Conditions: Schizophrenia
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 264
Healthy volunteers: no

Brief summary:
The objective of the study is to investigate the efficacy, safety and tolerability of BI 409306 once daily compared with placebo given for 28 weeks in patients with schizophrenia on antipsychotic treatment. The study is designed to show superiority of BI 409306 over placebo in preventing relapse of schizophrenia symptoms.

Detailed description:

Arms:
arm 1: 1 film-coated tablet of 50 milligrams (mg) of BI 409306 plus 1 tablet of 25 mg matching placebo were administered orally once daily for a treatment period of 28 weeks, followed by a withdrawal/taper period of 7 days, followed by a follow-up period of 3 weeks. arm 2: 1 film-coated tablet of 25 milligrams (mg) of BI 409306 plus 1 tablet of 50 mg matching placebo were administered orally once daily for a treatment period of 28 weeks, followed by a withdrawal/taper period of 7 days, followed by a follow-up period of 3 weeks. arm 3: 1 film-coated tablet of 25 milligrams (mg) of matching Placebo plus 1 tablet of 50 mg matching placebo were administered orally once daily for a treatment period of 28 weeks, followed by a withdrawal/taper period of 7 days, followed by a follow-up period of 3 weeks.

Interventions: intervention 1: BI 409306 intervention 2: Placebo
Intervention descriptions: intervention 1: 28 week treatment period intervention 2: 28 week treatment period

Protocol document:
Prot_000.pdf: 
001-MCS-40-106-RD-03 (14.0) / Saved on: 17 October 2016
Clinical Trial Protocol
TITLE PAGE
Document Number:
c14883409-02
EudraCT No.:
EU Trial No:
2017-002369-23
BI Trial No.:
1289-0049
BI Investigational 
Product(s):
BI 409306
Title:
A phase II randomised, double-blind, placebo-controlled study to 
evaluate the efficacy, safety, and tolerability of orally administered BI 
409306 during a 28-week treatment period as adjunctive therapy to 
antipsychotic treatment for the prevention of relapse in patients with 
schizophrenia.
Lay Title:
This study tests whether BI 409306 prevents patients with 
schizophrenia from becoming worse. This study looks at how well 
patients tolerate BI 409306 and how effective it is over 6 months.
Clinical Phase:
II
Trial Clinical 
Monitor:
Phone: 
Email: 
Coordinating 
Investigator:
Phone: 
Email:
Status:
Final Protocol (Revised Protocol based on global amendment 1)
Version and Date:
Version:
Date:
2.0
08 Nov 2017
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Proprietary confidential information.
2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.


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CLINICAL TRIAL PROTOCOL SYNOPSIS
Company name
Boehringer Ingelheim 
Finished product name
Not applicable
Active ingredient name:
BI 409306
Protocol date
21 Aug 2017
Revision date
08 Nov 2017
Trial number
1289-0049
Title of trial:
A phase II randomised, double-blind, placebo-controlled study to 
evaluate the efficacy, safety, and tolerability of orally administered 
BI 409306 during a 28-week treatment period as adjunctive therapy 
to antipsychotic treatment for the prevention of relapse in patients 
with schizophrenia.
Coordinating 
Investigator:
Phone: 
Email: 
Trial site(s):
Multicentre trial
Clinical phase:
II
Objective(s):
To investigate the efficacy, safety and tolerability of BI 409306 25mg 
and 50mg once daily compared with placebo given for 28 weeks in 
patients with schizophrenia on antipsychotic treatment. The study is 
designed to show superiority of BI 409306 over placebo in 
preventing relapse of schizophrenia symptoms.
Methodology:
Multinational, multicentre, randomised, double-blind, placebo-
controlled, parallel group study
Number of patients 
entered: 
387
Number of patients on 
each treatment:
129 patients per treatment group
Diagnosis :
Patients with diagnosis of schizophrenia per International Statistical 
Classification of Diseases and Related Health Problems, 10th
Revision (ICD-10)
Main in- and exclusion 
criteria
Male and female patients 18-55 years old with schizophrenia in the 
stable phase of illness on a stable antipsychotic medication 
regimen.  Patients can be treated with no more than two 


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antipsychotic medications. Eligible patients will have experienced 
at least 2 relapses within the past 5 years or at least 1 relapse if they 
were diagnosed less than 3 years ago.
Test product(s):
BI 409306
dose:
10 mg, 25 mg or 50 mg
During 28 week treatment period: 25 mg or 50 mg q.d.
During 7 day withdrawal/taper period during week 29 (10 mg
tablets):
Treatment Group
25 mg q.d.
50 mg q.d.
Week 29
Day 1
20 mg
40 mg
Day 2
20 mg
30 mg
Day 3
20 mg
30 mg
Day 4
10 mg
20 mg
Day 5
10 mg
20 mg
Day 6
10 mg
10 mg
Day 7
10 mg
10 mg
mode of 
administration:
p.o. (oral)
Comparator products:
Matching placebo
dose:
Not applicable
mode of 
administration:
p.o.
Duration of treatment:
28 weeks
Endpoints
Primary efficacy endpoint: 
The primary endpoint is time to first relapse until study end (planned 
at 28 weeks). Time of relapse will be obtained by selecting the 
earliest date from any, or all of the following 6 criteria:

Time to hospitalization (involuntary or voluntary admission), 
intensive outpatient therapy or use of home treatment, as an 
alternative to hospitalization, for decompensation of  
schizophrenia symptoms

Time to an assessment on the Clinical Global Impressions -
Severity (CGI-S) of ≥ 5 (markedly ill) and either:
-
an increase on any of the following individual Positive 
and Negative Syndrome Scale (PANSS) items: conceptual 
disorganization, hallucinatory behavior, suspiciousness, 
unusual thought content - to a score > 4 with an absolute 
increase of ≥2 on that specific item since randomisation 
or 


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-
an increase on any of the following individual PANSS 
items: conceptual disorganization, hallucinatory behavior, 
suspiciousness, unusual thought content -to a score > 4 
and an absolute increase of ≥4 on the combined 4 PANSS 
items  since randomisation
or
-
PANSS total score increase of ≥25% relative to baseline 
score or an increase of ≥10 points if baseline score was 
≤40

Time to a prescription for a new antipsychotic or time to an 
increase in dose of an ongoing antipsychotic medication for 
significant worsening of schizophrenia symptoms

Time to clinically significant homicidal ideation, in the 
investigator’s judgement 

Time to suicidal behavior, or time to assessment of suicidal 
ideation type 4 or 5 on the Columbia Suicide Severity Rating 
Scale (C-SSRS)

Time to deliberate self-injury and/or violent behaviour resulting 
in suicide or in clinically significant injury to the patient or 
another person or property damage, in the investigator’s 
judgement
Secondary efficacy endpoints:
Key secondary endpoint:

Change from baseline in Positive and Negative Symptom 
Score (PANSS) positive symptoms score after 28 weeks of 
treatment.

Secondary endpoints:

Time to new prescription or increase in dose of an ongoing 
antipsychotic medication.

Change from baseline in Clinical Global Impressions–
Severity (CGI-S) scale score after 28 weeks of treatment.

