of 
BI 425809 on cognitive functions at Screening Visit (Visit 1), Randomization
Visit (Visit 2, baseline), Visit 4 and (early) End of Treatment visit (e)EOT Visit.
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)
Schizophrenia Cognition Rating Scale (SCoRS) will be used to evaluate the everyday
functional capacity at Randomization Visit (Visit 2) and (early) End of Treatment visit
((e)EOT Visit).
SCoRS is a 20-item interview-based assessment of cognitive deficits and the degree to which
they affect day-to-day functions. Each item is rated on a 4-point scale. Higher ratings reflect a
greater degree of impairment. The composite score will be the average of non-missing
response. If five or more of the 20 items is missing, the composite score will be missing
(R13-2345; R16-4322).


Boehringer Ingelheim                                                                                                      28 Mar 2019
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M.I.N.I
The Mini-international neuropsychiatric interview is a short structured clinical interview 
which enables researchers to make diagnoses of psychiatric disorders (R07-1303). It should 
be performed at Screening Visit for eligibility confirmation.


Boehringer Ingelheim                                                                                                      28 Mar 2019
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Boehringer Ingelheim                                                                                                      28 Mar 2019
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ASSESSMENT OF SAFETY
5.3
5.3.1
Physical examination
A physical examination will be carried out as described in the Flow Chart.
A complete physical examination including, but not limited to, general appearance, skin, 
neck, eyes, ears, nose, throat, breast, lungs, heart, abdomen, back, lymph nodes, extremities, 
and nervous system will be performed. The physical examination will include examination of 
known and suspected sites of disease. A complete PE is also required at EOT Visit (week 12) 
or at early discontinuation (eEOT Visit).
Clinically relevant abnormal findings noticed after baseline assessment will be reported as
(S)AEs.
Body weight and height will be measured as indicated in the Flow Chart.
5.3.2
Vital Signs
Vital signs will be recorded at the study visits as described in the Flow Chart, including the 
(early) End of Treatment visit and the Follow-up Visit 2 (4 weeks after the end of treatment). 
Temperature, systolic/diastolic blood pressure, pulse rate will be measured after patients have 
been sitting comfortably for at least five minutes. The height is measured only at screening 
visit (Visit 1). 
Blood pressure measurement can be done manually or electronically (preferably with the 
same device at every visit).


Boehringer Ingelheim                                                                                                      28 Mar 2019
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Clinically relevant abnormal findings noticed after baseline assessment will be reported as
(S)AEs.
5.3.3
Safety laboratory parameters
The laboratory tests listed in Table 5.3.3: 1 will be performed at the central laboratory service 
provider. Patients do not have to be fasted for the blood sampling for the safety laboratory. 
Instructions on collection, handling/ processing, and shipping of the samples will be provided 
in the investigator site file by the central laboratory. For time points of laboratory sampling 
refer to the Flow Chart.
Laboratory results of the patients will be available to the respective investigator and to the BI 
Clinical Monitor of each country (central laboratory website), and selected abnormal 
laboratory alerts will be sent automatically to the sites and to the sponsor within 24 hours. 
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 
eCRF either on baseline condition (from V1 test) or on adverse event page (from subsequent 
visits test).
The following lab parameters will not be determined at each study visit:
TSH at screening only
Vitamin B12 and folate at screening only


Boehringer Ingelheim                                                                                                      28 Mar 2019
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Table 5.3.3: 1 Safety laboratory tests
Category
Test name
Haematology  
Hematocrit (Hct)
Hemoglobin (Hb)
(for patients with >2g/dL decrease in hemoglobin
since baseline, the following tests will be added:
serum ferritin, serum iron, TIBC, reticulocyte index)
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
Chemistry
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
eGFR


Boehringer Ingelheim                                                                                                      28 Mar 2019
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Table 5.3.3: 1 Safety laboratory tests (cont.)
Category
Test name
Pregnancy test  (females only)
Human urine chorionic gonadotropin 
Urinalysis (Stix) 
Urine Nitrite
Urine Protein
Urine Glucose
Urine Ketone
Urobilinogen
Urine Bilirubin
Urine RBC/ Erythrocytes
Urine WBC/ Leukocytes
Urine pH
Urine creatinine
Drug screening (urine) 
Cannabis
Benzodiazepine
Barbiturates
Opiates
Cocaine
Amphetamines
Methadone
PCP
Infections screening 
(only at the screening visit)
Hepatitis B Surface antigen (qualitative)
Hepatitis C antibodies (qualitative)
5.3.4
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. 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.


Boehringer Ingelheim                                                                                                      28 Mar 2019
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Additional ECGs may be collected by the investigator for safety reasons. Clinically relevant 
findings noticed at baseline assessment should be reported as baseline condition. Clinically 
relevant abnormal findings noticed after baseline assessment will be reported as adverse 
events 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.
5.3.5
Other safety parameters
Assessment of disease state
5.3.5.1
Positive and Negative Syndrome Scale (PANSS) will be used to evaluate the disease state. It
contains 30-items including seven positive symptom items, seven negative symptom items
and 16 general psychopathology symptom items. Each item is scored on the same seven-point
severity scale. Fourteen of the PANSS items require input from an informant. A trained rater
interviews the patient and the informant, estimated to take 30-40 minutes for evaluating the
subjects’ disease state at Screening Visit (Visit 1), Visit 2, Visit 4 and (e)EOT Visit. If the
patient’s disease state dramatically worsens, the patient should be withdrawn from the trial
(Please refer to Section 3.3.4.1). Any person who has been capable of observing the patient
over the past week may act as the informant. It is recommended that the informant should
interact with the subject at least 2 times a week. If the informant is not available for in person
interview at the scheduled visit, telephone interview is acceptable.
Assessment of suicidality
5.3.5.2
Suicidal risk is 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 is a self-rated
version of the C-SSRS using phone. 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 answering all relevant questions. This assessment should be conducted early in the 
visit to provide sufficient time for the report to be received at the trial site prior to subject 
departure. At the conclusion of each assessment, the site will receive an eC-SSRS Findings 
Report via email or fax. The report presents the findings for suicidal ideation, intensity of 
ideation, suicidal behavior, and lethality / medical damage (for actual suicide attempts only).


Boehringer Ingelheim                                                                                                      28 Mar 2019
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The C-SSRS / eC-SSRS has been widely used in large multinational clinical trials. The 
eCSSRS will be administered at the screening visit (using the ‘screening / baseline’ version)
with the aim to exclude subjects with active moderate or severe symptomatology within a
specified time prior to the screening visit. The life time history of suicidal ideation and 
behavior will also be recorded. After the screening visit the assessment ‘since last visit’ will
be performed at each clinic or phone visit (‘since last visit’ version). The investigator is to 
review positive and negative reports for plausibility and clinical relevance. Doubtful reports 
may be repeated or reports may be validated by a consulting psychiatrist. In cases when 
assessments need to be validated, the investigator-rated paper CSSRS questionnaire is to be 
used by a psychiatrist trained and certified for this questionnaire in order to collect data in a 
systematic way. The investigator rating on investigator-rated CSSRS will supersede the 
findings from the telephone interview. 
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, and/ or is to consult a psychiatrist. If the positive report is confirmed, appropriate
actions for the subject’s safety have to be initiated.
5.3.6
Assessment of adverse events
Definitions of AEs 
5.3.6.1
Adverse event
An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a medicinal product and which does not necessarily have 
to have a causal relationship with this treatment.
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product.
Adverse reaction
An adverse reaction is defined as a response to a medicinal product which is noxious and
unintended. Response in this context means that a causal relationship between a medicinal
product and an adverse event is at least a reasonable possibility. Adverse reactions may arise
from use of the product within or outside the terms of the marketing authorisation or from
occupational exposure. Conditions of use outside the marketing authorization include offlabel
use, overdose, misuse, abuse and medication errors.
Serious adverse event
A serious adverse event (SAE) is defined as any AE which:
results in death,
is life-threatening,
requires inpatient hospitalisation or prolongation of existing hospitalisation,
results in persistent or significant disability or incapacity,


Boehringer Ingelheim                                                                                                      28 Mar 2019
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is a congenital anomaly/birth defect,
or
is to be deemed serious for any other reason if it is an important medical event when 
based upon appropriate medical judgment which may jeopardize the patient and may 
require medical or surgical intervention to prevent one of the other outcomes listed in the 
above definitions.
Life-threatening in this context 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.
All reports of suicidal ideation type 4 or 5 and all reports of suicidal behavior from 
prospective monitoring in CSSRS (see Section 5.3.5.2 for details) that occur after the baseline 
visit are also considered to be life-threatening and must be reported as SAEs by the
investigator.
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 adverse event 
(AE) as defined in the protocol, and if it is considered an AE then it must be reported 
accordingly.
For ‘Self-injurious behavior, no suicidal intent’ (Type 11) standard AE / SAE reporting rules 
are to be applied.
Cancers of new histology and exacerbations of existing cancer must be classified as a serious 
event regardless of the duration between the discontinuation of the drug and must be reported 
as described in Section 5.3.7 Adverse event collection and reporting, subsections “AE 
collection” and “AE reporting to sponsor and timelines”.
For Japan only: The following events will be handled as “deemed serious for any other 
reason”. An AE which possibly leads to disability will be reported as an SAE.
AEs considered “Always Serious”
In accordance with the European Medicines Agency initiative on Important Medical Events, 
Boehringer Ingelheim has set up a list of AEs, which by their nature, can always be 
considered to be “serious” even though they may not have met the criteria of an SAE as given 
above.
The latest list of “Always Serious AEs” can be found in the RDC. A copy of the latest list of 
“Always Serious AEs” will be provided to you upon request. These events should always be 
reported as SAEs as described in Section 5.3.7.
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. AESI 


Boehringer Ingelheim                                                                                                      28 Mar 2019
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need to be reported to the Sponsor’s Pharmacovigilance Department within the same 
timeframe that applies to SAE, see Section 5.3.7.
The following are considered as AESIs:
Hepatic injury
A hepatic injury is defined by the following alterations of hepatic laboratory parameters: 

an elevation of AST and/or ALT >3 fold ULN combined with an elevation of total 
bilirubin >2 fold ULN measured in the same blood draw sample, and/or

marked peak 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 via the 
RDC-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 of AEs
The intensity of the AE should be judged based on the following:
Mild:
Awareness of sign(s) or symptom(s) that is/are easily tolerated
Moderate:
Enough discomfort to cause interference with usual activity
Severe:
Incapacitating or causing inability to work or to perform usual activities
Causal relationship of AEs
Medical judgment 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.
Yes:
There is a reasonable causal relationship between the investigational product 
administered and the AE.
No:
There is no reasonable causal relationship between the investigational product 
administered and the AE.
5.3.7
Adverse event collection and reporting
AE Collection
The following must be collected and documented on the appropriate CRF(s) / eCRF by the 
Investigator:

From signing the informed consent onwards through the Residual Effect Period (REP)
until the individual patient´s end of trial:
all AEs (serious and non-serious) and all AESIs.


Boehringer Ingelheim                                                                                                      28 Mar 2019
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
After the individual patient’s end of trial: 
the investigator does not need to actively monitor the patient for AEs but should only 
report relevant SAEs and relevant AESIs of which the investigator may become aware of.
Figure 5.3.7: 1 Collection and reporting of AEs/SAEs during the study
The REP is defined as 11 days after the last trial medication application. All AEs which 
occurred through the treatment phase and throughout the REP will be considered as on 
treatment (please also see Section 7.3.4). Events which occurred after the REP will be 
considered as post treatment events.
AE reporting to sponsor and timelines
The Investigator must report SAEs, AESIs, and non-serious AEs which are relevant for the 
reported SAE or AESI, on the BI SAE form via fax immediately (within 24 hours ) to the 
Sponsor’s unique entry point (country specific contact details will be provided in the ISF). 
The same timeline applies if follow-up information becomes available. In specific occasions 
the Investigator could inform the Sponsor upfront via telephone. This does not replace the 
requirement to complete and fax the BI SAE form.
Before administration of study medication at Visit 2, site staff will remind patients to report 
“any unusual visual perception they may experience”. If patients report a change in 
perception or any vision-related AE, site staff must record the patient’s verbatim description 
in the source documents and report it in the same way in the CRF (and SAE form, if
applicable). A local ophthalmology assessment will be required if any visual AE is rated as 
moderate or severe by the subject or at the discretion of the PI. The ophthalmologist will act 
as a consultant to the Investigator and may offer advice on the proper management and
treatment for the reaction.
In case of anemia with unknown reason as measured by the central laboratory the investigator 
should consult with an internist. Any clinically relevant finding from the internist´s 
consultation should be reported as an AE.
For Japan: All SAEs and AESIs must be reported immediately to the head of the trial site.


Boehringer Ingelheim                                                                                                      28 Mar 2019
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With receipt of any further information to these events, a follow-up SAE form has to be 
provided. For follow-up information the same rules and timeline apply as for initial 
information.
Information required
For each AE, the Investigator should provide the information requested on the appropriate 
(e)CRF pages and the BI SAE form, e.g. onset, end date, intensity, treatment required, 
outcome, seriousness, and action taken with the investigational drug(s). The Investigator 
should determine the causal relationship to the trial medication and the trial procedures 
outlined under Section 6.2.
The following should also be recorded as an (S)AE in the (e)CRF and SAE form (if 
applicable):
Worsening of the underlying disease or of other pre-existing conditions
Changes in vital signs, ECG, physical examination and laboratory test results, if they are 
judged clinically relevant by the Investigator.
If such abnormalities already pre-exist prior trial inclusion they will be considered as 
baseline conditions.
All (S)AEs, including those persisting after individual patient’s end of trial must be followed 
up until they have resolved, have been sufficiently characterized, or no further information 
can be obtained.
Pregnancy
In the rare case that a female subject participating in this clinical trial becomes pregnant after 
having taken trial medication, the Investigator must report immediately (within 24 hours) the 
drug exposure during pregnancy (DEDP) to the Sponsor’s unique entry point (country-
specific contact details will be provided in the ISF). The Pregnancy Monitoring Form for 
Clinical Trials (Part A) should be used. 
The outcome of the pregnancy associated with the drug exposure during pregnancy must be 
followed up and reported to the Sponsor’s unique entry point on the Pregnancy Monitoring 
Form for Clinical Trials (Part B). 
As pregnancy itself is not to be reported as an AE, in the absence of an accompanying SAE, 
only the Pregnancy Monitoring Form for Clinical Trials and not the SAE form is to be 
completed. If there is an SAE associated with the pregnancy then the SAE has to be reported 
on the SAE form in addition. 
The ISF will contain the Pregnancy Monitoring Form for Clinical Trials (Part A and B).