Patient Global Impressions-Improvement (PGI-I) scale score 
after 28 weeks of treatment.

Suicidal ideation and behaviour as assessed by C-SSRS after 
28 weeks of treatment.

Change from baseline in Personal and Social Performance 
scale (PSP) score after 28 weeks of treatment.
Safety criteria:
Physical examination, vital signs, laboratory tests, electrocardiogram 
(ECG), suicidality, extrapyramidal symptoms, and occurrence of 
serious and non-serious adverse events will be assessed.
Statistical methods:
For the primary endpoint of time to relapse, the equality of the hazard 
rates will be tested by the Wald test for the treatment effect in a 
stratified Cox proportional hazards model.   The model includes 
treatment as the only covariate and is stratified by country.  


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Secondary endpoints will be analysed descriptively using relative risk 
ratios and 95% confidence intervals.


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FLOW CHART
All Patients
Trial Periods
Screening 
Period1
Early 
D/C 
Option 1
Early D/C 
Options 2-4
End of 
Study
Visit 
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
EOT3 F/U4
EOT3
EOT3
F/U5
Study week
-4
2
4
6
8
10
12
14
16
18
20
22
24
26
28
29
32
Study day
-28
1
15
29
43
57
71
85
99
113 127 141 155 169 183 197 V16 +2 V16 +4 V16+7
V16+28
EOT 
+28 days
Visit window in days
 -28 to -7
N/A +/-3 +/-3 +/-3 +/-3 +/-3 +/-3 +/-3 +/-3 +/-3 +/-3 +/-3 +/-3 +/-3 +/-3 +/-1
+/-1
+/-1
+/-3
+/-3
Informed consent6
X
Demographics
X
Medical history
X
Physical examination
X
X
X
Vital signs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Height 
X
Weight
X
X
X
X
X
X
X
Pregnancy test (urine; females only) 7
X
X
X
X
X
X
X
X
X
X
X
12 lead-ECG8
X
X
X
X
Safety laboratory tests (urine/blood)9
X
X
X
X
X
X
X
X
X
X
Antipsychotic medication assessment in plasma10
X
X
X
X
X
Pharmacokinetic sampling (BI 409306)11
X
X
X
Urine drug screen
X
Pharmacogenomic sampling12
X
X
Optional DNA biobanking (requires separate ICF)13
X
Mini-international neuropsychiatric interview (M.I.N.I.) 
X
In-/Exclusion Criteria
X
X
Randomization 
X
Phone Visit14
X
X
X
X
X
X
X
Completed 
Patients
Early D/C Patients
Randomized Treatment Period
Withdrawal/
Taper2
Follow-up


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FLOW CHART (Cont.)
All Patients
Trial Periods
Screening 
Period1
Early 
D/C 
Option 1
Early D/C 
Options 2-4
End of 
Study
Visit 
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
EOT3 F/U4
EOT3
EOT3
F/U5
Study week
-4
2
4
6
8
10
12
14
16
18
20
22
24
26
28
29
32
Study day
-28
1
15
29
43
57
71
85
99
113 127 141 155 169 183 197 V16 +2 V16 +4 V16+7
V16+28
EOT 
+28 days
Visit window in days
 -28 to -7
N/A +/-3 +/-3 +/-3 +/-3 +/-3 +/-3 +/-3 +/-3 +/-3 +/-3 +/-3 +/-3 +/-3 +/-3 +/-1
+/-1
+/-1
+/-3
+/-3
Clinical Global Impressions -Severity (CGI-S)
X
X
X
X
X
X
X
X
X
X
Clinical Global Impressions-Improvement (CGI-I)
X
X
X
Patient Global Impressions –Improvement (PGI-I)
X
X
X
Personal and Social Performance scale (PSP) 
X
X
X
Positive and Negative Syndrome Scale (PANSS)
X
X
X
X
X
X
X
X
X
X
X
X
X
Columbia Suicide Severity Rating Scale (C-SSRS)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Interactive Response Technology (IRT) Use15
X
X
X
X
X
X
X
X
X
X
X
X
Dispense study drug
X
X
X
X
X
X
X
X16
Smartphone app training, set-up/
In-clinic drug administration
X
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant therapy
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Compliance check
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Termination of trial medication
X
X
X
Trial Completion
X
Vital Status17
X
Early D/C Patients
Randomized Treatment Period
Withdrawal/
Taper2
Follow-up
Completed 
Patients


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1.
Screening Visit procedures are not required to be completed on the same day. 
2.
Patients will be randomised to either abrupt withdrawal or slow taper of study drug for 7 days. Vital signs, 
suicidality and adverse events will be closely monitored during this period.
3.
End of Treatment (EOT) for patients who complete the treatment and withdrawal/taper periods will be completed 
at Visit 19. Patients who discontinue study drug prematurely should ideally be observed until study end as if they 
were still receiving blinded study treatment. There are 4 options for observing patients after premature drug 
discontinuation. Sections 3.3.4.1 and 6.2.2 and 6.2.2.1 provide additional information.
Early Discontinuation (D/C) Option 1: An EOT Visit must be conducted within 7 days of the last dose of study 
medication for patients who agree to conduct regularly scheduled visits after premature drug discontinuation. 
Thereafter, patients should be followed up according to the regular visit schedule. Visit 16 will be the final visit for 
patients choosing this Early D/C Option.  
Early D/C Options 2-4: An EOT Visit must be conducted within 7 days of the last dose of study medication for 
patients who agree to conduct the remaining visits over the phone, or patients who agree to be contacted or data 
collected via alternative sources approximately 28 weeks after the patient was randomised.
4.
Patients who complete the treatment and withdrawal/taper periods will be scheduled for a Follow-Up Visit 28 days 
after Visit 16.  Patients who enter the withdrawal/taper period, but discontinue taking their study drug will have a 
Follow-up Visit as planned at Week 32.
5.
Patients who prematurely discontinue study medication and choose Early D/C Option 1 do not need a Follow-Up 
Visit if they discontinued >4 weeks prior to Visit 16. If a patient choosing Early D/C Option 1 discontinues <4 
weeks prior to Visit 16, a Follow-up Visit will be performed 28 days after the EOT Visit. Patients who 
prematurely discontinue study medication and choose Early D/C Options 2-4 will have a Follow-Up Visit 
performed 28 days after the EOT visit. See Sections 3.3.4.1, 6.2.2, and 6.2.2.1. 
6.
Written informed consents for main study and optional pharmacogenomics test for deoxyribonucleic acid (DNA) 
banking must be obtained before any study-related procedures and assessments are performed. The registration of 
patients for the study is through the Interactive Response Technology (IRT). Re-consenting may become necessary 
when new relevant information becomes available and should be conducted according to the sponsor’s and 
Institutional Review Board (IRB)/ Independent Ethics Committee’s (IEC) instructions.
7.
Female patients of childbearing potential must perform urine (dipstick) pregnancy test at Visits 1 through EOT. 
8.
A 12-lead electrocardiogram (ECG) is to be performed during the scheduled visits or within 24 hours prior to the 
visit, except for Visit 1 (Screening Visit), where the ECG test will be performed only after a written informed 
consent for the main study has been obtained.
9.
Routine laboratory tests are hematology, chemistry, coagulation, and urinalysis as described in Table 5.2.3:1. 
Patients should be fasting for at least 8 hours prior to blood samples collection, except at Visit 1. 
10. Blood samples will be collected to check the presence of antipsychotic medication(s) in plasma. A sample should 
also be collected at the time a relapse is diagnosed.
11. Pharmacokinetic samples will be collected to measure BI 409306 and its two metabolites CD 13896 and CD 14084. 
See Sections 5.3 and 10.1 for details.
12. One blood sample will be taken at screening visit for genotyping of CYP2C19 from all patients taking medication 
known to be strong or moderate inhibitors of CYP1A2. One additional blood sample for genotyping of genes 
involved in absorption, distribution, metabolism and elimination will be collected preferably at Visit 2. However, 
collection of this sample at later visits is permitted. 
13. Collection of a sample for DNA biobanking is optional (See Section 5.4.1 for more details). Participating patients 
are required to give informed consent specifically for biobanking. DNA biobanking requires only one blood 
sample to be taken, preferably at Visit 2 (Randomisation). However, collection at later visits is permitted as long as 
the informed consent for biobanking remains valid. 
14. Interim phone visits are scheduled to assess the overall status of the patient, check compliance, and to collect new 
AE and concomitant medication information.  If symptom worsening is suspected, an unscheduled in-clinic visit 
should be scheduled. See Section 6.2.2. Columns are shaded in grey in the Flow Chart to indicate phone visits.
15. The study staff must utilize the Interactive Response Technology (IRT) for entering the patient into the system for 
screening, randomisation, and study medication allocation and tracking.
16. Patients who complete the 28 week treatment period will be dispensed a one-week wallet for the withdrawal/taper 
period.
17. Patients who have prematurely discontinued study drug and have not continued making regular visits (in person or 
phone) must have Vital Status collected approximately 28 weeks after the patient was randomised.


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TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS .....................................................................2
FLOW CHART........................................................................................................................6
TABLE OF CONTENTS ........................................................................................................9
ABBREVIATIONS................................................................................................................12
1.
INTRODUCTION...............................................................................................14
1.1
MEDICAL BACKGROUND.............................................................................14
1.2
DRUG PROFILE................................................................................................15
1.3
RATIONALE FOR PERFORMING THE TRIAL.........................................17
1.4
BENEFIT - RISK ASSESSMENT.....................................................................18
2.
TRIAL OBJECTIVES AND ENDPOINTS......................................................20
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS........20
2.1.1
Main objectives....................................................................................................20
2.1.2
Primary endpoint(s)............................................................................................20
2.1.3
Secondary endpoints...........................................................................................21
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.........................22
3.1
OVERALL TRIAL DESIGN AND PLAN .......................................................22
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)......................................................................................23
3.3
SELECTION OF TRIAL POPULATION .......................................................24
3.3.1
Main diagnosis for trial entry ............................................................................24
3.3.2
Inclusion criteria .................................................................................................25
3.3.3
Exclusion criteria ................................................................................................26
3.3.4
Withdrawal of patients from therapy or assessments .....................................27
3.3.4.1
Withdrawal from trial treatment ...........................................................................27
3.3.4.2
Withdrawal of consent for trial participation........................................................29
3.3.4.3
Discontinuation of the trial by the sponsor...........................................................29
4.
TREATMENTS...................................................................................................30
4.1
INVESTIGATIONAL TREATMENTS ...........................................................30
4.1.1
Identity of the Investigational Medicinal Products..........................................30
4.1.2
Selection of doses in the trial..............................................................................31
4.1.3
Method of assigning patients to treatment groups...........................................31
4.1.4
Drug assignment and administration of doses for each patient......................31
4.1.5
Blinding and procedures for unblinding...........................................................33
4.1.5.1
Blinding.................................................................................................................33
4.1.5.2
Unblinding and breaking the code ........................................................................33


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4.1.6
Packaging, labelling, and re-supply...................................................................33
4.1.7
Storage conditions...............................................................................................34
4.1.8
Drug accountability.............................................................................................34
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS ................................................................................................35
4.2.1
Other treatments and emergency procedures..................................................35
4.2.2
Restrictions ..........................................................................................................35
4.2.2.1
Restrictions regarding concomitant treatment ......................................................35
4.2.2.2
Restrictions on diet and life style..........................................................................36
4.2.2.3
Restrictions regarding women of childbearing potential......................................36
4.3
TREATMENT COMPLIANCE........................................................................36
5.
ASSESSMENTS..................................................................................................38
5.1
ASSESSMENT OF EFFICACY........................................................................38
5.2
ASSESSMENT OF SAFETY.............................................................................38
5.2.1
Physical examination ..........................................................................................38
5.2.2
Vital signs.............................................................................................................39
5.2.3
Safety laboratory parameters ............................................................................39
5.2.4
Electrocardiogram ..............................................................................................41
5.2.5
Other safety parameters.....................................................................................41
5.2.5.1
Assessment of Suicidality.....................................................................................41
5.2.6
Assessment of adverse events.............................................................................42
5.2.6.1
Definitions of AEs ................................................................................................42
5.2.6.2
Adverse event collection and reporting ................................................................45
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS...................................................................................47
5.3.1
Assessment of Pharmacokinetics.......................................................................47
5.3.2
Methods of sample collection .............................................................................48
5.3.2.1
Plasma sampling for analysis of BI 409306 and metabolites ...............................48
5.3.4
Pharmacokinetic – pharmacodynamic relationship........................................48
5.4
ASSESSMENT OF BIOMARKER(S) ..............................................................49
5.4.1
Biobanking...........................................................................................................49
5.4.1.1
Methods and Timing of Pharmacogenomic Sample Collection ...........................49
5.4.2
Pre-specified Pharmacogenomic Analysis ........................................................49
5.6
APPROPRIATENESS OF MEASUREMENTS..............................................50
6.
INVESTIGATIONAL PLAN.............................................................................52
6.1
VISIT SCHEDULE.............................................................................................52
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS .................52
6.2.1
Screening Period .................................................................................................52
6.2.2
Treatment period(s)............................................................................................53
6.2.2.1
Withdrawal/Taper Period......................................................................................54
6.2.3
Follow up period and trial completion..............................................................55