Boehringer Ingelheim                                                                                                      28 Mar 2019
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Boehringer Ingelheim                                                                                                      28 Mar 2019
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Boehringer Ingelheim                                                                                                      28 Mar 2019
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OTHER ASSESSMENTS
5.6
Not applicable.
APPROPRIATENESS OF MEASUREMENTS
5.7
All measurements performed during this trial are acceptable measurements and commonly
used in monitoring safety aspects or assessing treatment response in patients with CIAS.
The scheduled measurements are appropriate to see drug induced changes in physical
examination, vital signs, ECG and standard laboratory values. These primary and secondary
efficacy endpoints and safety endpoints are standard and accepted for evaluation of safety
and tolerability of an oral drug, and they are widely used in this kind of studies. The period of 
12 weeks of treatment with BI 425809 is deemed appropriate to see a change in cognitive 
function in schizophrenic patients. 
Therefore, the appropriateness of all measurements applied in this trial is given.


Boehringer Ingelheim                                                                                                      28 Mar 2019
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6.
INVESTIGATIONAL PLAN
VISIT SCHEDULE
6.1
All patients are to adhere to the visit schedule as specified in the Flow Chart with time
window 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. The trial medication packs 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 adverse event 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. When the total sample 
size for the main study is reached, randomization in the imaging sub-study will stop and this 
may result in the number of patients randomized in the sub-study being less than 150 which is 
the planned sample size for the sub-study.
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
6.2
The following recommendations for the conduct of the neuropsychological assessments need
to be followed:

Each assessment of the Neuropsychological Rating Scales should preferentially be 
done by the same members of the site staff for a given patient throughout the study 
period. 

In addition, it is recommended that 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 should always be performed at the same time of the day, within a window 
of +/- 60 minutes at Visit 1, 2, 4 and/or (e) EOT. Preferably, the assessment of the
MCCB is done in the morning. If the cognitive testing can’t be started at the same 
time within the allowed time frame (±60 minutes) at a scheduled visit, the visit should 
be rescheduled within the allowed visit window.

Study procedures of Screening Visit (Visit 1), Visit 2, Visit 4 and (e)EOT Visit can be 
split into 2 sequential days. If the study procedures are split into 2 sequential days, the 
MCCB,  
 
should be performed at the first day of the two sequential days 
(i.e., the day prior to Day 1), and the psychopathologic assessments should be 
performed on the second day. 


Boehringer Ingelheim                                                                                                      28 Mar 2019
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
During the testing, patients are allowed to take short breaks as needed, in the
judgement of the rater/investigator. 

The members of the site staff that will be administering the Neuropsychological 
Rating Scales have to be properly trained (either at the investigator training or 
individually) 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.
Study procedures to be performed at each visit are listed in the Flow Chart. Additional details
regarding visit procedures are provided below.
Patients do not have to come fasted for any trial visit.
6.2.1
Screening and run-in period(s)
Screening Period
After patients have been informed about the trial, written informed consent in accordance 
with GCP and the local legislation must be obtained prior to any study related procedures 
taking place. Once consented, the patient is considered to be enrolled in the trial and to have 
started screening. The patient should be recorded on the enrolment log and be registered in 
the IRT system as a screened patient.
One additional written informed consent for unspecified pharmacogenomics study must be 
obtained if the patient is willing to provide the blood sample for DNA banking.
Screening (Visit 1) should take place from -28 days to -7 days before Visit 2.
Demographics consist of gender, age, ethnicity, smoking and alcohol history and will be
obtained after the main informed consent form is signed.
Baseline Conditions
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. The investigator will review the ECG recording and record any 
ECG abnormality of clinical significance under baseline conditions.


Boehringer Ingelheim                                                                                                      28 Mar 2019
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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 concomitant medications will be documented after the informed consent of main study is 
signed.
Once Visit 1 procedures are complete and laboratory results are received, inclusion/exclusion 
criteria must be reviewed again. If the patient is still eligible according to inclusion/exclusion 
criteria, the patient should be contacted to schedule next visit.
If a patient does not meet inclusion/exclusion criteria the patient must be recorded in eCRFs 
as a screen failure. Patient must be registered as screen failure in IRT.
Patients who failed screening may repeat the screening phase once after discussion between 
investigator and sponsor. Rescreening will only be allowed if the reasons for screening failure 
were reversible and have been resolved, based on investigator judgement. Permission to 
rescreen patients must be obtained from the TCM. The patient who will be rescreened needs 
to be re-consented. All the study procedures of Screening Visit (Visit 1) must be repeated.
Medical History:
Psychiatric and relevant non-psychiatric history will be obtained after the main informed 
consent form is signed.
Baseline disease state will be assessed by PANSS. Positive scale item P1-P7 will be used for 
confirming the eligibility of study inclusion criterion # 3 at Visit1 and Visit 2.
The MCCB, M.I.N.I and the Baseline/screening scale of the eC-SSRS will be administered 
for eligibility confirmation. 
Cognitive assessments of Screening Visit should be done at least 7 days prior to cognitive 
baseline assessments performed at Visit 2. 
6.2.2
Treatment period(s)
The randomized treatment period is from Visit 2 to Visit (e) EOT.
Patients should not take trial medication before coming to the clinic.
Throughout the treatment period, 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
Randomization visit 2
As soon as eligibility of a screened patient is confirmed, the patient may enter the study and
Visit 2 can be conducted. This visit includes the assessment of the endpoints and
randomization via IRT. IRT should not be called before the patient has completed the
assessment of the neuropsychological endpoints.


Boehringer Ingelheim                                                                                                      28 Mar 2019
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At the start of Visit 2 it should be ensured that all Visit 1 procedures have been successfully
completed and eligibility has been confirmed (including results of the neuropsychological
rating scales performed at Visit 1).
Study procedures have to be completed according to the Flow Chart.
Sufficient trial drug for 42 treatment days (plus 7 day reserve) will be dispensed. The study 
medication will be assigned by the IRT at Visit 2.
Patients should be instructed not to take their trial medication before the visits as they will be 
dosed while in the clinic.
Visit 3, Visit 5
Study procedures have to be completed according to the Flow Chart.
The visits be performed at week 3 (Visit 3) and week 9 (Visit 5) after randomization to 

determine trial medication compliance: Remaining trial medication will be counted. If 
non-compliance is detected, refer to Section 4.3.

check for Adverse Events and changes in concomitant medication

Women of childbearing potential must perform urine dip stick pregnancy test.

eC-SSRS will be completed by the patient
Patients should be instructed to bring all trial medication (used and unused blisters) with them.
Visit 4
Study procedures have to be completed according to the Flow Chart.
The MCCB should be performed at the same time of day as at V2 (+/- 60 minutes time 
window).
Sufficient trial drug for 42 treatment days (plus 7 day reserve) will be dispensed. The study 
medication will be assigned by the IRT at Visit 4.
The 1st dose of study medication from the newly assigned medication kit will be taken at the 
clinic 
Patients should be instructed not to take 
their trial medication before the visit as they will be dosed while in the clinic after safety lab 
 are taken.


Boehringer Ingelheim                                                                                                      28 Mar 2019
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End of Treatment (Visit 6):
Study procedures have to be completed according to the Flow Chart.
Cognitive assessments of EOT Visit cannot be performed before Day 85. The final evaluation 
of cognitive function must be performed after patients complete 12-week treatment period. 
For the patients who discontinue the study medication early, the cognitive assessments of 
(e)EOT Visit must be performed within 7 days after last dose intake.
6.2.3
Follow Up Period and Trial Completion
Follow up visits will be conducted as described in the Flow Chart at 1 week after end of 
treatment to capture early withdrawal effects and at 4 weeks after treatment based on the half-
life of the trial medication.
If patient discontinues trial medication early, termination of trial medication page must be 
completed and Follow-up Visits should be completed at 1 and 4 weeks after eEOT Visit.
Follow-up visit 1 (1 week after end of treatment) can be conducted as a phone contact.
AEs which have not recovered at Follow-up Visit 2 should be followed until they are
resolved, or deemed reasonably followed up by the investigator on consultation with BI.


Boehringer Ingelheim                                                                                                      28 Mar 2019
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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
STATISTICAL DESIGN - MODEL
7.1
Refer to Section 3.1 for details on the design of this trial.
The primary objectives of this trial are the establishment of proof-of-concept with respect to a 
non-flat dose-response curve together with the definition of one or more suitable doses with 
respect to the efficacy and safety of orally administered once daily dosing of BI 425809 for 
further testing in pivotal phase III trials in patients with schizophrenia on stable antipsychotic 
treatment. For this purpose the MCPMod approach is employed (R10-1424; R15-1961).
The primary endpoint is change from baseline in cognitive function as measured by the 
composite MCCB score after 12 weeks of treatment. Change from baseline in everyday 
functional capacity as measured by SCoRS global ratings after 12 weeks of treatment is the 
secondary endpoint.
NULL AND ALTERNATIVE HYPOTHESES
7.2
The null hypothesis is that there is a flat dose response pattern across placebo and any dose of 
BI 425809 within the tested dose range of 0 to 25mg on the mean change in the composite 
MCCB score from baseline to Week 12. The alternative hypothesis is that there is a non-flat 
dose response pattern indicating a benefit of BI 425809 compared to placebo.
The MCPMod procedure allows simultaneous evaluation of different plausible dose response 
patterns whilst protecting the overall probability of type I error (one-sided alpha of 0.05). The 
pre-specified dose response patterns and the corresponding parameters are outlined in Section 
7.3.1 and Section 7.7.
PLANNED ANALYSES
7.3
The following patient analysis sets are defined for this trial:

Treated Set (TS): includes all patients who signed informed consent and were treated 
with at least one dose of the trial medication. Patients in TS are analyzed under the 
actual trial medication received at randomization. The TS is used for safety analyses as 
well as demographics and baseline characteristics.

Full Analysis Set (FAS): includes all patients in treated set who had non-missing 
baseline and at least one non-missing post-baseline and on-treatment measurement on 
any efficacy endpoint. Patients in FAS are analyzed according to the intent-to-treat 


Boehringer Ingelheim                                                                                                      28 Mar 2019
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principle, i.e., patients in FAS are analyzed under the randomized trial medication. The 
FAS is used for efficacy analyses.
Data from patients who were screened but not randomized will be listed but not included in 
any summary or inferential statistics. Specifications or important protocol violations will be 
provided in the TSAP. 
7.3.1
Primary endpoint analyses
Primary analysis of the primary endpoint
7.3.1.1
The analyses of PoCC and dose finding are carried out using the MCPMod approach (R10-
1424) in combination with Mixed effects Model Repeated Measures (MMRM) approach 
(R15-4293) whereby several plausible dose response patterns/models are evaluated, while 
keeping full control of the overall type I error rate of 5% 1-sided, to identify the best-fitting 
model or subset of models. The MMRM model as specified in Section 7.3.1.2 will be fitted 
for the MCPMod.
For the PoCC testing and for the sample size calculation, the basic shape of each of the 
models to be tested must be pre-defined. Six different models are considered in the analysis: 
linear, linear in log, Emax, Sigmoid Emax, logistic and beta model. Except in the beta model, 
the maximum effect is assumed to be achieved at the maximum dose being tested. For the 
sample size calculation, the maximum standardized effect size is assumed to be 0.35. Further 
details are given in Section 7.7.
The active BI 425809 doses are 2 mg, 5 mg, 10 mg, and 25 mg once daily. The following 
model assumptions and resulting graphs (Figure 7.3.1.1: 1) have been selected to cover both 
plausible and a diverse range of dose response patterns:  

Linear:
no assumptions needed

Linear in log:
no assumptions needed

Emax:
20% of the maximum effect is achieved at 2 mg

Sigmoid Emax:
25% of the maximum effect is achieved at 5 mg
          
75% of the maximum effect is achieved at 10 mg

Logistic:
10% of the maximum effect is achieved at 5 mg
        
50% of the maximum effect is achieved at 10 mg

Beta model:           75% of the maximum effect is achieved at 2 mg
                              87.5% of the maximum effect is achieved at 5 mg
                             25% of the maximum effect is achieved at 25 mg
                             Maximum effect achieved at 10 mg
Scalar parameter = 26
                                


Boehringer Ingelheim                                                                                                      28 Mar 2019
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PoCC is established if at least one model is statistically significant, rejecting the null 
hypothesis of a flat dose response relation over 12 weeks for the primary endpoint (mean 
change from baseline in composite MCCB score) jointly for each of the candidate dose 
response models with a contrast test controlled for the family-wise type I error rate at one-
sided α = 0.05.
If PoCC is established, the best-fitting model(s) from the above set of six models can be 
refitted to the data without any parameter assumptions to generate new estimates of the model 
parameters from the data. The final model will be obtained via weighted model averaging 
across the significant models based on the Akaike Information Criterion (AIC) (the smaller 
the AIC value the better the model fit). The target dose(s) can then be determined from that 
model by incorporating information on the minimum clinically relevant effect as well as 
safety information. The target dose should be chosen within the dose range investigated 
(0mg-25mg) though the actual modelling will be performed on a broader range of doses 
including extrapolation.
Figure 7.3.1.1: 1 Shape of the dose response patterns considered plausible in the MCPMod


Boehringer Ingelheim                                                                                                      28 Mar 2019
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7.3.2
Secondary endpoint analyses
If considered relevant, the MCPMod approach will also be applied to the secondary efficacy 
endpoint. In addition, exploratory treatment comparisons will be conducted using an MMRM 
approach similar to the one specified for the primary efficacy endpoint. More details on the 
analysis of secondary efficacy endpoint will be specified in the TSAP.
7.3.4
Safety analyses
Adverse events will be coded using the Medical Dictionary for Regulatory Activities
(MedDRA) coding dictionary. Standard BI summary tables and listings will be produced. All 
adverse events with an onset between the start of treatment and the end of the residual effect 
period (REP), a period of 11 days after the last dose of trial medication, will be assigned to 
the treatment period for evaluation.