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7.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE
...............................................................................................................................56
7.1
STATISTICAL DESIGN - MODEL.................................................................56
7.2
NULL AND ALTERNATIVE HYPOTHESES ...............................................56
7.3
PLANNED ANALYSES.....................................................................................57
7.3.1
Primary endpoint analyses.................................................................................58
7.3.2
Secondary endpoint analyses .............................................................................59
7.3.4
Safety analyses.....................................................................................................60
7.3.5
Pharmacokinetic and pharmacodynamic analyses..........................................62
7.4
INTERIM ANALYSES ......................................................................................62
7.5
HANDLING OF MISSING DATA ...................................................................62
7.6
RANDOMISATION ...........................................................................................62
7.7
DETERMINATION OF SAMPLE SIZE .........................................................62
8.
INFORMED CONSENT, TRIAL RECORDS, DATA PROTECTION, 
PUBLICATION POLICY, AND ADMINISTRATIVE STRUCTURE ........64
8.1
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED 
CONSENT ...........................................................................................................64
8.2
DATA QUALITY ASSURANCE ......................................................................65
8.3
RECORDS...........................................................................................................65
8.3.1
Source documents ...............................................................................................65
8.3.2
Direct access to source data and documents.....................................................66
8.3.3
Storage period of records ...................................................................................67
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS ..................................67
8.5
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY........67
8.5.1
Collection, storage and future use of biological samples and corresponding 
data.......................................................................................................................67
8.6
TRIAL MILESTONES.......................................................................................68
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL ...................................68
9.
REFERENCES....................................................................................................70
9.1
PUBLISHED REFERENCES............................................................................70
9.2
UNPUBLISHED REFERENCES......................................................................72
10.
APPENDICES.....................................................................................................74
10.1
PHARMACOKINETIC ANALYSES...............................................................74
10.1.1
Handling of missing data....................................................................................74
10.2
HANDLING PROCEDURE OF BLOOD SAMPLES FOR PLASMA 
CONCENTRATION-TIME MEASUREMENTS ...........................................74
10.3
TIME SCHEDULE FOR PHARMACOKINETIC (PK) BLOOD 
SAMPLING.........................................................................................................75
11.
DESCRIPTION OF GLOBAL AMENDMENT(S) .........................................76


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ABBREVIATIONS
AD
Alzheimer’s disease
AE
Adverse Event
AESI
Adverse Event of Special Interest
ALT
Alanine aminotransferase (SGPT)
APS
Attenuated Psychosis Syndrome
AST
Asparatate aminotransferase (SGOT)
BI
Boehringer Ingelheim
BLQ
Below the limit of quantification
bpm
Beats per minute
CA
Competent Authority
CGI-I
Clinical Global Impressions-Improvement
CGI-S
Clinical Global Impressions-Severity
cGMP
Cyclic guanosine monophosphate
CIAS
Cognitive impairment associated with schizophrenia
Cmax
Maximum concentration
CML
Clinical Monitor Local
Cpress
Residual concentration in plasma
CRA
Clinical Research Associate
CRF
Case Report Form, paper or electrocic (sometimes referred to as “eCRF”)
CRO
Contract Research Organization
CSF
Cerebrospinal Fluid
C-SSRS
Columbia Suicide Severity Rating Scale
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
CYP
Cytochrome P450
D/C
Discontinuation
DDI
Drug-drug interaction
DILI
Drug Induced Liver Injury
DNA
Deoxyribonucleic acid
DSM-5
Diagnostic and Statistical Manual of Mental Disorders, 5th Edition
ECG
Electrocardiogram
EDC
Electronic Data Capture
EM
Extensive metabolizers
EOT
End of treatment
EudraCT
European Clinical Trials Database
FAS
Full Analysis Set
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GLP
Good Laboratory Practice
GMP
Good Manufacturing Practice
HIPAA
Health Insurance Portability and Accountability Act
HR
Hazard Ratio


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IB
Investigator’s Brochure
IC 50
Half maximal inhibitory concentration
ICD-10
International Statistical Classification of Diseases and Related Health 
Problems, 10th Revision
ICF
Informed Consent Form
IEC
Independent Ethics Committee
IRB
Institutional Review Board
IRT
Interactive Response Technology
ISF
Investigator Site File
ITT
Intent to Treat
IUD
Intrauterine device
IUS
Intrauterine hormone releasing systems
LTP
Long term potentiation
MCCB
MATRICS Consensus Cognitive Battery
MedDRA
Medical Dictionary for Regulatory Activities
M.I.N.I.
Mini-international neuropsychiatric interview
NMDA
N-methyl-D-aspartate
NOA
Not analysed
NOP
No peak detectable
NOR
No valid result
NOS
No sample available
OPU
Operative Unit
PANSS
Positive and Negative Syndrome Scale 
PCP
Phencyclidine
PD
Pharmacodynamics
PDE9
Phosphodiesterase-9
PGI-I
Patient Global Impressions –Improvement
PI
Principal Investigator
PK
Pharmacokinetics
PM
Poor metabolizers
p.o.
per os (oral)
PSP
Personal and Social Performance scale 
PTM
Planned time
q.d.
quaque die (once a day)
REP
Residual Effect Period
RRR
Relative Risk Reduction
SAE
Serious Adverse Event
SOP
Standard Operating Procedure
SUSAR
Suspected Unexpected Serious Adverse Reactions
TCM
Trial Clinical Monitor
TS
Treated set
ULN
Upper limit of normal
URS
User requirement specifications
WHO
World Health Organization
WOCBP
Woman of childbearing potential


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1.
INTRODUCTION
BI 409306 is a Phosphodiesterase-9 (PDE9) inhibitor under development for the treatment of 
Alzheimer's disease (AD), reduction of relapse in patients with schizophrenia, and prevention 
of first episode of psychosis in patients with attenuated psychosis syndrome (APS) 
[c01694347-09].
1.1
MEDICAL BACKGROUND
Schizophrenia is a chronic and disabling illness affecting approximately 1% of the 
population, with the majority of patients experiencing multiple relapses during the course of 
the illness. Relapse can be assessed in many ways, however regardless of characterization it 
is clear that acute psychotic exacerbation in these individuals has serious negative 
consequences, including a risk of patients harming themselves or others, of jeopardizing 
personal relationships, education or employment status, and of further stigmatization of the 
illness.   As well, relapse has been posited to incur biological risk in that active psychosis 
may reflect actual disease progression such that patients may not recover their previous level 
of function and treatment refractoriness may emerge [R15-1782].
Multiple factors likely contribute to incurring risk of relapse. Most prominently, in a meta-
analysis of longitudinal studies it was found that non-adherence with medication significantly 
increased the risk for relapse after first-episode psychosis. In a prospective, 5 year follow-up 
of first-episode psychosis patients it was found that the most common risk factor was 
antipsychotic medication discontinuation. Besides this explanation, substance abuse or other 
reasons for relapse (called natural or primary) clearly exist which include stress, diminished 
resilience, hormonal or immunological problems. Irrespective of etiology, psychosis relapse 
is postulated to be accompanied with or due to, a hyperdopaminergic state [R17-0970].
In clinical settings withdrawal from treatment is common, especially in the early stages of 
illness. In the CATIE study, a well-designed “real-world” trial, it was found that 74 percent 
of patients discontinued the study medication before 18 months leading the authors to note 
“Only a minority of patients in each group took their assigned drug for the duration of phase 
1 (rates of discontinuation ranged from 64 to 82 percent). This outcome indicates that 
antipsychotic drugs, though effective, have substantial limitations in their effectiveness in 
patients with chronic schizophrenia” [R12-3534].
Therefore, despite the clearly demonstrated benefits of antipsychotic therapy in relapse pre-
vention, ongoing maintenance treatment carries its own burden, including substantial risk of 
relapse, significant side-effects and even the possibility of brain morphological changes.
In recognition of the associated risks with disease exacerbation, improving medication adher-
ence and relapse prevention have been emphasized as key components of the management of 
schizophrenia. 
Given the difficulties in identifying those at risk of relapse, the ineffectiveness of rescue 
medications in preventing full-blown psychotic recurrence and the potentially serious conse-


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quences, every effort needs to be made to provide effective options beyond adherence-sup-
porting strategies alone. 
1.2
DRUG PROFILE
BI 409306 is a new chemical entity (NCE) intended for oral administration. Film coated 
immediate release tablets of 10mg, 25 mg and 50mg will be applied in this trial.
Non-clinical Summary
In vitro and in vivo non-clinical pharmacological studies were performed to determine 
potency, selectivity and efficacy of BI 409306 in cellular and animal models. In brief, BI 
409306 is a potent and selective PDE9 inhibitor. It enhances long term potentiation (LTP) in 
rat hippocampal slices indicating improvement of cellular processes crucial for memory 
formation, and it increases cyclic guanosine monophosphate (cGMP) levels in rat brain 
indicating target engagement in vivo. In vivo proof-of-concept regarding memory 
enhancement/improvement could be achieved in two rodent cognition models addressing 
working memory and recognition memory domains (for details please refer to Section 5.1 of 
the Investigator’s Brochure (IB) [c01694347-09])
Standard non-clinical in vitro and in vivo studies on drug metabolism and pharmacokinetics 
(PK) were performed including studies for the identification of drug metabolizing enzymes, 
cytochrome inhibition and induction, involvement of transporters, permeability studies, 
pharmacokinetics and metabolism studies in animals and whole body autoradiography in rats 
(Section 5.2 of the Investigator’s Brochure (IB) [c01694347-09].
BI 409306 was tested in a comprehensive panel of in vitro and in vivo General Pharmacology 
tests (non- Good Laboratory Practice (GLP)) and in the core battery of Safety Pharmacology 
tests (GLP). The major findings were cardiovascular effects which were similar to those 
described for other PDE inhibitors and considered to be secondary to a cGMP related 
vasodilatation. Repeat-dose oral toxicity studies were conducted with daily oral (gavage) 
administration of BI 409306 to mice, rats, and dogs for up to 13 weeks. Target organs 
identified in these studies were the cardiovascular system (rats and dogs), liver (rats), adrenal 
glands (rats), ovaries (rats), and spleen (rats). Adverse effects in rats were mainly limited to 
the highest dose tested. Only an adaptive finding in the adrenal glands of rats interpreted as 
being secondary to the cardiovascular effects occurred at lower dose levels. Cardiovascular 
effects in dogs occurred also at lower doses but can be monitored in clinical trials. Chronic 
toxicity studies in rats and dogs are ongoing. The genotoxicity profile of BI 409306 was 
tested in the standard battery of genotoxicity tests and a comet-assay in rats. The overall 
assessment revealed that BI 409306 is not genotoxic. BI 409306 was not teratogenic in rats 
and rabbits and, based on preliminary results, did not alter the fertility and early embryonic 
development in rats [c01694347-09].
Clinical Summary
In all 12 healthy volunteer trials, the most frequent drug related adverse events were visual 
side effects that occurred shortly after dosing, mostly resolved within 1 h, i.e., in close 


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connection to maximum BI 409306 plasma concentrations, as the concentration-time profile 
sharply and steeply peaks within the first 1-2 hours and then rapidly declines afterwards. 
Overall, there were no relevant changes observed for laboratory, electrocardiogram (ECG) 
recordings, and vital signs following treatment with BI 409306 when compared to placebo. 
Only a rapid and short lasting increase in supine pulse rate of 12.5 ± 2.7 beats per minute 
(bpm) was reported in Chinese CYP2C19 poor metabolizers subjects treated with BI 409306 
(100 mg single dose) in study 1289.4. Following this observation, pharmacometric analysis 
of all available human data revealed a BI 409306 plasma concentration dependent increase in 
supine pulse rate in typical subjects reaching a maximum of 7-13 bpm (median) at the high 
exposure end in CYP2C19 poor metabolizers treated with BI 409306 at 100 mg. The 
maximum effects of BI 409306 on pulse rate were generally achieved at maximum BI 
409306 plasma concentrations (20-30 minutes post dose) and disappeared rapidly with 
declining concentrations [c01694347-09]. The effects of BI 409306 on pulse rate were further 
examined in healthy male volunteers under resting and exercise conditions following single 
oral doses of 50 and 200 mg [c03808525-01]. In line with previous results, heart rate profiles 
closely correlated with drug systemic exposure profiles and the heart rate increase was 11.51 
bpm at the maximum individual plasma concentration measured during exercise.
Altogether, good to satisfactory safety and tolerability were observed in single doses of BI 
409306 (up to 350mg in CYP2C19 extensive metabolizers (EM); up to 100mg in CYP2C19 
poor metabolizers (PM)) in healthy young volunteers and multiple doses (14 days up to 
100mg EM/50mg PM) of BI 409306 in healthy young and elderly subjects. In addition data 
from completed studies demonstrate that the increase in heart rate was transient, closely 
related to the time of maximum drug concentrations, and of low amplitude [c01694347-09]. 
Study 1289.18 was conducted to assess safety, tolerability, PK and pharmacodynamics (PD) 
of BI 409306 25 mg, 50 mg, or 100 mg once a day (q.d.) for 14 days in patients with mild-to-
moderate schizophrenia. Satisfactory safety and tolerability were observed while PK mirrored 
that of healthy volunteers. Recently completed study 1289.6 (proof of concept study in 
patients with cognitive impairment associated with schizophrenia (CIAS)) failed to achieve 
the primary endpoint of improving cognition as assessed by the MATRICS Consensus 
Cognitive Battery (MCCB), however demonstrated acceptable safety and tolerability at all 
doses. The percentage of subjects with any AE increased with increasing BI 409306 dose, 
ranging from 33.3% in the 10 mg group to 53.5% in the 100 mg group. The incidence of AEs 
in the 10 mg and 25 mg dose groups was similar to that of the placebo group. Most AEs were 
mild or moderate in intensity, with only 2 subjects in the BI 409306 groups and 4 subjects in 
the placebo group experiencing severe adverse events (AEs). Most striking was the finding 
that Serious AEs (SAEs), including 8/8 psychiatric SAEs, were only reported in the placebo 
group vs. none in the active arms.  Further, it was noted that results of the C-SSRS showed 
suicidal ideation was reported in no subjects in the 10 mg group, 1 subject (1.2%) in the 25 
mg group, 2 subjects (2.5%) in the 50 mg, 1 subject (1.2%) in the 100 mg group, and 6 
subjects (3.6%) in the placebo group.  It was further noted that the severity of the suicidal 
ideation present was more severe within the placebo subjects, with 3 placebo subjects
reporting “Active suicidal ideation with any methods (not plan) without intent to act” and one 
subject reporting “Active suicidal ideation with some intent to act, without specific plan” vs. 
zero such findings in the active dose groups [c01694347-09; c09340078-01].