Boehringer Ingelheim                                                                                                      28 Mar 2019
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All treated patients will be included in the safety analysis and will be summarized under the 
actual trial medication received at randomization. In general, safety analyses will be 
descriptive in nature and will be based on BI standards. No hypothesis testing is planned.
Statistical analysis and reporting of adverse events will concentrate on treatment-emergent 
adverse events. To this end, all adverse events occurring between the start of treatment and 
the end of the residual effect period will be considered ‘treatment-emergent’.  The residual 
effect period is defined as 11 days after the last dose of trial medication. Adverse events that 
start before first drug intake and deteriorate under treatment will also be considered as 
‘treatment-emergent’.
Frequency, severity, and causal relationship of adverse events will be tabulated by system 
organ class and preferred term after coding according to the current version of the MedDRA.
Frequency tables for all adverse events, protocol-specified adverse event of special interest 
(AESI), serious adverse event (SAE), adverse event leading to death, adverse event leading to 
discontinuation, investigator assessed drug-related adverse event and serious adverse event 
will be generated for treatment-emergent adverse events. In addition, summary statistics and 
descriptive analyses will be conducted for other safety parameters including worsening of 
disease state as assessed by PANSS and suicidality as assessed by C-SSRS.
Laboratory data will be analysed both quantitatively as well as qualitatively. The latter will 
be done via comparison of laboratory data to their reference ranges. Values outside the 
reference range as well as values defined as clinically relevant will be highlighted in the 
listings. Treatment groups will be compared descriptively with regard to distribution 
parameters as well as with regard to frequency and percentage of patients with abnormal 
values or clinically relevant abnormal values.
Vital signs, physical examinations, or other safety-relevant data observed at screening, 
baseline, during the course of the trial and at the end-of-trial evaluation will be assessed with 
regard to possible changes compared to findings before start of treatment.


Boehringer Ingelheim                                                                                                      28 Mar 2019
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INTERIM ANALYSES
7.4
No interim analysis is planned.
HANDLING OF MISSING DATA
7.5
Every effort will be made to collect complete data at the specific time points. In general, for 
completely missing visits missing data will not be imputed and will be handled through the 
MMRM using a restricted maximum likelihood method under the “missing at random” 
assumption. Details on the handling of missing data will be specified in the TSAP prior to 
unblinding.
RANDOMIZATION
7.6
Eligible patients will be randomized with ratio of 1:1:1:1:2 to BI 425809 2 mg, 5 mg, 10 mg 
25 mg and placebo. The randomization will be implemented in blocks to achieve balanced 
allocation to each treatment arm. In addition, randomization will be stratified for the main 
study alone and for the main study and the imaging substudy, i.e., patients who give consent 
to participate in the imaging substudy besides the main study will be randomized with the 
same ratio of 1:1:1:1:2 to the five treatment arms as for those who consent to the main study 
but do not consent to participate in the imaging substudy. When the total sample size for the 
main study is achieved, the randomization to the stratum of the imaging sub-study will stop.
The randomization will be conducted via an interactive response technology (IRT). BI will 
arrange for the randomization and the packaging and labelling of trial medication. The 
randomization list will be generated using a validated system, which involves a pseudo-
random number generator so that the resulting treatment will be both reproducible and non-
predictable. The block size will be documented in the CTR. Access to the codes will be 
controlled and documented.


Boehringer Ingelheim                                                                                                      28 Mar 2019
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DETERMINATION OF SAMPLE SIZE
7.7
For the purposes of calculating the sample size for this phase II trial, we consider a range of 
standardized effect sizes showing better efficacy of BI 425809 as compared to placebo in the 
composite MCCB score change from baseline after 12 weeks of treatment, i.e., 0.3, 0.35, 0.4 
and 0.45, and assume the six candidate dose response patterns as described in Section 7.3.1.1.
Since the randomization allocation ratio for the four BI 425809 dose arms and placebo is 
1:1:1:1:2, the sample size required for the placebo arm and the active treatment arms are 
displayed separately. Table 7.7: 1 below gives the sample size calculations under different 
effect sizes using 1-sided type I error rate of 0.05 and 80% power. The sample size 
calculations are performed using the MCPMod approach assuming the six plausible dose 
response patterns as described in Section 7.3.1.1 and implemented using the statistical 
software R package ‘DoseFinding’ (R15-2001) version 0.9-12 released on 28 SEP 2014
(depends on R version ≥ 2.15.0). The R codes for the sample size calculations as well as the 
analyses using the MCPMod approach will be provided in the TSAP.
Table 7.7:1 
Sample size calculation under different effect sizes for the composite 
MCCB score change from baseline with 80% power and one-sided 
alpha of 0.05
Standardized Effect size
0.3
0.35
0.4
0.45
Power = 80%
   N for Placebo
204
150
116
92
   N for each active treatment arm
102
75
58
46
   Total
612
450
348
276
   Adjusting for 10% dropout
      N for Placebo
228
168
130
104
      N for each active treatment arm
114
84
65
52
      Total
684
504
390
312
A sample size of 75 evaluable patients in each of the BI 425809 arm and 150 evaluable 
patients in the placebo arm is needed to establish PoCC of a standardized effect size of 0.35 
with an average power of 80% and one-sided alpha of 0.05. Assuming a 10% dropout rate
which is considered reasonable based on CIAS trials to date, 84 patients in each of the BI 
425809 arm and 168 patients in the placebo arm are required. Therefore a total sample size of 
504 evaluable patients with 84 patients in each of the BI 426809 arm and 168 patients in the 
placebo arm is chosen for this phase II trial.
The sample size calculations in Table 7.7: 2 consider a range of effect size and power for a 
direct comparison between BI 425809 doses and the placebo. Two-sample t-test is used for 
these exploratory treatment comparisons without adjusting for multiplicity.


Boehringer Ingelheim                                                                                                      28 Mar 2019
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Table 7.7: 2
Sample size calculations under different effect sizes and power for the 
composite MCCB score change from baseline with one-sided alpha of 
0.05
Effect size
0.3
0.35
0.4
0.45
0.5
0.55
Power = 85%
N for each active treatment arm
151
111
85
68
55
46
N for Placebo
302
222
170
136
110
92
Total sample size adjusting for 
10% dropout
1008
744
570
456
372
312
Power = 80%
N for each active treatment arm
132
97
75
59
48
40
N for Placebo
264
194
150
118
96
80
Total sample size adjusting for 
10% dropout
882
648
504
396
324
270
Power = 75%
N for each treatment arm
117
86
66
53
43
36
N for Placebo
234
172
132
106
86
72
Total sample size adjusting for 
10% dropout
780
576
444
354
288
240
The two-sample t-test method with unequal n’s in nQuery Advisor® 6.1 statistical package by Statistical Solutions Ltd is 
used for the sample size calculations.


Boehringer Ingelheim                                                                                                      28 Mar 2019
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8.
INFORMED CONSENT, DATA PROTECTION, TRIAL
RECORDS
The trial will be carried out in compliance with the protocol, the ethical principles laid down 
in the Declaration of Helsinki, in accordance with the ICH Harmonized Tripartite Guideline 
for Good Clinical Practice (GCP), relevant BI Standard Operating Procedures (SOPs), the 
Japanese GCP regulations (Ministry of Health and Welfare Ordinance No 28, March 27, 
1997) and relevant regulations.
Standard medical care (prophylactic, diagnostic and therapeutic procedures) remains in 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 subjects against any immediate hazard, and also of any serious breaches of 
the protocol or of ICH GCP and the Japanese GCP regulations (Ministry of Health and 
Welfare Ordinance No 28, March 27, 1997).
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 Clinical Trial Report.
The rights of the investigator / trial site and of the sponsor with regard to publication of the 
results of this trial are described in the investigator contract / trial site’s contract. As a general 
rule, no trial results should be published prior to finalisation of the Clinical Trial Report.
The certificate of insurance cover is made available to the Investigator and the patients, and is
stored in the ISF (Investigator Site File).”
TRIAL APPROVAL, PATIENT INFORMATION, AND INFORMED 
8.1
CONSENT
This trial will be initiated only after all required legal documentation has been reviewed and 
approved by the respective Institutional Review Board (IRB) / Independent Ethics Committee 
(IEC) and competent authority (CA) according to national and international regulations. The 
same applies for the implementation of changes introduced by amendments.
Prior to patient participation in the trial, written informed consent must be obtained from each 
patient (or the patient’s legally accepted representative) according to ICH / GCP and to the 
regulatory and legal requirements of the participating country. Each signature must be 
personally dated by each signatory and the informed consent and any additional patient-
information form retained by the Investigator as part of the trial records. A signed copy of the 
informed consent and any additional patient information must be given to each patient or the 
patient’s legally accepted representative.
The Investigator must give a full explanation to trial patients by using the patient information 
form, which is prepared avoiding the use of technical terms and expressions. The patient is 


Boehringer Ingelheim                                                                                                      28 Mar 2019
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given sufficient time to consider participation in the trial. The Investigator obtains written 
consent of the patient’s own free will with the informed consent form after confirming that 
the patient understands the contents. The Investigator must sign (or place a seal on) and date 
the informed consent form. If a trial collaborator has given a supplementary explanation, the 
trial collaborator also signs (or places a seal on) and dates the informed consent.
Re-consenting may become necessary when new relevant information becomes available and 
should be conducted according to the sponsor’s instructions.
DATA QUALITY ASSURANCE
8.2
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.
RECORDS
8.3
Case Report Forms (CRF) / (e)CRF 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
Source documents provide evidence for the existence of the patient and substantiate the 
integrity of the data collected. Source documents are filed at the Investigator’s site.
Data reported on the CRF must be consistent with the source data or the discrepancies must 
be explained. The Investigator may need to request previous medical records or transfer 
records, depending on the trial; current medical records must also be available.
For eCRFs all data must be derived from source documents.
8.3.2
Direct access to source data and documents
The Investigator / institution will permit trial-related monitoring, audits, IRB / IEC review 
and regulatory inspection, providing direct access to all related source data / documents. 
CRF/eCRF and all source documents, including progress notes and copies of laboratory and 
medical test results must be available at all times for review by the Sponsor’s clinical trial 
monitor, auditor and inspection by health authorities (e.g. FDA). The Clinical Research 
Associate (CRA) / on site monitor and auditor may review all CRF / eCRF, and written 


Boehringer Ingelheim                                                                                                      28 Mar 2019
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informed consents. The accuracy of the data will be verified by reviewing the documents 
described in Section 8.3.1.
8.3.3
Storage period of records
Trial site(s):
The trial site(s) must retain the source documents and essential documents for a period 
defined by the Japanese GCP regulation (for Japanese sites) and trial site’s contract with the 
sponsor.
Sponsor:
The Sponsor must retain the essential documents according to the Sponsor’s SOPs.
LISTEDNESS AND EXPEDITED REPORTING OF ADVERSE EVENTS
8.4
8.4.1
Listedness
To fulfil the regulatory requirements for expedited safety reporting, the Sponsor evaluates 
whether a particular adverse event is "listed", i.e. is a known side effect of the drug or not. 
Therefore, a unique reference document for the evaluation of listedness needs to be provided. 
For the BI 425809 this is the current version of the Investigator’s Brochure (c02156531). 
The current versions of these reference documents are provided in the ISF. No AEs are 
classified as listed for matching placebo, trial design, or invasive procedures.
8.4.2
Expedited reporting to health authorities and IEC / IRB
Expedited reporting of serious adverse events, e.g. suspected unexpected serious adverse 
reactions (SUSAR) to health authorities and IEC / IRB, will be done according to local 
regulatory requirements.
STATEMENT OF CONFIDENTIALITY
8.5
Individual patient medical information obtained as a result of this trial is considered 
confidential and disclosure to third parties is prohibited with the exceptions noted below. 
Patient confidentiality will be ensured by using patient identification code numbers.
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 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.


Boehringer Ingelheim                                                                                                      28 Mar 2019
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END OF TRIAL
8.6
The end of the trial is defined as last patient out (for details please refer to Section 6.2.3)
The IEC / competent authority in each participating EU member state will be notified about 
the end or early termination of the trial.
When the trial is completed, the Investigator should inform the head of the trial site of the 
completion in writing, and the head of the trial site should promptly inform the IRB and 
Sponsor of the completion in writing.
PROTOCOL VIOLATIONS
8.7
The investigator should document any deviation from the protocol regardless of their reasons. 
Only when the protocol was not followed in order to avoid an immediate hazard to trial 
subjects or for other medically compelling reason, the principal investigator should prepare 
and submit the records explaining the reasons thereof to the sponsor, and retain a copy of the 
records.
COMPENSATION AVAILABLE TO THE PATIENT IN THE EVENT OF 
8.8
TRIAL RELATED INJURY
In the event of health injury associated with this trial, the Sponsor is responsible for 
compensation based on the contract signed by the trial site.


Boehringer Ingelheim                                                                                                      28 Mar 2019
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9.
REFERENCES
PUBLISHED REFERENCES
9.1
R07-1303
Sheehan DV, Lecrubier Y, Sheehan KH, Amorim P, Janavs J, Weiller E, 
Hergueta T, Baker R, Dunbar GC. The Mini-International Neuropsychiatric 
Interview (M.I.N.I): the development and validation of a structured 
diagnostic psychiatric interview for DSM-IV and ICD-10. Symp 
'Depression and Anxiety: New Tools for Diagnosis and Treatment', 
Chicago, 15 Aug 1997. J Clin Psychiatry 59 (Suppl 20), 22 - 57 (1998). 
R10-1424
Pinheiro J, Bornkamp B, Bretz F. Design and analysis of dose-finding 
studies combining multiple comparisons and modelling procedures. J 
Biopharm Stat 2006. 16(5): 639-656.
R10-5094
Evans JD, Bond GR, Meyer PS, Kim HW, Lysaker PH, Gibson PJ, Tunis S. 
Cognitive and clinical predictors of success in vocational rehabilitation in 
schizophrenia. Schizophr Res 70, 331 - 342 (2004).
R10-5096
Kurtz MM, Wexler BE, Fujimoto M, Shagan DS, Seltzer JC. Symptoms 
versus neurocognition as predictors of change in life skills in schizophrenia 
after outpatient rehabilitation. Schizophr Res 102, 303 - 311 (2008).
R10-5100
McGurk SR, Moriarty PJ, Harvey PD, Parrella M, White L, Davis KL. The 
longitudinal relationship of clinical symptoms, cognitive functioning, and 
adaptive life in geriatric schizophrenia. Schizophr Res 42, 47 - 55 (2000).
R10-5104
Velligan DI, Mahurin RK, Diamond PL, Hazleton BC, Eckert SL, MillerAL
The functional significance of symptomatology and cognitive function in 
schizophrenia. Schizophr Res 25, 21 - 31 (1997).


Boehringer Ingelheim                                                                                                      28 Mar 2019
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R10-5108
Barnett JH, Robbins TW, Leeson VC, Sahakian BJ, Joyce EM, Blackwell 
AD. Assessing cognitive function in clinical trials of schizophrenia. 
Neurosci Biobehav Rev 34, 1161 - 1177 (2010). 
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Buchanan RW, Davis M, Goff D, Green MF, Keefe RSE, Leon AC, 
Nuechterlein KH, Laughren T, Levin R, Stover E, Fenton W, Marder SR. A 
summary of the FDA-NIMH-MATRICS workshop on clinical trial design 
for neurocognitive drugs for schizophrenia.
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Neurocognitive Drugs for Schizophrenia, 23 Apr 2004. Schizophr Bull 31 
(1), 5 - 19 (2005).
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Keefe RSE, Poe M, Walker TM, Kang JW, Harvey PD. The Schizophrenia 
Cognition Rating Scale: an interview-based assessment and its relationship 
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Buchanan RW, Keefe RSE, Umbricht D, Green MF, Laughren T, Marder 
SR. The FDA-NIMH-MATRICS guidelines for clinical trial design of 
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Transporter I Inhibitor, N-methylglycine (Sarcosine), Added to Clozapine 
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HJ, Spaans E, Haes JU de, Kam ML de, Franson KL, Cohen AF, Gerven 
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Boehringer Ingelheim                                                                                                      28 Mar 2019
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Ouellet D, Sutherland S, Wang T, Griffini P, Murthy V. First-time-in-
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Martin-Facklam M, Patat A, Hofmann C, Boetsch C, Banken L, Biedinger 
U, Boutouyrie-Dumont B. Safety, tolerability and pharmacokinetics of 
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in healthy volunteers. 3rd Biennial Conf of the Schizophrenia International 
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Umbricht D, Martin-Facklam M, Pizzagalli F, Youssef E, Yoo K, 
Dorflinger E, Bausch A, Arrowsmith R, Alberati D, Santarelli L. Glycine 
transporter type 1 (GlyT1) inhibitor RG1678: results of the proof-of-
concept study for the treatment of negative symptoms in schizophrenia. 
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Apr 2011 Schizophr Bull 37 (Suppl 1), 324, Abstr (2011). 
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Lin CH, Lane HY, Tsai GE. Glutamate signaling in the pathophysiology 
and therapy of schizophrenia. Pharmacol Biochem Behav 100, 665 – 677 
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Tsai G, Lane HY, Yang P, Chong MY, Lange N. Glycine transporter 1 
inhibitor, N-methylglycine (sarcosine), added to antipsychotics for the 
treatment of schizophrenia. Biol Psychiatry 55, 452 - 456 (2004). 
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Kay SR, Fiszbein A, Opler LA. The positive and negative syndrome scale 
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Boehringer Ingelheim                                                                                                      28 Mar 2019
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amplitude reduction in schizophrenia: a retrospective longitudinal study. 
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Bugarski-Kirola D, Arango C, Fleischhacker WW, Bressan R, Nasrallah H, 
Lawrie S, Blaettler T, Garibaldi G, Reid C, Marder S. Efficacy and safety 
of adjunctive bitopertin versus placebo in subjects with persistent 
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: 


Boehringer Ingelheim                                                                                                      28 Mar 2019
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Umbricht D, Alberati D, Martin-Facklam M, Borroni E, Youssef EA, 
Ostland M, Wallace TL, Knoflach F, Dorflinger E, Wettstein JG, Bausch A, 
Garibaldi G, Santarelli L. Effect of bitopertin, a glycine reuptake inhibitor, 
on negative symptoms of schizophrenia: a randomized, double-blind, proof-
of-concept study. JAMA Psychiatry 71 (6), 637 - 646 (2014).
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Bugarski-Kirola D, Wang A, Abi-Saab D, Blaettler T. A phase II/III trial of 
bitopertin monotherapy compared with placebo in patients with an acute 
exacerbation of schizophrenia- results from the CandleLyte study. Eur 
Neuropsychopharmacol 24 (7), 1024 - 1036 (2014).


Boehringer Ingelheim                                                                                                      28 Mar 2019
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Blaettler T, Bugarski-Kirola D, Fleischhacker WW, Bressan R, Arango C, 
Abi-Saab D, Napieralski J, Dixon M, Marder S. Efficacy and safety of 
adjunctive bitopertin (10 and 20 mg) versus placebo in subjects with 
persistent predominant negative symptoms of schizophrenia treated with 
antipsychotics - results from the phase III FlashLyte study.
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efficient statistical methodology for model-based design and analysis of 
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brain injury on cognitive functioning. Int Rev Psychiatry 15 (4), 341 - 349 
(2003).
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Heinrichs RW, Zakzanis KK. Neurocognitive deficit in schizophrenia: a 
quantitative review of the evidence. Neuropsychology 12 (3), 426 - 445 
(1998).
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Dickinson D, Ramsey ME, Gold JM. Overlooking the obvious: a meta-
analytic comparison of digit symbol coding tasks and other cognitive 
measures in schizophrenia. Arch Gen Psychiatry 64 (5), 532 - 542 (2007).
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Pinheiro J, Bornkamp B, Glimm E, Bretz F. Model-based dose finding 
under model uncertainty using general parametric models. Stat Med 33 
(10), 1646 - 1661 (2014)


Boehringer Ingelheim                                                                                                      28 Mar 2019
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Uriel Heresco-Levy, Daniel C. Javitt, Richard Ebstein, Agnes Vass, Pesach 
Lichtenberg, Gali Bar, Sara Catinari, and Marina Ermilov. D-Serine 
Efficacy as Add-on Pharmacotherapy to Risperidone and Olanzapine for 
Treatment-Refractory Schizophrenia. Biol Psychiatry 2005;57: 577–585.
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Aaron L. Mishara and Terry E. Goldberg. A Meta-Analysis and Critical 
Review of the Effects of Conventional Neuroleptic Treatment on Cognition 
in Schizophrenia: Opening a Closed Book. Biol Psychiatry.2004;55:1013–
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Donald C. Goff, MD Corinne Cather, PhD, Jennifer D. Gottlieb, PhD, A. 
Eden Evins, MD, MPH, Jared Walsh, BA, Lisa Raeke, MA, Michael W. 
Otto, PhD, David Schoenfeld, PhD and Michael F. Green, PhD. Once-
Weekly D-Cycloserine Effects on Negative Symptoms and Cognition in 
Schizophrenia: An Exploratory Study Schizophr Res. 2008 December ; 106 
(2-3): 320–327.
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Knowles EE, David AS, Reichenberg A. Processing speed deficits in 
schizophrenia: reexamining the evidence. Am J Psychiatry. 2010 Jul; 167 
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Boehringer Ingelheim                                                                                                      28 Mar 2019
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Meltzer HY, Green MF, Capuano G, Stroup TS, McEvoy JP, Swartz MS, 
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Investigators; Neurocognitive Working Group. Neurocognitive effects of 
antipsychotic medications in patients with chronic schizophrenia in the 
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Guochuan Tsai, Pinchen Yang, Li-Chen Chung, Nicholas Lange, and
Joseph T. Coyle. D-Serine Added to Antipsychotics for the Treatment of 
Schizophrenia Biol Psychiatry 1998;44:1081–1089. 
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Hsien-Yuan Lane, Ching-Hua Lin, Yu-Jhen Huang, Chun-Hui Liao, Yue-
Cune Chang and Guochuan E. Tsai. A randomized, double-blind, placebo-
controlled comparison study of sarcosine (N-methylglycine) and D-serine 
add-on treatment for schizophrenia. International Journal of 
Neuropsychopharmacology (2010), 13, 451–460.
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Weiser M, Heresco-Levy U, Davidson M, Javitt DC, Werbeloff N, Gershon 
AA, Abramovich Y, Amital D, Doron A, Konas S, Levkovitz Y, Liba D, 
Teitelbaum A, Mashiach M, Zimmerman Y. A multicenter, add-on 
randomized controlled trial of low-dose d-serine for negative and cognitive 
symptoms of schizophrenia. J Clin Psychiatry. 2012 Jun;73(6):e728-34.
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Buchanan RW, Javitt DC, Marder SR, Schooler NR, Gold JM, McMahon 
RP, Heresco-Levy U, Carpenter WT. The Cognitive and Negative 
Symptoms in Schizophrenia Trial (CONSIST): the efficacy of 
glutamatergic agents for negative symptoms and cognitive impairments.
Am J Psychiatry 164:10, October 2007.
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Goff DC, Tsai G, Levitt J, Amico E, Manoach D, Schoenfeld DA, Hayden 
DL, McCarley R, Coyle JT. A placebo-controlled trial of D-cycloserine 
added to conventional neuroleptics in patients with schizophrenia. Arch 
Gen Psychiatry. 1999 Jan; 56(1):21-7.


Boehringer Ingelheim                                                                                                      28 Mar 2019
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Boehringer Ingelheim                                                                                                      28 Mar 2019
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R16-4322
Keefe RSE, Davis VG, Spagnola NB, Hilt D, Dgetluck N, Ruse S, et al.
Reliability, validity and treatment sensitivity of the Schizophrenia 
Cognition Rating Scale. Eur Neuropsychopharmacol 25 (2), 176 - 184 
(2015)


Boehringer Ingelheim                                                                                                      28 Mar 2019
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UNPUBLISHED REFERENCES
9.2
U07-1110
 A prospective randomized trial to compare 
a fixed dose combination of telmisartan 80 mg plus hydrochlorothiazide 25 
mg with a fixed dose combination of telmisartan 80 mg plus 
hydrochlorothiazide 12.5 mg in patients with uncontrolled hypertension 
who fail to respond adequately to treatment with a fixed dose combination 
of telmisartan 80 mg plus hydrochlorothiazide 12.5 mg. 502.480. 6 
February 2007.
c02156531
 Investigator Brochure, BI 425809 
001-MCS-36-472
Boehringer Ingelheim SOP: „Standart Operation Procedure“, current
version, IDEA for CON


Boehringer Ingelheim                                                                                                      28 Mar 2019
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10.
APPENDICES
INSTRUCTIONS FOR USE
10.1
10.1.1
Batteries and questionnaires
Batteries and questionnaires which will be used in the clinical trial 1346.9 for assessing the 
end points and disease status were listed below:
1.
MATRICS Consensus Cognitive Battery (MCCB)
2.
Schizophrenia Cognition Rating Scale (SCoRS)
3.
Positive and Negative Syndrome Scale (PANSS)
4.
Columbia-Suicide Severity Rating Scale (C-SSRS) Screening/Baseline Version
5.
Columbia-Suicide Severity Rating Scale (C-SSRS) Since Last Visit Version
For templates and instructions of the batteries and questionnaires, please refer to the ISF
Section 15 “Trial Specific Supplies”.
10.1.2
Definition of positive Reports of Suicidal Ideation and Behavior
Results from each assessment of suicidal ideation and behavior per subject and visit will be 
categorized as positive or negative.
Positive reports of suicidal ideation and behavior are to be generated for
ANY of the following findings:
Ideation
-
Active suicidal ideation with method and intent but no plan (type 4)
-
Active suicidal ideation with method, intent and plan (type 5)
Behavior
-
Completed suicide
-
Suicide attempt
-
Interrupted attempt
-
Aborted attempt
-
Preparatory actions toward imminent suicidal behaviors
Negative reports of suicidal ideation are generated when there are no indications of the 
above, i.e. suicidal ideation of type 1-3.
Positive reports have to be reported as Serious Adverse Events (SAEs), negative reports can 
be reported as (Serious) Adverse Events (AEs) as per investigator´s judgment.


Boehringer Ingelheim                                                                                                      28 Mar 2019
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Boehringer Ingelheim                                                                                                      28 Mar 2019
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Boehringer Ingelheim                                                                                                      28 Mar 2019
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Boehringer Ingelheim                                                                                                      28 Mar 2019
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Boehringer Ingelheim                                                                                                      28 Mar 2019
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Boehringer Ingelheim                                                                                                      28 Mar 2019
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Boehringer Ingelheim                                                                                                      28 Mar 2019
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Boehringer Ingelheim                                                                                                      28 Mar 2019
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Boehringer Ingelheim                                                                                                      28 Mar 2019
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Boehringer Ingelheim                                                                                                      28 Mar 2019
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Boehringer Ingelheim                                                                                                      28 Mar 2019
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Boehringer Ingelheim                                                                                                      28 Mar 2019
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Boehringer Ingelheim                                                                                                      28 Mar 2019
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Boehringer Ingelheim                                                                                                      28 Mar 2019
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Boehringer Ingelheim                                                                                                      28 Mar 2019
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OPHTHALMOLOGIC SUBSTUDY
10.8
10.8.1
Flowchart
MAIN 
Trial Periods
Screening 
Period
Randomized Treatment Period End of Trial
Visit
1
2
3
4 
5
6 
EOT
Follow
-up 1
Follow
up 2
Study-Day 
7 to – 28 
1
22
43
64
85
EOT+
7
EOT+
28
SUB
Sub-study Visit
Screening
On-
treatment
Post 1²
Time window for visits
-28 to -7 days
± 10
± 3
Sub-study Informed 
Consent
X
Best Corrected Visual
Acuity
X
X1
X
Color Vision Test
(F-M 100)
X
X1
X
Pupil Diameter
Measurement
X
X1
X
Anterior / Posterior
Biomicroscopy
X
X1
X
Intra-ocular Pressure
X
X1
X
Ocular Coherence
Tomography
X
X1
X
Indirect Funduscopy
X
X1
X
1Visual procedures to be completed at estimated peak exposure time point (120-300 minutes after dosing). Dosing on these 
days should be scheduled accordingly at the discretion of the investigator. 
2If clinically relevant changes (compared to baseline) are documented at visit Post1 the same procedures need to be repeated 
at visit FU2±10 days. Further follow-up in case of ongoing AEs at the discretion of the investigator.
10.8.2
Objective
To investigate the ocular safety of BI 425809 in patients with Schizophrenia following oral 
administration of  2mg, 5mg, 10mg and 25mg compared to placebo in a 12 week treatment 
period.


Boehringer Ingelheim                                                                                                      28 Mar 2019
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10.8.3
Selection of Study Population
This sub-study will enrol patients from selected study sites participating in the 1346.9 study 
who will additionally meet the below criteria. 
Inclusion Criteria
10.8.3.1
1.
Patients who have given informed consent to participate in the 1346.9 and who (at the 
end of the screening visit procedures) can be foreseen to be randomized to active 
treatment in the discretion of the investigator.
2.
Patients must have given written informed consent to the sub-study in accordance with 
GCP and local legislation prior to any sub-study procedures. 
Exclusion Criteria
10.8.3.2
1.
Presence of active ocular conditions with or without visual impairment due to any causes 
(e.g. wet-aged macular degeneration, pathologic myopia, cataract, chorioretinal macular 
lesion, amblyopia, active diabetic retinopathy, uncontrolled glaucoma, active 
inflammation or infection, etc.) in one eye or both eyes at the screening phase that may 
interfere with the ocular assessments or analyses and interpretation of the results from 
this study, in the clinical judgment of the investigator.
2.
Planned ocular treatment (e.g. intravitreal antivascular growth factor, corticosteroids) or 
surgery during the study period.
3.
Current or planned use of ocular or systemic corticosteroids.
4.
Current or planned use of medications known to be toxic to the retina, lens, optic nerve 
(e.g. choroquine/hydrochoroquine, chlorpromazine, tamoxifen, desferoximine, etc.).
10.8.4
Sub-study Design
Ophthalmologic safety assessments will be done at the time-points described in the flowchart.
At least 60 patients required to have approximately 8-10 evaluable patients for each of the 4 
BI 425809 dose arms and approx. 16 - 20 evaluable patients for the placebo arm. 
Patient recruitment status in this sub-study will be monitored closely to enable and to open 
the recruitment into this sub-study in additional countries, if this is required to meet the 
targeted recruitment.