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None of the safety data presented a safety issue for further clinical trials.
For a more detailed description of the BI 409306 profile, including pharmacokinetics and 
pharmacodynamics, please refer to the current Investigator’s Brochure (IB) [c01694347-09].
1.3
RATIONALE FOR PERFORMING THE TRIAL
The etiology of schizophrenia is believed to originate from abnormalities in brain 
development which are linked to an insult to the brain in fetal development.  In addition, 
susceptibility genes for schizophrenia linked to synaptogenesis and neuronal connectivity 
may contribute to such abnormal brain development. These disturbances manifest into 
abnormalities of dopaminergic and glutamatergic circuits after completion of brain 
development, i.e at beginning of adulthood. Thus, these abnormalities are considered to be 
the pathophysiological basis of positive, negative and cognitive symptoms in patients with 
schizophrenia [P17-01959, R17-0563]. More specifically, negative and cognitive symptoms 
(e.g. social withdrawal, flat affect or memory impairment) are believed to be a consequence 
of hypoactivation of the meso-cortical dopamine pathway and/or excitatory-inhibitory 
imbalance of indirect cortico-cortical glutamate circuits. Positive symptoms, i.e. psychosis, 
seem to be caused by hyperactivation of the meso-limbic dopamine pathway due to 
hyperactivation of the cortico-brainstem glutamate pathway and/or by increased cortical 
activation induced by reduced thalamic inhibition (filtering) due to meso-limbic dopamine 
hyperactivation (i.e. dysfunction of cortico-striatal-thalamic-cortical loop) [P17-01959, R17-
0563]. In the course of the illness most patients with schizophrenia experience multiple 
relapses which are characterized by acute psychotic exacerbation associated with striatal 
dopamine hyperfunction [R17-0972, R17-0973]. Hence, psychosis represents a state of 
aberrant salience due to a dysregulated hyperdopaminergic state, and accordingly, current 
antipsychotics do not eradicate psychotic symptoms but dampen them [R17-0970, R17-
0969]. There are manifold explanations for relapse in patients under antipsychotic 
medication. One would be interventional or secondary relapse due to antipsychotic non-
adherence and/or substance abuse, another one would be natural or primary relapse due to 
stress, diminished resilience, hormonal or immunological problems [R17-0971]. By both 
ways, psychosis relapse would be accompanied with or due to a hyperdopaminergic state as 
shown e.g. in a study applying a psychosocial stress task to patients with schizophrenia [R16-
1601]. 
Due to the functional interaction of the dopaminergic with the glutamatergic system in the 
pathophysiology of schizophrenia, it is plausible that an approach which aims at ameliorating 
the dysfunctional glutamatergic system in schizophrenia such as PDE9 inhibition 
[c01694347-09], might also represent a viable approach for prevention of relapse or reduction 
of symptoms associated with exacerbation in patients with schizophrenia. Clinical support for 
this is found in the results of the completed 1289.6 phase 2 proof of concept trial with BI 
409306 assessing treatment of cognitive impairment associated with schizophrenia in which a 
striking imbalance (100% vs.0%) of SAEs of psychiatric worsening in the placebo arm vs. 
none in any active arm occurred [c09340078-01]. Further support for this idea arises from 
published preclinical animal studies evaluating the effect of PDE9 inhibition in rodent models 
related to the meso-limbic dopamine pathway and cortico-striatal-thalamic-cortical loop. In 


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these animal experiments, it has been shown that the PDE9 inhibitor PF-4447943 potentiated 
the effect of the antipsychotic drug risperidone on prepulse inhibition and improved auditory 
gating deficits induced by a hyperdopaminergic state, but it did not show relevant 
antipsychotic-like effects in the amphetamine-induced hyperlocomotion test [R16-2785]. 
This clearly indicates that PDE9 inhibition is able to ameliorate a hyperdopaminergic state 
based on functional interaction within the cortico-striatal-thalamic-cortical loop/circuit 
(prepulse inhibition and auditory gating tests), but not meso-limbic dopamine pathway 
(hyperlocomotion test). As described above, dysfunction of both pathways/circuits - alone or 
together - are crucially involved in the pathophysiology of positive symptoms of 
schizophrenia (i.e. psychosis). Therefore, PDE9 inhibition as add-on to antipsychotic 
treatment would represent a novel therapeutic approach for reduction of disease relapse.  
Taken together, these preclinical and clinical findings suggest that inhibition of PDE9 by BI 
409306 represents a rational approach for reduction of disease relapse via ameliorating the 
hyperdopaminergic state of the cortico-striatal-thalamic-cortical circuit considered to play a 
crucial role in psychosis.
The therapeutic benefit or specific adverse events in patients cannot always be anticipated 
during the trial setup. Later on there may be new scientific knowledge about biomarkers and 
other factors contributing to diseases or the action of a drug. In order to be able to address 
future scientific questions, patients will be asked to voluntarily donate biospecimens for 
banking. If the patient agrees, banked samples may be used for future drug development 
projects, e.g. to identify patients that are more likely to benefit from a treatment or experience 
an adverse event, and thereby better match patients with therapies.
1.4
BENEFIT - RISK ASSESSMENT
Overall, BI 409306 shows a favorable nonclinical safety profile. There was no genotoxic 
potential of BI 409306. The toxicological profile of BI 409306 is characterized by cardiac 
effects which seem to be consistent with those described for phosphodiesterase inhibitors in 
general. Previous clinical trials found that BI 409306 was well tolerated in young and elderly 
healthy subjects in single doses of 0.5 to 350 mg and multiple doses up to 100 mg once daily.  
Data from the recently completed 1289.6 trial in 518 subjects with schizophrenia 
demonstrated AEs for 10mg and 25mg to be in the range of placebo.  The most frequent drug 
related adverse events reported in all trials were visual side effects that occurred shortly after 
dosing and mostly resolved within 1 hour [c09340078-01].  A dedicated ocular safety study 
demonstrated no relevant changes to ocular parameters [c09168615-01] and a dedicated 
cardiovascular safety study found exercise testing did not suggest a clinically relevant impact 
on heart rate or cardiac function [c03808525-01]. All adverse effects generally were 
restricted to doses 100 mg or higher and were reversible [U12-1034-01; U13-1182-01; U12-
2165-01; U13-1303-01]. Cardiac function will be monitored during the study according to the 
Flow Chart.
No effect on dopaminergic systems in pharmacological models has been noted and no 
adverse effects on glucose homeostasis have been seen (as seen with neuroleptics used off-
label in this population).  Drug-drug interaction (DDI) identified to date suggests potential 
liability for CYP2C19 poor metabolizers if medication inhibiting CYP1A2 is co-administered 