Boehringer Ingelheim                                                                                                      28 Mar 2019
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10.8.5
Ophthalmological examinations
The following ophthalmological assessments will be performed in this study, at time-points 
given in the Flow Chart. All assessments should be evaluated by an ophthalmologist or 
certified ophthalmic technicians. The ophthalmologist will serve as a consultant to the 
investigator and report the results of the ophthalmological examinations supported by 
worksheets provided from study level. These worksheets will serve as source data and will be 
archived in the patients chart at the study site. All test results in each visit will be documented 
in the above mentioned source documents and entered in the eCRF. Any abnormal findings 
will be documented, and if applicable, severity grading 1-4 (1 = very mild, 2 = mild, 3 = 
moderate, 4 = severe) will be provided. 
Any deterioration observed during the ophthalmologic assessments should be reported to the 
investigator and based on the clinical judgment, can be documented as an AE. The 
investigator may consult with the ophthalmologist on the grading of AEs at any time.
In case of clinical abnormal findings an additional ophthalmologic examination may be 
considered.
The description of the ophthalmological assessments below is meant to represent the current 
medical standard for these examinations. The ophthalmologist may deviate from these 
descriptions if deemed medically appropriate if it is (per medical judgment) ensured that the 
same diagnostic standard is met and the same medical conclusion can be drawn. Any 
deviation and the potential diagnostic consequences should be documented and 
communicated to the study site.
Best Corrected Visual Acuity (BCVA)
BCVA will be determined using Early Treatment Diabetic Retinal Scale (ETDRS) charts at a 
4-meter testing distance under standard, certified lighting condition (Precision Vision CAT 
N02425). ETDRS Chart 1(CAT 2111) will be used for the right eye, Chart 2 (CAT 2112) for 
the left eye and Refraction Chart R (CAT 2110) for the refractive error. If the patient is 
unable to read at least the 20/100 line, the test will be repeated with the distance reduced to 
one meter. For those unable to read the ETDRS chart at any distance, the following steps will 
be count fingers, hands movements and light/no light perception. The same optotype will be 
used for each patient throughout the study. The refractive error using Refraction Chart R will 
be determined at the baseline visit and collected throughout the remainder of the study period 
when BCVA is performed. Both eyes will be evaluated separately and the results captured in 
the eCRF, as well as the occurrence of any deviations from ETDRS chart reading.
Farnsworth-Munsell 100 hue test (F-M 100)
Color vision testing using the Farnsworth-Munsell 100 (Munsell Color Services Lab, X-Rite, 
Inc.) hue test will be used to evaluate each patient’s category of color vision or color vision 
deficiency in both eyes, separately. It consists of 93 colors mounted in plastic caps, housed in 
four separate cases (Serial No. 555103180814, 08/2014). Each case consists of two hinged 
panels which contain a quarter of the 85 numbered, removable color caps. Two caps are 
repeated and fixed as pilot colors at either end of one panel in each case, making a total of 93 
caps. Each hue cap between the fixed anchors can be adjusted as the observer sees fit. The 


Boehringer Ingelheim                                                                                                      28 Mar 2019
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final arrangement of the hue caps represents the aptitude of the visual system in discerning 
differences in color hue.
The standard software included in the FM 100 package will be used for scoring and analyzing 
the results. Total error score (TES) will be used as a measurement of color vision. Total error 
score and level of color vision deficiency classification (e.g. superior, average, low 
discrimination) will be recorded on the eCRF. Examination of color vision will be performed 
at during screening), Day 64±10 (peak exposure), and at End of Trial + 7.
Pupil Diameter Measurement
Both left and right pupil measurements will be taken separately using a pupil gauge under 
standardized lighting conditions. Measurements for each eye will be recorded in the eCRF.
Anterior and posterior biomicroscopy
The anterior and posterior chamber slit lamp examination will be done in conjunction with a 
biomicroscope (for example Haag Streit BC900). The examination of the anterior segment 
and posterior segments will include the eyelid, sclera, conjunctiva, cornea, iris, lens, and the 
anterior vitreous. The binocular slit-lamp examination (stereoscopic magnified view of the 
ocular structures) will be also performed for further documentation of the ocular findings. 
The anterior and posterior chamber slit lamp examination will be performed in both eyes. 
Examination results of normal or abnormal will be indicated, and if abnormal to provide the 
condition and severity grading from 1-4 scale. Photographs will be taken if a clinically 
significant abnormality is noted per ophthalmologist discretion. Results will be recorded in 
the eCRF. 
Intra-Ocular Pressure Measurement (IOP)
Intra-ocular pressure of both eyes will be measured separately (using the Goldmann 
applanation tonometry (Haag Streit AT900) or a similar device). 
Spectral domain optical coherence tomography (SD-OCT)
High definition optical coherence tomography (spectral domain OCT) will be performed to 
evaluate the retinal and sub-retinal structures of both eyes. The central retinal thickness, 
along with other anatomical findings such as presence or not of intra-retinal fluid, sub-retinal 
fluid, and choroid and retinal pigmented epithelial layer changes will be documented and 
recorded in the eCRF. OCT images of both eyes will be captured and reported as normal or 
abnormal, and the central retinal thickness measurements will be recorded.
Further explanations and description of abnormalities will be provided for all abnormal 
results. 
A central service vendor will be used to harmonize the OCT procedure and to centrally assess 
the results.
Indirect fundoscopy
Dilated indirect fundoscopy of the retina will be performed in previously dilated eyes (topical 
mydriatic eyedrops) with a proper lens and either a slit lamp microscope or a light attached to 
a headband. Indirect fundoscopy of the retina will be performed at Day -1 (Baseline), at Visit 
5 (Day 64)  and at End of Trial. Results of normal or abnormal exams will be recorded on the 
eCRF, with further explanation and severity gradings (Grade 1-4) for abnormal results. 


Boehringer Ingelheim                                                                                                      28 Mar 2019
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Photographs will be taken if a clinically significant abnormality is noted per ophthalmologist 
discretion.
10.8.6
Endpoints
All of the analyses of the ophthalmologic measurement will be exploratory and no formal 
endpoints will be defined.
10.8.7
Planned Analyses Determination of Sample Size
Planned Analyses
10.8.7.1
No statistical testing will be performed. All safety analyses will be assessed in a descriptive 
way based on change from baseline for the following measurements at Week 9 (Visit 5) and 
Week 12 (Visit 6 – EoT visit):

Number of letters correct based on the best corrected visual acuity test (BCVA)

Total error score from the Farnsworth-Munsel 100 hue testing (F-M 100)

Pupil diameter measurement

Categorical changes (normal/abnormal) from the anterior and posterior biomicroscopy 
exam

Intra-ocular pressure (IOP)

Central retinal thickness as measured by High definition ocular coherence 
tomography (SD OCT)

Categorical changes (normal/abnormal) from indirect fundoscopy of the retina.
Sample Size
10.8.7.2
It is planned to include a total of at least 60 subjects in this sub-study. The planned sample 
size is not based on a power calculation. The size of 10 subjects per dose group (with 20 
patients in the placebo group) is in general considered as sufficient for the exploratory 
evaluation of multiple dose ophthalmologic assessment.


Boehringer Ingelheim                                                                                                      28 Mar 2019
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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
GLOBAL AMENDMENT 1
11.1
Number of global amendment
1
Date of CTP revision
21 Apr 2016
EudraCT number
2016-000285-28
BI Trial number
1346.9
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 4 oral doses of BI 425809 
once daily over 12 week treatment period in 
patients with Schizophrenia
To be implemented only after 
approval of the IRB / IEC /
Competent Authorities
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
1.2
Description of change
A typo was corrected and information on Cyp2b6 
induction was added.
Rationale for change
New information was added.
Section to be changed
2.1
Description of change
Information on a planned sub-study with 
ophthalmologic safety assessments was added.
Rationale for change
New information was added. 
Section to be changed
3.3.3
Description of change
Herbal remedies were added to exclusion criterion 
# 13.
Rationale for change
Herbal medications that may potentially interfere 
with efficacy assessments were excluded.
Section to be changed
4.2.2.1
Description of change
“e.g” was added to the restriction for methadone 


Boehringer Ingelheim                                                                                                      28 Mar 2019
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Doc. No.: c03559983-04                                  Trial Protocol                                       Page 109 of 116
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and suboxon. 
Rationale for change
Clarification was added.
Section to be changed
4.2.2.1
Description of change
Information regarding CYP2B6 sensitive drugs 
was added.   
Rationale for change
New information was added. 
Section to be changed
5.1.1
Description of change
WMS II was changed to WMS-III.
Rationale for change
Correction of typo.
Section to be changed
5.4.1 and Appendix 10.2
Description of change
Recording of food intake with study drug was 
added. 
Rationale for change
Information will be required to study impact of 
food intake on exposure. 
Section to be changed
5.1.2
Description of change
Correction to seven cognitive domains of MCCB. 
Rationale for change
Correction of typo. 
Section to be changed
5.3.6
Description of change
The following sentence was deleted: The reason for 
the decision on causal relationship for unlisted AEs
needs to be provided in the (e)CRF. 
Rationale for change
Clarification was received that this sentence is no 
longer required by local regulation of Japan.  


Boehringer Ingelheim                                                                                                      28 Mar 2019
BI Trial No.: 1346.9
Doc. No.: c03559983-04                                  Trial Protocol                                       Page 110 of 116
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GLOBAL AMENDMENT 2
11.2
Number of global amendment
2
Date of CTP revision
13 Dec 2017
EudraCT number
2016-000285-28
BI Trial number
1346.9
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 4 oral doses of BI 425809 
once daily over 12 week treatment period in 
patients with Schizophrenia
To be implemented only after 
approval of the IRB / IEC / 
Competent Authorities
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
Flowchart
Section to be changed
2.2  
Description of change
“Proof of Concept” (PoC) was amended to “Proof 
of Clinical Concept” (PoCC)
Rationale for change
Correction
Section to be changed
2.3
Description of change
Addition of new information
Rationale for change
To align with IB update


Boehringer Ingelheim                                                                                                      28 Mar 2019
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Section to be changed
3.3.2
Description of change
Excl crit. #5 was updated: tubal occlusion/litigation 
no longer considered permanent sterilization but 
highly effective method of birth control 
Rationale for change
To align with current guideline “Change to 
definition of Childbearing Potential” 001-MCS-40-
106_RD-20
Section to be changed
3.3.3
Description of change
Excl crit #9: it was added that patients requiring 
change in ongoing stable benzodiazepine regimen 
will be excluded
Rationale for change
Clarification
Section to be changed
3.3.3
Description of change
Excl crit #20: wording to be changed to Known 
history of HIV infection and/or a positive result for 
ongoing Hepatitis B or C infection on the Visit 1 
central lab report
Rationale for change
To check for ongoing infections at the time of 
screening
Section to be changed
2.3 and 3.3.3
Description of change
Excl crit #23: wording to be changed to 
Hemoglobin less than  120 g/L (12g/dL) in men or 
115 g/L (11.5g/dL) in women
Rationale for change
new information was added
Section to be changed
3.3.3
Description of change
Excl crit #26: wording to be changed to positive 
urine drug screen at screening except for BZDs 
taken according to prescription and as an ongoing, 
stable regimen. 
Rationale for change
For clarification to align with Excl. Crit#9 which 
allows ongoing stable BZD use 
Section to be changed
3.3.3
Description of change
Exclusion criterion #28: wording was changed to 
“Patients for which cognitive impairment or 
symptom severity compromises the validity of the 
cognitive outcome measures, in the clinical 
judgement of the investigator”
Rationale for change
Clarification
Section to be changed
3.3.3
Description of change
Exclusion criterion #29: wording was changed to 
„Patient who did not make an effortful attempt to 
complete the cognition battery at screening in the 
clnical judgement of the investigator“
Rationale for change
Clarification
Section to be changed
4.1.3


Boehringer Ingelheim                                                                                                      28 Mar 2019
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Description of change
Wording was changed to: “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 (150mg per 
day).”
Rationale for change
Clarification
Section to be changed
4.2.2.1
Description of change
Wording amended to Patients should not receive 
more than 4mg benztropine or no more than 50mg 
diphenhydramine (or equivalent doses of other 
anticholinergic or antihistaminic medication)
Rationale for change
For clarification 
Section to be changed
4.2.2.1
Description of change
Wording amended to “Patient will not begin or 
increase frequency/duration of psychotherapy 
during the trial period, receive electroconvulsive 
therapy, nor begin any type of 
traditional/complementary therapies”
Rationale for change
For clarification 
Section to be changed
4.2.2.2
Description of change
Cautionary statement regarding driving was 
amended “As a general precaution for CNS- active 
drugs, it is recommended that subjects should 
exercise caution when driving or operating 
machinery after drug administration.”
Rationale for change
Clarification – more general recommendation 
without specific timeframe
Section to be changed
4.2.2.2
Description of change
Wording amended to: “There are no other 
restrictions on diet, exercise, or smoking except 
that the patient’s usual habits, including nicotine 
and caffeine intake, should not be significantly
changed”
Rationale for change
Clarification
Section to be changed
Description of change
Rationale for change


Boehringer Ingelheim                                                                                                      28 Mar 2019
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Section to be changed
Description of change
Rationale for change
Section to be changed
Description of change
Rationale for change
Clarification 
Rationale for change
Administrative reasons
Section to be changed
5.3.3
Description of change
The following wording was added: “Clinically 
significant abnormal laboratory results should be 
reported by the investigators in eCRF either on 
baseline condition (from V1 test) or on adverse 
event page (from subsequent visits test).”
Rationale for change
Clarification
Section to be changed
5.3.3
Description of change
Hepatitis B Surface antigen (qualitative) and 
Hepatitis C antibodies (qualitative) testing were 
added to the safety lab test plan
Rationale for change
To check for ongoing infections at the time of 
screening
Section to be changed
5.3.4
Description of change
Central vendor for ECG was added. Existing ECG 
at screening will no longer be accepted. 