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with BI 409306, and for CYP2C19 non-poor metabolizers if the patient is concomitantly 
taking medications that inhibit both CYP1A2 and CYP2C19. However, this can be monitored 
and managed in this population [c01694347-09].
Although neither teratogenic, nor effect on fertility and early embryonic development has 
been seen in toxicology studies, no studies have been done with BI 409306 in pregnant 
women or women who are nursing their infants. It is unknown if BI 409306 is safe for 
pregnant women, unborn babies and infants who are nursing. It is unknown either if BI 
409306 has an effect on sperm or eggs [c01694347-09].
Hence, female patients who are nursing or pregnant are not allowed to join the study. Patients 
who are of child-bearing potential must accept to use a highly effective form of birth control 
throughout the trial and follow-up period.
A potential effect of BI 409306, a centrally acting compound, on suicidality cannot be ruled 
out. Therefore, suicidality monitoring will be performed pre-dose and throughout the study to 
ensure that potential suicidality will be recognized in order to apply appropriate action.
This is an experimental drug and therefore an individual benefit cannot be guaranteed. Given 
the acceptable safety profile in nonclinical and toxicology studies, the good tolerability in the 
clinical trials completed to date, and the careful monitoring planned during the study visits, 
the sponsor feels the risk to the participating patients is minimized and balanced by a 
potential benefit due to the intensive medical care received. Patients randomised to the 
placebo arm will continue to receive standard of care treatment. Even if there is no direct 
benefit for the patients during participation in this trial, it can be assumed that the trial results 
may contribute to better drug development in the future for this unmet medical need.
Although rare, a potential for drug-induced liver injury (DILI) is under constant surveillance 
by sponsors and regulators. Therefore, this trial requires timely detection, evaluation, and 
follow-up of laboratory alterations in selected liver laboratory parameters to ensure patients´ 
safety, see also Section 5.2.6, adverse events of special interest.


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2.
TRIAL OBJECTIVES AND ENDPOINTS
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS
2.1.1
Main objectives
The objective of the study is to investigate the efficacy, safety and tolerability of BI 409306  
25mg and 50mg once daily compared with placebo given for 28 weeks in patients with 
schizophrenia on antipsychotic treatment. The study is designed to show superiority of BI 
409306 over placebo in preventing relapse of schizophrenia symptoms.
2.1.2
Primary endpoint(s)
The primary endpoint is time to first relapse until study end (planned at 28 weeks). Time of 
relapse will be obtained by selecting the earliest date from any, or all of the following 6
criteria:

Time to hospitalization (involuntary or voluntary admission), intensive outpatient therapy
or use of home treatment, as an alternative to hospitalization, for decompensation of  
schizophrenia symptoms

Time to an assessment on the Clinical Global Impressions - Severity (CGI-S) of ≥ 5 
(markedly ill) and either:
-
an increase on any of the following individual PANSS items: conceptual 
disorganization, hallucinatory behavior, suspiciousness, unusual thought content -
to a score > 4 with an absolute increase of ≥2 on that specific item since 
randomisation 
or 
-
an increase on any of the following individual PANSS items: conceptual 
disorganization, hallucinatory behavior, suspiciousness, unusual thought content -
to a score > 4 and an absolute increase of ≥4 on the combined 4 PANSS items  
since randomisation
or
-
PANSS total score increase of ≥25% relative to baseline score or an increase of 
≥10 points if baseline score was ≤40

Time to a prescription for a new antipsychotic or time to an increase in dose of an 
ongoing antipsychotic medication for significant worsening of schizophrenia symptoms

Time to clinically significant homicidal ideation, in the investigator’s judgement 

Time to suicidal behavior, or time to assessment of suicidal ideation type 4 or 5 on the 
Columbia Suicide Severity Rating Scale (C-SSRS)


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
Time to deliberate self-injury and/or violent behaviour resulting in suicide or in clinically 
significant injury to the patient or another person or property damage, in the investigator’s 
judgement
2.1.3
Secondary endpoints
Key secondary endpoint:

Change from baseline in Positive and Negative Symptom Score (PANSS) positive 
symptoms score after 28 weeks of treatment.
Secondary endpoints:

Time to new prescription or increase in dose of an ongoing antipsychotic medication.

Change from baseline in Clinical Global Impressions–Severity (CGI-S) scale score 
after 28 weeks of treatment.

Patient Global Impressions-Improvement (PGI-I) scale score after 28 weeks of 
treatment.

Suicidal ideation and behaviour as assessed by C-SSRS after 28 weeks of treatment.

Change from baseline in Personal and Social Performance scale (PSP) score after 28 
weeks of treatment.


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN AND PLAN
This is a multicentre, multinational, randomised, double-blind, placebo-controlled parallel 
group trial. In total, 387 patients with schizophrenia are planned for randomisation in this 
study.  
Patients are included in the study once informed consent has been signed. Patients suitable 
after screening will be randomised to the 28 week treatment period assigned at a ratio of 1:1:1
to one of three treatment arms as shown in Figure 3.1: 1. After completion of the treatment 
period, patients will enter the 7 day withdrawal/taper period and then be scheduled for a 
follow-up visit. Randomisation into the withdrawal/taper period will be done up front, with 
patients from each treatment arm being randomised to withdrawal or taper in a 1:1 ratio.  The 
randomisation will be stratified by country.
Figure 3.1: 1
Overview of trial design
The primary treatment comparison will be BI 409306 25 mg q.d. and 50 mg q.d. combined 
vs. placebo.  Please refer to Sections 7.2 and 7.3.1 for the detailed analysis strategy.
Screening
Randomisation
BI 409306 25 mg q.d.
Taper
BI 409306 50 mg q.d
Withdrawal
Placebo 
F/U Visit 
Treatment 
Period
(28 weeks)
Withdrawal/
Taper
(7 days)
F/U 
Period
(21 days)
Screening 
Period
(28 days)
Taper
Withdrawal
Withdrawal
Taper


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3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)
A randomised, double-blind, parallel group design was chosen for this study to observe the 
effects of BI 409306 compared to placebo in preventing relapse of schizophrenia symptoms.  
The primary efficacy analysis is planned to be conducted after 28 weeks of treatment. A 
review of the literature illustrates wide variability in relapse rates in schizophrenia over 12 
months (e.g. 20.9% to 60.8%) [See Figure 3.2: 1].  Possible reasons for variability in relapse 
rate include variations in definition of relapse utilized, differences in study population (e.g. 
outpatients vs. inpatients), differences in study methodology (e.g. different modes of data 
collection), and different study periods and treatment settings.
Figure 3.2: 1 Relapse Rates Reported in the Literature 
PRC = Peoples Republic of China
[R17-2079; R17-2083; R17-2075; R17-2735; R17-2082; R17-2081; R17-2077; R17-2080; R17-2078]
The 28 week treatment period selected for this trial in combination with inclusion/exclusion
criteria is expected to result in a population likely to experience relapse somewhere in the 
middle of this range, and is felt to be a reasonable study duration for a phase II study.  
Specifics regarding the power calculation and range of effect sizes covered are provided in 
Section 7.7.
Patients will be randomised to either abrupt withdrawal or slow taper of study drug for 7 days
after the 28 week treatment period to monitor for signs and symptoms of withdrawal. Vital 
signs, suicidality and adverse events will be closely monitored during this period. The 