Boehringer Ingelheim                                                                                                      28 Mar 2019
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Rationale for change
Safety considerations and to align with 1346.23 
trial 
Section to be changed
5.3.6.1
Description of change
The following wording was added: Cancers of new 
histology and exacerbations of existing cancer must 
be classified as a serious event regardless of the 
duration between the discontinuation of the drug 
and must be reported as described in section 5.3.7 
Adverse event collection and reporting, subsections 
“AE collection” and “AE reporting to sponsor and 
timelines”.
Rationale for change
Alignment with new wording for current protocol 
template
Section to be changed
5.4.,7.3.5 and Appendix 10.2
Description of change
The following sentence was added “When the total 
sample size for the main study is reached, 
randomization in the imaging sub-study will stop 
and this may result in the number of patients 
randomized in the sub-study being less than 150 
which is the planned sample size for the sub-
study.”
Rationale for change
Clarification
Section to be changed
6.2.2
Description of change
Wording was amended to: “The 1st dose of study 
medication from the newly assigned medication kit
will be taken at the clinic within 15 minutes 
 
 
Rationale for change
Clarification
Section to be changed
7.6


Boehringer Ingelheim                                                                                                      28 Mar 2019
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Description of change
Clarification regarding randomization and 
stratification into the main trial and the imaging 
sub-study
Rationale for change
Clarification
Section to be changed
Appendix 10.8
Description of change
Addition of ophthalmologic sub-study protocol as 
appendix 10.8
Rationale for change
 as ophthalmologic 
substudy will be implemented in several countries.
Section to be changed
5.3.6.1 
Description of change
Information about self injury, no suicidal intent and 
AE reporting for negative report (suicidal ideation 
type 1, 2 or 3) was added
Rationale for change
Clarification
Section to be changed
3.3.3 Exclusion criteria 
Description of change
The following wording was added to exclusion 
criterion # 16: “that would jeopardize the patient´s 
safety while participating in the trial and their 
capability to participate”
Rationale for change
Clarification


Boehringer Ingelheim                                                                                                      28 Mar 2019
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GLOBAL AMENDMENT 3
11.3
Date of amendment
28 Mar 2019
EudraCT number
EU number
2016-000285-28
BI Trial number
1346.9
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 4 oral doses of BI 425809 
once daily over 12 week treatment period in 
patients with Schizophrenia
Global Amendment due to urgent safety reasons
Global Amendment
Section to be changed
5.3.5.2  Assessment of suicidality
Description of change
Addition of investigator rated C-SSRS assessment 
to allow psychiatrists to repeat or validate the 
telephone assessment in case doubtful reports from 
the telephone assessment are obtained. 
Rationale for change
The protocol asks for psychiatrists review of the 
report and requests that doubtful report should be 
repeated or reports be validated. However there is 
currently no systematic process to allow 
psychiatrists to repeat or validate the telephone 
assessment in case of doubt. Therefore we will 
provide sites with access to the investigator rated 
C-SSRS and provide corresponding training for 
this assessment, so psychiatrist can repeat doubtful 
reports. 


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c03559983
4.0
clinical-trial-protocol-version-04
A phase II randomised, double-blinded, placebo-controlled parallel group trial to
examine the efficacy and safety of 4 oral doses of BI 425809 once daily over 12
week treatment period in patients with Schizophrenia
Approval-Clinical Trial Leader
03 Apr 2019 09:04 CEST
Approval-Team Member Medicine
03 Apr 2019 09:08 CEST
Author-Trial Clinical
Pharmacokineticist
03 Apr 2019 09:27 CEST
Approval-Translational Medicine
Expert
03 Apr 2019 09:35 CEST
Approval-Therapeutic Area 
03 Apr 2019 09:55 CEST
Approval-Biostatistics
04 Apr 2019 01:43 CEST
Verification-Paper Signature
Completion
05 Apr 2019 13:35 CEST


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Document Number: 
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c03559983
4.0

SAP_001.pdf: 
TITLE PAGE
TRIAL STATISTICAL ANALYSIS PLAN
c25706980-02
BI Trial No.:
1346.9
Title:
A phase II randomised, double-blinded, placebo-controlled parallel 
group trial to examine the efficacy and safety of 4 oral doses of BI 
425809 once daily over 12 week treatment period in patients with 
Schizophrenia
Clinical Trial Protocol (c03559983-04), including Global Protocol 
Amendment 1 (21APR2016), Global Protocol Amendment 2 
(13DEC2017), Global Protocol Amendment 3 (28MAR2019)
Investigational
Product(s):
BI 425809
Responsible trial 
statistician(s):
Phone: 
Fax: 
Date of statistical 
analysis plan:
17 FEB 2020 SIGNED
Version:
REVISED (Version 4)
Page 1 of 34
Proprietary confidential information
2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.


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1.
TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
1.
TABLE OF CONTENTS......................................................................................2
LIST OF TABLES...................................................................................................................4
2.
LIST OF ABBREVIATIONS ..............................................................................5
3.
INTRODUCTION.................................................................................................7
4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY......................8
5.
ENDPOINTS .........................................................................................................9
5.1
PRIMARY ENDPOINT .......................................................................................9
5.2
SECONDARY ENDPOINTS.............................................................................10
5.2.1
Key secondary endpoint .....................................................................................10
5.2.2
Secondary endpoints...........................................................................................10
5.4.1
Variables from Ophthalmologic Sub-study......................................................12
6.
GENERAL ANALYSIS DEFINITIONS ..........................................................14
6.1
TREATMENTS...................................................................................................14
6.2
IMPORTANT PROTOCOL DEVIATIONS....................................................14
6.3
SUBJECT SETS ANALYSED...........................................................................17
6.5
POOLING OF CENTRES .................................................................................20
6.6
HANDLING OF MISSING DATA AND OUTLIERS....................................20
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS ...................21
7.
PLANNED ANALYSIS......................................................................................23
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS.........23
7.2
CONCOMITANT DISEASES AND MEDICATION .....................................23
7.3
TREATMENT COMPLIANCE........................................................................24
7.4
PRIMARY ENDPOINT .....................................................................................25
7.4.1
Primary analysis of the primary endpoint........................................................25
7.5
SECONDARY ENDPOINT ...............................................................................27
7.5.1
Key secondary endpoint .....................................................................................27
7.5.2
(Other) Secondary endpoint...............................................................................27
7.5.2.1
Primary analysis of the secondary endpoint .........................................................27
7.7
EXTENT OF EXPOSURE.................................................................................28
7.8
SAFETY ANALYSIS..........................................................................................29
7.8.1
Adverse Events ....................................................................................................29


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7.8.2
Laboratory data ..................................................................................................30
7.8.3
Vital signs.............................................................................................................30
7.8.4
ECG......................................................................................................................30
7.8.5
Others...................................................................................................................30
8.
REFERENCES....................................................................................................32
10.
HISTORY TABLE..............................................................................................34


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LIST OF TABLES
Table 5: 1 
Endpoints and time points of measurement........................................................9
Table 6.1: 1
Treatment descriptions .....................................................................................14
Table 6.1: 2
Analysing treatment periods (same for all treatment groups) ..........................14
Table 6.2: 1
Handling of iPDs ..............................................................................................15
Table 6.3: 1
Subject sets analysed ........................................................................................19
Table 6.7: 1
Planned and actual study days..........................................................................22
Table 7.4.1: 1 Optimal contrast coefficients............................................................................26
Table 10: 1
History table .....................................................................................................34


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2.
LIST OF ABBREVIATIONS
Term
Definition / description
AE
Adverse Event
AESI
Adverse Event of Special Interest
AIC
Akaike Information Criterion
ANCOVA
Analysis of Covariance
ANOVA
Analysis of Variance
ATC
Anatomical, Therapeutic, Chemical
BCVA
Best Corrected Visual Acuity
BI
Boehringer Ingelheim
CRF
Case Report Form
C-SSRS
Columbia Suicide Severity Rating Scale
CT
Concomitant Therapy
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
DBL
Database Lock
ECG
Electrocardiogram
EOT
End of Treatment
FAS
Full Analysis Set
F-M 100
Farnsworth-Munsel 100
FU
Follow-up
ICH
International Conference on Harmonisation
IDEA
International Document Management & Electronic Archiving
IOP
Intra-Ocular Pressure
IPD
Important Protocol Deviation
IVRS
Integrated Voice Response System
LLT
Lower Level Term
MATRICS
Measurement and Treatment Research to Improve Cognition in 
Schizophrenia


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Term
Definition / description
MCCB
MATRICS Consensus Cognitive Battery
MCPMod
Multiple Comparison Procedures and Modelling
MMRM
Mixed effects Model Repeated Measures
MRI
Magnetic Resonance Imaging
PANSS
Positive and Negative Syndrome Scale
PPS
Per Protocol Set
PT
Preferred Term
QD
Quaque Die (once a day)
RDC
Remote Data Capture
REP
Residual Effect Period
RPM
Report Planning Meeting
RS
Randomised Set
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SAS
Statistical Analysis Software
SCoRS
Schizophrenia Cognition Rating Scale
SD-OCT
High Definition Ocular Coherence Tomography (SD-OCT)
SOC
System Organ Class
SS
Screened Set
STD
Standard Deviation
TOM
Trial Oversight Meeting
TS
Treated Set
TSAP
Trial Statistical Analysis Plan
ULN
Upper Limit of Normal
VAS
Visual Analog Scale
WHO
World Health Organisation


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3.
INTRODUCTION
As per International Conference on Harmonisation (ICH) E9 (1), the purpose of this 
document is to provide a more technical and detailed elaboration of the principal features of 
the analysis described in the protocol, and to include detailed procedures for executing the 
statistical analysis of the primary and secondary variables and other data.
This Trial Statistical Analysis Plan (TSAP) assumes familiarity with the Clinical Trial 
Protocol (CTP), including Protocol Amendments. In particular, the TSAP is based on the 
planned analysis specification as written in CTP Section 7 “Statistical Methods and 
Determination of Sample Size”. Therefore, TSAP readers may consult the CTP for more 
background information on the study, e.g., on study objectives, study design and population, 
treatments, definition of measurements and variables, planning of sample size, randomisation.
R Version 3.3.2 with “DoseFinding” package (2) will be used for analyses based on Multiple 
Comparison Procedures and Modelling (MCPMod) and SAS® Version 9.4 will be used for 
all other analyses.


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4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY
In the third paragraph in the 1346.9 CTP Section 7.1 (on page 65), the second sentence states 
“Change from baseline in everyday functional capacity as measured by SCoRS global ratings 
after 12 weeks of treatment is the secondary endpoint”. This is inconsistent with the 
specifications in Section 5.1.2 in the CTP. It is clarified in this TSAP that the secondary 
endpoint in 1346.9 study is “change from baseline in everyday functional capacity as 
measured by SCoRS total score after 12 weeks of treatment”.


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5.
ENDPOINTS
The primary objectives of this trial are to establish proof-of-clinical-concept (POCC) with 
respect to a non-flat dose-response curve together with the definition of one or more suitable 
doses with respect to the efficacy and safety of orally administered once daily dosing of BI 
425809 in patients with schizophrenia on stable antipsychotic treatment. Table 5: 1 below lists
the different endpoints and the corresponding measurement time points.
Table 5: 1
Endpoints and time points of measurement
Screening 
(Visit 1)
Day -28 to -7
Baseline (Visit 
2)
Day 1
Week 3 
(Visit 3)
Day 22 ± 3 
days
Week 6 (Visit 4)
Day 43 ± 3 days
Week 9 (Visit 5)
Day 64 ± 3 days
Week 12 (Visit 6) or 
EOT
Day 85# + 3 days
Follow-up 1
EOT + 7 days ± 
3 days
MCCB
MCCB
MCCB
MCCB
SCoRS
SCoRS
Cpre,ss,3
Cpre,ss,4, C2,ss, 
C3.5,ss
eC-SSRS
eC-SSRS
eC-SSRS
eC-SSRS
eC-SSRS
eC-SSRS
eC-SSRS†
BCVA#
BCVA
BCVA
F-M 100#
F-M 100
F-M 100
Pupil diameter#
Pupil diameter
Pupil diameter
Anterior and 
posterior 
biomicroscopy 
exam#
Anterior and 
posterior 
biomicroscopy 
exam
Anterior and 
posterior 
biomicroscopy 
exam
IOP#
IOP
IOP
SD-OCT#
SD-OCT
SD-OCT
Fundoscopy#
Fundoscopy
Fundoscopy
† eC-SSRS is also measured at the second follow-up visit (end of study visit): FU2 (EOT + 28 days ± 7 days)
# Endpoints collected only in subjects participated in the ophthalmology sub-study
5.1
PRIMARY ENDPOINT
Change from baseline in MCCB overall composite score at Week 12 is the primary efficacy 
endpoint. The MCCB overall composite t-score is derived from the seven domain scores 
obtained from a total of ten tests (see CTP Table 5.1.1: 1) and is measured at screening (Visit 


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1), baseline (Visit 2), Week 6 (Visit 4), and Week 12 (Visit 6). See CTP Sections 5.1.1 and 
5.2.1 for details. A larger overall composite t-score indicates better cognition.
5.2
SECONDARY ENDPOINTS
5.2.1
Key secondary endpoint
There is no key secondary endpoint in this trial.
5.2.2
Secondary endpoints
Change from baseline in SCoRS total score assessed by interviewer at Week 12 is the
secondary efficacy endpoint. SCoRS total score is derived as the sum of non-missing 
responses from 20 interview-based items rated by an interviewer on a 4-point scale with 
higher rating indicating greater degree of impairment in day-to-day functions due to cognitive 
deficits. A response of “N/A” to an item is treated as missing. If six or more of the 20 items 
are missing for a subject at a visit, then the corresponding SCoRS total score is missing for 
that subject at the visit. If five or less of the 20 items are missing for a subject at a visit, then 
the item(s) with missing value(s) will be imputed first with the average of the non-missing 
item values, and then the SCoRS total score for the subject at the visit will be derived as the 
sum of non-missing item values and the imputed item values. SCoRS total score is measured 
at baseline (Visit 2) and Week 12 (Visit 6) or End of Treatment (EOT visit). See CTP 
Sections 5.1.2 and 5.2.1 for details.
For safety, the percentage of subjects with serious adverse event (SAE) (including clinically 
relevant abnormalities of physical examination, vital signs, electrocardiogram (ECG) test and 
laboratory tests) are secondary endpoint.


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5.4.1
Variables from Ophthalmologic Sub-study
The following variables are collected at baseline (Visit 2), Week 9 (Visit 5) and one week 
after EOT (Follow-up Visit 1) and analysed for the ophthalmologic sub-study:

Number of correct letters from the Best Corrected Visual Acuity (BCVA) test in each 
eye

Total error score (TES) and level of color vision deficiency classification (i.e. low, 
average and superior discrimination) from the Farnsworth-Munsel 100 (F-M 100) hue 
testing in each eye

Pupil diameter measurement in each eye


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
Categorical changes (normal / abnormal) from the anterior and posterior 
biomicroscopy exam in each eye

Intra-ocular pressure (IOP) in each eye

Central retinal thickness in each eye as measured by the High Definition Ocular 
Coherence Tomography (SD-OCT)

Categorical changes (normal / abnormal) from the indirect fundoscopy of the retina in 
each eye.
Changes from baseline to Week 9 and from baseline to follow-up visit 1 are derived for each 
of the above ocular measurements.
Please refer to Table 5: 1 for the different endpoints and the corresponding measurement time 
points.


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENTS
For basic trial information on treatments to be administered, assignment of dose group, and 
selection of doses, see CTP Section 4.
Table 6.1: 1
Treatment descriptions
Long Name
Short Name
Placebo
Placebo
BI 425809 2 mg QD
BI 2mg
BI 425809 5 mg QD
BI 5mg
BI 425809 10 mg QD
BI 10mg
BI 425809 25 mg QD
BI 25mg
Table 6.1: 2
Analysing treatment periods (same for all treatment groups)
Analysing Treatment 
Period
Start Date
Stop Date
Screening
Date of informed consent
Date of the first treatment 
administration
On-treatment
Date of the first treatment 
administration
Date of the last treatment 
administration + REP + 1 day
Follow-up
Date of the last treatment 
administration + REP + 1 day
Date of the last per protocol 
visit
REP is the residual effect period which is defined as 11 days after the last dose of trial treatment.
6.2
IMPORTANT PROTOCOL DEVIATIONS
A protocol deviation (PD) is important if it affects the rights or safety of the study subjects, or 
if it can potentially influence the primary outcome measurement(s) in a non-negligible way.
A list of important PDs (IPDs) is given in Table 6.2: 1. Important PDs will be reviewed at 
Trial Oversight Meeting (TOM) conducted periodically during the trial. A list of protocol 
deviations (treatments are blinded) will be discussed at the Report Planning Meetings (RPMs)
before data unblinding.
If the data show other important PDs, this table will be supplemented accordingly at TOMs or 
RPMs or through team review of the manual PD log. The decision whether a subject will be 
excluded from the analysis will be made at the final RPM prior to Database Lock (DBL).


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Table 6.2: 1
Handling of IPDs
Category/Code
Description
Example/Comment
Excluded 
from
A
Entrance criteria not met
A1
Inclusion criteria not met 
A1.1
No diagnosis of Schizophrenia per DSM-5
or medically and psychiatrically not stable
IN3 in the CTP not met
PPS
A1.2
Age <17 or >52
IN2 in the CTP not met. 
Check age in demographic 
page 
None
A1.3
Not exhibit reliability, physiologic 
capability or have insufficient educational 
level 
IN6 in the CTP not met
None
A1.4
No consistent informant identified 
IN7 in the CTP not met
None
A1.5
Violation of IN4
Either one of the first two 
bullet points in IN4 regarding 
typical and/or atypical 
antipsychotics use
None
A2
Exclusion criteria met 
A2.1
Any exclusion criteria met
EX1-EX29 in the CTP
None
A2.2
Any of the exclusion criteria for the 
ophthalmologic sub-study met
See CTP Section 10.8.3.2
EYE
B
Informed consent
B1
Informed consent not available/not done
B1.1
Informed consent not available/not done
IN1. No patient signature on 
ICF. Not follow local law 
requirement for informed 
consent.
All
B1.2
Ocular measurements taken without ICF 
for ophthalmologic sub-study
Signed ICF for main study 
available but not for 
ophthalmologic sub-study, but 
ocular measurements were 
taken; not an IPD if consent 
for the ophthalmologic sub-
study was given late
EYE


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Table 6.2: 1
Handling of IPDs (cont’d)
Category/Code
Description
Example/Comment
Excluded 
from
C
Trial medication and randomisation
C1
Incorrect trial medication taken
C1.1
Incorrect trial medication taken during 
study
Any deviation. Check whether 
the medication packages 
dispensed (med. numbers 
entered into RDC) has the 
correct content (to be seen 
from the med. number list that 
was the basis for packaging). 
If content was correct, the 
deviation will only be noted. 
Otherwise, the cases will be 
described individually and 
possibly excluded. 
In addition, check whether the 
dispensed packages match the 
randomised treatment of the 
patient (IVRS assignment). If 
not, and if treated consistently 
throughout the trial, analyse as 
treated.
None
C2
Randomisation order not followed
C2.1
Error by the vendor who implemented the 
randomisation scheme
E.g., the same randomisation
number was given to different 
patients or the assignment of 
duplicate medication numbers 
or incorrect medication 
numbers. Or wrong stratum. 
Verify by comparing the
medication numbers and 
randomisation numbers from 
IVRS.
If a patient actually receives 
the correct medication despite 
the wrong kit, such deviation 
will only be noted.
None
C3
Non-compliance with trial medication
C3.1
<80% cumulative compliance rate with trial
medication during the entire treatment 
period
<80% cumulative compliance
rate with trial medication
during the entire treatment 
period is considered as an 
IPD.
None


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Table 6.2: 1
Handling of IPDs (cont’d)
Category/Code
Description
Example/Comment
Excluded 
from
D
Concomitant medication
D1
Prohibited medication (including 
prohibited procedures) use before the 
first administration of trial medication
All medications before first 
drug administration (those 
defined in CTP Section 4.2.2). 
To be determined on a case by 
case basis.
None
D2
Prohibited medication (including 
prohibited procedures) use during the 
treatment period (including follow-up 
period)
As defined in CTP Section 
4.2.2. To be determined on a 
case by case basis.
None
D2.1
Used restricted medications within 8 hours 
before taking MCCB after Visit 1
E.g., anticholinergic agents, 
antihistamine, benzodiazepine, 
benztropine, 
diphenhydramine, sleep 
medication
PPS
D3
Subjects who stopped taking all 
antipsychotics and refused to re-take 
antipsychotics during the study
None
F
Incorrect timing of endpoint measurements or administration of trial medication
F1
Primary endpoint performed at 
incorrect date/time
F1.1
MCCB measured outside the allowed time 
window
MCCB should be performed at 
the same time of the day, i.e. 
within +/- 120 minutes at 
Visits 4 and / or EOT as 
compared with Visit 2 MCCB 
administration time.
None
F1.2
Baseline MCCB measured after first drug 
administration
Visit 2 MCCB should be 
measured before the first drug 
administration
None
F1.3
EOT MCCB measured >10 days after last 
drug administration
E.g. EOT MCCB measured 
>10 days after last drug 
administration
None
Z
Other
Z1
Serious issue of protocol deviation
Cases reported from site 
monitoring
None
Z2
Other protocol deviation affecting 
efficacy and possibly safety 
E.g. substantial change in 
nicotine consumption; positive 
drug screening during study
None
Z3
Other protocol deviation affecting safety 
only 
E.g. abnormal hemoglobin 
measurement; not reported or 
under-reported suicidal 
ideation; DILI cases not 
handled properly
None
6.3
SUBJECT SETS ANALYSED

Screened Set (SS):
The screened set consists of all subjects who signed informed consent and were 
screened for the trial with at least one screening procedure done at Visit 1.


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
Randomised Set (RS):
The randomised set consists of all subjects who were screened for the trial and who 
were randomised to trial treatment, regardless of whether any trial treatment was 
administered.

Treated Set (TS):
The treated set consists of all subjects who were randomised and treated with at least 
one dose of trial treatment. The TS is used for the analysis of safety variables.

Full analysis set (FAS):
The full analysis set consists of all randomised subjects who were treated with at least 
one dose of trial treatment and had a baseline and at least one evaluable post-baseline 
on-treatment measurement of the primary or secondary efficacy endpoints. The FAS is
used for the primary and secondary analyses of the efficacy endpoints.

Per protocol set (PPS):
The per protocol set is nested within the FAS and only includes subjects in the FAS 
who do not have any important protocol deviations which are specified to be excluded
from the sensitivity analysis of the efficacy endpoints using the PPS (see Table 6.2: 1). 
If the number of subjects in the PPS is less than 90% of the number of subjects in the 
FAS, then the PPS is used for the sensitivity analysis of the primary and secondary 
efficacy endpoints.

Ophthalmologic Sub-study Set (EYE):
The ophthalmologic sub-study set consists of all treated subjects who consented to 
participate in the ophthalmologic sub-study (including late/retrospective consent to the 
ophthalmologic sub-study) and had evaluable ophthalmologic measurements.


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Table 6.3: 1
Subject sets analysed
Subjects Sets Analysed
Class of endpoints
TS 
FAS
PPS
EYE
Primary endpoint –
primary analysis using MCPMod & 
secondary analysis using pair-wise 
comparisons approach and descriptive
statistics
X
X 
(subset)
X*
(other) Secondary 
 
endpoints – primary analysis using 
MCPMod and secondary analysis 
using pair-wise comparisons and 
descriptive statistics
X
X*
(only 
secondary 
efficacy 
endpoint)
Safety variables
X
X
Variables in Ophthalmologic Sub-
study
X
Demographic/baseline 
variables/exposure
X
X
X
* Only if the number of subjects in the PPS is <90% of the number of subjects in the FAS, sensitivity analysis of the primary 
and secondary efficacy endpoints using PPS will be conducted.


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6.5
POOLING OF CENTRES
This section is not applicable, because the study was performed in only one centre.
6.6
HANDLING OF MISSING DATA AND OUTLIERS
Every effort should be taken to collect complete data at each visit for each subject. If not 
specified otherwise, missing data are not imputed and remain missing. Potential outliers will 
be reported and analysed as observed.
MCCB
All imputations will be carried out separately for each study visit since there may be 
differences in test performance at different time points.
For the domains of Working Memory (consisting Letter-Number Span test and Wechsler 
Memory Scale 3rd ed. Spatial Span subtest) and the Speed of Processing (consisting Trail 
Making Test Part A, Brief Assessment of Cognition in Schizophrenia – Symbol Coding 
subtest, and Category Fluency test – animal naming), if one of the tests consisting of a domain 
has missing value at a visit, the corresponding domain score can still be derived using the 
observed test raw score for that visit. If more than one of the tests consisting of a domain have 
missing value at a visit, the corresponding domain score is missing at that visit.
For the other five domains (Verbal Learning, Reasoning and Problem Solving, Visual 
Learning, Attention / Vigilance, and Social Cognition) which has only one test, if the test has 
missing value at a visit, the corresponding domain score is missing.
If a domain score is missing at a visit, the missing T-score of this domain can be imputed 
using the following algorithm:
 = 
 + 
 −

Where  is the missing T-score at Visit i to be imputed for domain j of subject k

 is the mean T-score at Visit i on domain j from all subjects

 is the mean T-score at Visit i on all available domains from subject k

 is the mean T-score at Visit i of all available domains from all subjects.
In order to produce a more plausible imputed value that reflects the naturally occurring 
variability around the measure of a subject’s cognitive ability, a small amount of random 
variance will be added to each predicted value . Multiplying the square root of the mean 
square error of  by a random value drawn from a standard normal distribution, Z ~ N(0, 
1), the final imputed T-score of the missing domain would become:


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 =  +  () ∗
This will not only preserve the independent nature of the collected data, but also prevent 
exaggerating the precision of the treatment differences (3).
For baseline assessment, at least two-thirds of the cognitive domains (i.e., a minimum of five 
out of the seven domains for the MCCB overall composite score and a minimum of four out 
of the six domains for the MCCB neurocognitive composite score) need to be successfully 
assessed at baseline for it to be counted as a test occasion with non-missing baseline value.
For post-baseline assessments, at least half of the domains (i.e., a minimum of four out of the 
seven domains for the MCCB overall composite score and a minimum of three out of the six 
domains for the MCCB neurocognitive composite score) need to be successfully assessed to 
be considered a test occasion with non-missing value.
EOT measurement of MCCB endpoints which were collected >10 days after the last trial 
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.
Missing or incomplete AE dates are imputed according to (4).
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
In general, baseline values are the measurements taken on the day of the first administration 
of trial medication (Visit 2), and immediately prior to the first administration of trial
medication. If this value is not available, the measurement at the screening visit (Visit 1) is 
used (PANSS and eC-SSRS), but this does not apply for MCCB measurement.
Visits are labelled according to the flow chart in the protocol: Visit 1 (screening), Visit 2 
(randomisation and start of treatment, also baseline), Visit 3 (Week 3), Visit 4 (Week 6), Visit 
5 (Week 9), Visit 6 (Week 12), and End of Treatment (EOT), Follow-up 1 (FU1) (7 days after 
EOT), Follow-up 2 (FU2) (28 days after EOT). Planned and actual test days are included in 
the analysis data sets and are calculated relative to the beginning of study as indicated in 
Table 6.7: 1 below. 


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Table 6.7: 1
Planned and actual study days
Visit
Relative to study start
Planned test day
Actual test day
2
1
Day 1 – Day 2
3
22
Day 3 – Day 39
4
43
Day 40 – Day 60
5
64
Day 61 – Day 81
6 / EOT
85 for completed 
subjects
Day 81 – Day 101
EOT
N/A (for early 
discontinued 
subjects)
Date of the last administration of 
trial medication to date of the last 
administration of trial medication 
+ 8 days (for early discontinued 
subjects)
FU1
EOT + 7 days
EOT + 4 days to EOT + 10 days
FU2
EOT + 28 days
EOT + 21 days to EOT + 35 days
For efficacy endpoints with planned measurements at baseline, Week 6 and Week 12, actual 
measurement collected between Day 3 and Day 60 will be mapped to Week 6 and actual 
measurement collected between Day 61 and the actual EOT visit date will be mapped to
Week 12, and baseline is the measurement collected at Visit 2. If multiple measurements are 
mapped into the same time point using the time window, then the first measurement will be 
used in the analysis.


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7.
PLANNED ANALYSIS
In general the display format of the analysis results follow BI guideline and standards as 
much as possible.
For End-Of-Text tables, the set of summary statistics is: N / Mean / Standard Deviation (STD) 
/ Min / Median / Max.
For tables that are provided for endpoints with some extreme data, median, quartiles and 
percentiles are preferred to mean, standard deviation, minimum and maximum.
In general, means, medians, and percentiles are presented to one more decimal place than the 
raw data and STDs 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 include all possible categories defined (even if 
there is no count in a category) and display the number of observations in a category as well 
as the percentage (%) relative to the number of subjects in the respective treatment group 
(unless otherwise specified, all subjects in the respective subject set whether they have non-
missing values or not). Percentages are rounded to one decimal place. The category missing is 
displayed only if there are actually missing values.
If a table presents only categorical data, “[N (%)]” is displayed in the column header only.
Abbreviations (e.g. Wors.) or acronyms (e.g. PD) will not be displayed in tables and subject 
data listings without any explanation. They will be either spelled out or explained in 
footnotes.
If applicable, conversion from days to weeks, months and years will be as follows:

weeks = days ÷ 7

months = 12 × days ÷ 365.25

years = days ÷ 365.25.
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Only standard descriptive statistics and summary tables are planned for this section of the 
report based on the treated set and other subject sets as appropriate. Data will be summarised 
by treatment group and a "total" column will be included in the summary table.
7.2
CONCOMITANT DISEASES AND MEDICATION
Only descriptive statistics are planned for this section of the report based on the treated set
and other subject sets as appropriate.
Concomitant diseases are coded similarly as AEs based on the most current MedDRA® 
version. A summary of concomitant diseases will be provided by treatment group, system 
organ class (SOC), and preferred term (PT).


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Concomitant therapies (CTs) are coded according to WHO DD. CTs will be classified 
according to the Anatomical, Therapeutic, Chemical (ATC) classification system. The third 
ATC level will be used to categorise CTs by therapy type. In situations where a medical 
product may be used for more than one equally important indication, there are often several 
classification alternatives. As appropriate, subjects receiving CTs with more than one possible 
ATC level-three category will be counted more than once and footnote will clarify this 
possible multiple counting in tables. CTs will be summarised in two groups: psycho-active 
and non-psycho-active concomitant medications. CTs of special interest, e.g. antipsychotic 
CTs, may also be defined and explored in detail.
7.3
TREATMENT COMPLIANCE
Treatment compliance is calculated at Week 3, 6, 9, and 12/EOT using the following formula:
Treatment Compliance = (number of tablets actually taken during a time period) / (number of 
tablets that should have been taken during a time period) * 100.
For early discontinued subjects, if there is documented evidence for taking the subject off the 
drug, for example due to an adverse event, then the drug stop date should be used to derive 
the treatment period for treatment compliance; if there is no documented evidence for taking 
the subject off the drug, for example a subject came to a planned in-office visit and informed 
the study investigator that she/he has already stopped taking the drug several days ago 
because she/he did not want to continue the study, then this in-office visit is the EOT visit and 
the EOT visit date should be used to derive the treatment period for treatment compliance. 
The following is an example to illustrate the calculation of treatment compliance.
Scenario 1

A subject started treatment on June 5, 2019

This subject had an AE on June 10, 2019

Study investigator decided to stop the trial medication for this subject on June 11, 
2019

This subject had EOT visit on June 17, 2019 for early discontinuation
Treatment Compliance for Scenario #1 = (number of tablets this subject actually took
between June 5 and 11, 2019) / (number of tablets that this subject should have taken between 
June 5 and 11, 2019) * 100
Scenario 2

A subject started treatment on June 5, 2019

This subject decided to stop taking the trial medication on June 10, 2019

This subject came to office for the planned Visit 3 on June 26, 2019 per CTP 
flowchart, withdrew consent for continuing with this trial, and then Visit 3 became 
EOT visit


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Treatment compliance for Scenario #2 = (number of tablets this subject actually took between 
June 5 and 26, 2019) / (number of tablets this subject should have taken between June 5 and 
26, 2019) * 100.
The cumulative treatment compliance during the entire treatment period is derived using the 
following formulas:
For completers: if a subject’s observed treatment compliance rates are 85% at Week 3, 90% 
at Week 6, 100% at Week 9 and 100% at EOT, then the cumulative treatment compliance rate 
= (0.85*3 + 0.90*3 + 1*3 + 1*3)/12 * 100% = 93.75%.
For early discontinued subject: if a subject’s observed treatment compliance rates are 85% at 
Week 3, 100% at Week 6, 50% at EOT visit, and this subject did not discontinue early due to 
AE, then the cumulative treatment compliance rate = (0.85*3 + 1*3 + 0.5*((EOT date – drug 
start date + 1)/7 – 6))/((EOT visit date – drug start date + 1)/7) * 100% = 85.7% if EOT visit 
date – drug start date + 1 = 50 days. If there is documented evidence of early discontinuation 
due to AE before the EOT visit date for this subject, then replace EOT visit date with the 
documented drug stop date in the above formula.
If any one of the by-visit treatment compliance rates is missing, then the cumulative treatment 
compliance should be non-evaluable.
Only descriptive statistics are planned for this section of the report. Summary statistics of 
compliance, by-visit and cumulative compliance, in the treated set will be given for the 
number of subjects as well as the corresponding percentage with compliance in the categories 
<80%, 80% - 100%, >100% - 120%, >120% for by-visit compliance and <80%, 80% - 100%, 
>100% for cumulative compliance.
7.4
PRIMARY ENDPOINT
7.4.1
Primary analysis of the primary endpoint
The MCPMod approach (6, 7) is implemented in two main stages: (1) trial design stage; (2) 
trial analysis stage. The procedures for the trial design stage, including the selection of 
candidate models covering a suitable range of dose-response shapes and sample size and 
power calculations are provided in the CTP Section 7.3.1 and 7.7. The procedures for the trial 
analysis stage are specified below. FAS is used for the primary analysis of the primary 
efficacy endpoint.
The change from baseline in MCCB overall composite t-score at Week 12 as well as the 
corresponding variance-covariance matrix are estimated using a mixed effects model repeated 
measure (MMRM) including the fixed categorical effects of treatment, visit and treatment-by-
visit interaction, as well as the fixed continuous covariates of the baseline MCCB overall 
composite t-score and the baseline-by-visit interaction, and subject is considered as random 
effect. The unstructured covariance matrix is used to estimate the within subject errors. Then 
the pair-wise comparison procedure will be implemented using the optimal contrast tests 
which control the family-wise type I error rate at one-sided α=0.05. The optimal contrasts 
corresponding to the candidate models are calculated as in the trial design stage and shown in 


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Table 7.4.1: 1 below. These contrasts will be updated using the expected model means from
the candidate set and the estimated variance-covariance matrix from the data.
Table 7.4.1: 1 Optimal contrast coefficients
Optimal Contrast Coefficients for Dose
Model
0
2mg
5mg
10mg
25mg
Linear
-0.593
-0.212
-0.085
0.127
0.762
Linear in log
-0.844
-0.012
0.146
0.271
0.439
Emax
-0.773
-0.142
0.083
0.292
0.539
Sigmoid Emax
-0.623
-0.295
-0.078
0.389
0.606
Logistic
-0.542
-0.254
-0.181
0.231
0.745
Beta model
-0.782
0.173
0.358
0.441
-0.190
Proof of concept is established if at least one dose-response model is statistically significant, 
i.e. the null hypothesis of a flat dose-response curve is rejected indicating a benefit of one BI 
425809 dose over placebo.
Once the significance of a dose-response signal is established, the dose-response profile and 
the target dose can be estimated using the model averaging method. The selected dose-
response model(s) is re-fitted to the data without any parameter assumptions to generate a set 
of new estimates of the model parameters from the data. The final dose-response model is 
obtained via the weighted model averaging based on Akaike Information Criterion (AIC) (the 
smaller the AIC value the better the model fit). Estimate of the target dose is the smallest dose 
producing an effect greater than or equal to the target effect size of 0.35 based on the final 
dose-response model as well as considering safety information and other relevant information.
The MCPMod trial analysis will be implemented by calling an R function/package within 
SAS.


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7.5
SECONDARY ENDPOINT
7.5.1
Key secondary endpoint
This section is not applicable as no key secondary endpoint has been specified in the protocol.
7.5.2
(Other) Secondary endpoint
7.5.2.1
Primary analysis of the secondary endpoint
The MCPMod approach will be applied to the secondary endpoint of change from baseline in 
SCoRS total score by interviewer at Week 12 using an ANCOVA model including treatment 
and baseline SCoRS total score as covariates using the FAS.


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7.7
EXTENT OF EXPOSURE
Extent of exposure will be summarised for the treated set using descriptive statistics for days 
of exposure as well as number (%) of subjects whose total exposure falls in the defined 
categories: <30 days, 30 to <42 days, 42 to <60 days, 60 to <90 days, >=90 days.


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7.8
SAFETY ANALYSIS
All safety analyses will be performed on the treated set and other subject sets as appropriate.
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 analyses of AEs will follow the BI guideline (8). AEs will be coded with the 
most current version of MedDRA®.
For analysis multiple AE occurrence data on the CRF will be collapsed into an AE provided 
that all of the following applies:

All AE attributes are identical (lower level term (LLT), intensity, action taken, therapy 
required, seriousness, reason for seriousness, relationship, outcome)

The occurrences were time-overlapping or time-adjacent (time-adjacency of 
2 occurrences is given if the second occurrence started on the same day or on the day 
after the end of the first occurrence).
For further details on summarisation of AE data, please refer to (4, 8).
The analysis of AEs will be based on the concept of treatment emergent adverse events. That 
means that all adverse events occurring between the date of the first administration of trial 
treatment till the date of the last administration of trial treatment + residual effect period will 
be assigned to the on-treatment period label with the trial treatment assigned on Day 1 of the 
first treatment cycle. All AEs occurring before the first administration of trial treatment will 
be assigned to ‘screening’ and all AEs occurring after the residual effect period will be 
assigned to ‘follow-up’. For details on the treatment definition, see Section 6.1.
Adverse events of special interest (AESIs)
A hepatic injury is defined by the following alterations of hepatic laboratory parameters:

an elevation of AST and / or ALT ≥ 3 fold ULN combined with an elevation of total 
bilirubin ≥ 2 fold ULN measured in the same blood draw sample; and / or

marked peak aminotransferase (ALT and / or AST) elevations ≥ 10 fold ULN.
See CTP Section 5.3.6.1.
Other significant AE (according to ICH E3)
According to ICH E3 (9), AEs classified as "other significant" needs to be reported and will 
include those non-serious and non-significant AEs with


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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 TOM.
An overall summary of AEs will be presented.
The frequency of subjects with AEs will be summarised by treatment, primary system organ 
class (SOC) and preferred term (PT). The SOCs will be sorted by default alphabetically and 
PTs will be sorted by frequency within an SOC. Separate tables will be provided for patients 
with 

related AEs

serious AEs

serious related AEs

AESIs

Other significant AE (according to ICH E3)

AEs leading to death

AE leading to discontinuation of trial medication

AEs occurred with incidence in the preferred term >2%

AEs occurred with incidence in the preferred term >5%

AEs occurred during the follow-up period.
7.8.2
Laboratory data
The analyses of laboratory data will be descriptive in nature and will follow (10).
Descriptive statistics for laboratory values will be displayed using the converted values. Shift 
tables of change in laboratory measurements 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.
7.8.3
Vital signs
Only descriptive statistics are planned for this section of the report.
7.8.4
ECG
Clinical relevant abnormal ECG findings will be reported and analysed as AEs.
7.8.5
Others
Ophthalmologic variables


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Each ophthalmologic variable is measured for both the right eye and the left eye. For the total 
error score from F-M 100 test, the average of the total error scores from the right and the left 
eye will be used in the analysis.
For continuous variables, summary statistics including mean, median, standard deviation, 
minimum, maximum will be presented for the change from baseline measurements. In 
addition, paired t-test and 95% CI will be derived comparing Week 9 with baseline 
measurements.
For categorical variables, shift tables will be presented for the categorical changes from 
baseline.


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8.
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.
Bomkamp B, Pinheiro J, Bretz F. R Package ‘DoseFinding’ (February 19, 2015). 
website:cran.r-project.org/web/packages/DoseFinding/DoseFinding.pdf (access date 28 
April 2015); Comprehensive R Archive Network. 2015 [R15-2001]
3.
Little R. and Rubin D. Statistical Analysis with Missing Data. 2nd ed. New York: John 
Wiley & Sons. 2002
4.
BI-KMED-BDS-HTG-0035: “How to Guide: Handling of missing and incomplete AE 
dates”, current version, IDEA for CON
5.
001-MCS-36-472: “Standards and processes for analyses performed within Clinical 
Pharmacokinetics/Pharmacodynamics”, current version, IDEA for CON
6.
Pinheiro J, Bomkamp B, Bretz F. Design and analysis of dose-finding studies combining 
multiple comparisons and modeling procedures. J Biopharm Stat. 2006; 16 (5): 639-656
[R10-1424]
7.
Pinheiro J, Bomkamp B, Glimm E, Bretz F. Model-based dose finding under model 
uncertainty using general parametric models. Stat Med. 2014; 33 (10): 1646-1661 [R15-
4293]
8.
BI-KMED-BDS-HTG-0041: “How to Guide: Analysis and Presentation of Adverse Event 
Data from Clinical Trials”, current version, IDEA for CON
9.
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.
10. BI-KMED-BDS-HTG-0042: “How to Guide: Handling, Display and Analysis of 
Laboratory Data”, current version, IDEA for CON


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10.
HISTORY TABLE
Table 10: 1
History table
Version
Date
(DD-Mmm-YY)
Author
Sections 
changed
Brief description of change
Initial 
(Version 1)
27-Jun-2016
All
This is the initial TSAP before study 
initiation which is planned on 25-Jul-
2016.
Initial 
Revised 
(Version 2)
05-Mar-2018
6.2
This is the revised initial TSAP based 
on the protocol amendment (protocol 
version 3.0 dated 13-Dec-2017) after 
the clinical hold was lifted and before 
this trial is re-started on 11-Apr-2018.
Final 
(Version 3)
20-Nov-2019
4, 5, 6, 
7, 8, 9
This is the revised and final version
after the initial TSAP.
Revised 
(Version 4)
17-Feb-2020
4
5.2.2
6.2
6.6
6.7
Correct a typo in a sentence in CTP 
Section 7.1 for the secondary efficacy 
endpoint.
Clarified derivation of SCoRS total 
score and missing data handling rule
Revised iPD table 6.2: 1 based on 
decision at RPM and TOM
Clarified missing data handling rule for 
SCoRS total score
Clarified time window derivation based 
decision at RPM and TOM


APPROVAL / SIGNATURE PAGE 
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c25706980
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8-01-tsap
A phase II randomised, double-blinded, placebo-controlled parallel group trial to
examine the efficacy and safety of 4 oral doses of BI 425809 once daily over 12
week treatment period in patients with Schizophrenia
Author-Trial Statistician
17 Feb 2020 16:55 CET
Approval-Medical Writer
17 Feb 2020 17:31 CET
Approval-Team Member Medicine
17 Feb 2020 17:57 CET
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Approval-Clinical Trial Leader
18 Feb 2020 08:54 CET


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