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proposed post-treatment follow-up period is considered to be sufficient for the 
pharmacodynamic effect of BI 409306 to discontinue and allow for assessment of 
reversibility of any unexpected adverse effects. 
There is currently no approved medication specifically indicated for the prevention of relapse 
of schizophrenia symptoms as adjunctive treatment to antipsychotics. Since there is not an 
approved comparator available for this study, a placebo control group is being used in this 
study design. It should be noted that all patients, including those in the placebo group, are 
permitted to remain on other non-excluded psychotropic medications.  The risk to the control 
group is discussed in Section 1.4.
3.3
SELECTION OF TRIAL POPULATION
It is planned that approximately 50 trial centres in 4 countries will be participating in this trial 
to randomise 387 patients.  
It is expected that approximately 8 patients will be randomised at each trial centre. If 
enrolment is delayed, additional centres may be recruited. 
To avoid differential centre influence on study results, permission to randomise more than 20 
patients per site must be obtained from the Trial Clinical Monitor (TCM).
Screening of patients for this trial is competitive, i.e., screening for the trial will stop at all 
centres when it is determined that an ample number of patients have been screened to ensure 
that a sufficient number of patients will be randomised to trial treatment. Investigators will be 
notified when the appropriate number of patients has been screened and enrollment 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.
Patients who fail screening may repeat the screening phase once after discussion between the 
investigator and sponsor, provided that the reason for screen failure was reversible and has 
resolved. Permission to rescreen patients must be obtained from the TCM or Clinical Monitor 
Local (CML), and documentation of approval filed in the Investigator Site File (ISF). 
Rescreened patients must be re-consented and be given a new patient number. All Visit 1 
procedures must be repeated.
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.
3.3.1
Main diagnosis for trial entry
Patients with an International Statistical Classification of Diseases and Related Health 
Problems, 10th Revision (ICD-10) diagnosis of schizophrenia will be the basis for trial entry. 


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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. ICD-10 diagnosis of schizophrenia > one year prior to randomisation. 
2. Outpatients in the stable phase of illness, as assessed by the investigator after review of 
medical records or documented discussion with treating clinician. 
3. Patients currently taking a stable dose of antipsychotic medication(s) for at least 12
weeks prior to randomisation.
4. Detectable level of current antipsychotic medication(s) in plasma from blood drawn at 
Visit 1 (unless no assay is available for the antipsychotic(s) currently prescribed).
5. Patients who have experienced at least 2 relapses within the past 5 years or at least 1 
relapse if they were diagnosed less than 3 years ago. Relapse is defined as the patient 
having any of the following using the above number of relapses and time frames:

Hospitalization for psychosis (involuntary or voluntary admission), intensive 
outpatient therapy or use of home treatment as an alternative to hospitalization
(verified via medical record).

Emergency Department visit for worsening schizophrenia symptoms (verified via 
medical record).

Deliberate self-injury and/or violent behaviour resulting in significant injury to 
another person or property (verified by police record or treating mental health 
provider written record or documented phone conversation).

Change in the patient’s antipsychotic medication or increase in antipsychotic 
medication dosage due to worsening of schizophrenia symptoms (verified by 
pharmacy records or treating mental health provider written record or documented 
phone conversation).
6. CGI-S score ≤4 at Visits 1 and 2.
7. PANSS total score <80 and a score of ≤ 4 on individual PANSS items conceptual 
disorganization, hallucinatory behavior, suspiciousness, and unusual thought content at 
Visit 1.
8. Of full age (according to local legislation, usually ≥ 18 years) and ≤ 55 years at the time 
of informed consent. 
9. Patients must have an identified informant who will be consistent throughout the study.
10. Patients who report living at the same address for the 3 months prior to randomisation.
11. Male or female patients. 


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-
Female patients of childbearing potential1 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. Patients must agree to use 
birth control throughout the trial and for at least 28 days after treatment has ended. 
Acceptable methods of birth control include combined estrogen-progestin oral, 
intravaginal or transdermal contraceptives, progestogen-only oral, injectable or 
implantable contraceptives, intrauterine devices (IUDs), intrauterine hormone 
releasing systems (IUSs), bilateral tubal occlusion, vasectomized sexual partner, and 
complete sexual abstinence (if acceptable by local health authorities) is allowed when 
this is in line with the preferred and usual lifestyle of the patient. Periodic abstinence 
(e.g., calendar, ovulation, symptom-thermal, post-ovulation methods) and withdrawal 
are not acceptable methods of contraception. 
-
Male patients who are able to father a child must be ready and able to be abstinent or 
use adequate contraception for the duration of study participation and for at least 28 
days after treatment has ended.
12. Signed and dated written informed consent in accordance with ICH-GCP and local 
legislation prior to admission to the trial. If the patient has a legal representative, then 
this legal representative must give written informed consent as well.
_______________________________________________________________
1 A woman is considered of childbearing potential (WOCBP), i.e. fertile, following menarche and until becoming postmenopausal unless 
permanently sterile.
Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy.
Tubal ligation is NOT a method of permanent sterilisation.
A postmenopausal state is defined as no menses for 12 months without an alternative medical cause.
3.3.3
Exclusion criteria
1. Patients treated with more than two antipsychotic medications (including more than two 
dosage forms).
2. Patients who are currently being treated with clozapine, or who have been treated with 
clozapine in the past 5 years.
3. Patients with a categorical diagnosis of another current major psychiatric disorder per the 
Mini-international neuropsychiatric Interview (M.I.N.I.).
4. Homicidal behaviour (in the investigator’s judgement) in the past 2 years.
5. Any suicidal behavior in the past 2 years (i.e. actual attempt, interrupted attempt, aborted 
attempt, or preparatory acts or behavior).
6. Any suicidal ideation of type 4 or 5 in the Columbia Suicide 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).
7. In the judgment of the investigator, any clinically significant finding from the physical 
examination or laboratory value deviating from normal or any evidence of a clinically 
significant concomitant disease or any other clinical condition that would jeopardize a 
patient’s safety while participating in the clinical trial.
8. Other known neurological diseases (including but not limited to any kind of seizures or 
stroke).


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9. Any documented active or suspected malignancy or history of malignancy within 5 years 
prior to screening, except appropriately treated basal cell carcinoma of the skin or in situ 
carcinoma of uterine cervix.
10. Planned elective surgery requiring general anesthesia, or hospitalization for more than 
1 day during the study period.
11. Significant history of drug or alcohol dependence or abuse (Substance Use Disorder as 
defined in DSM-5 or ICD-10) within the last six months prior to informed consent (Not 
including caffeine or nicotine).
12. Patients who must or wish to continue the intake of restricted medications (see Section 
4.2.2.1) or any drug considered likely to interfere with the safe conduct of the trial.
13. Patients taking strong or moderate CYP1A2 inhibitors who are also a CYP2C19 Poor 
Metabolizer (PM). Patients taking medication known to be strong or moderate inhibitors 
of CYP1A2 must be prospectively genotyped to ensure they are not poor metabolizers of 
CYP2C19. (A list of CYP1A2 and CYP2C19 inhibitors can be found in the ISF). 
14. Patients taking strong or moderate CYP1A2 inhibitors who are also taking concomitant 
strong or moderate CYP2C19 inhibitors. (A list of CYP1A2 and CYP2C19 inhibitors can 
be found in the ISF.)
15. Patients with a history of moderate to severe hepatic impairment (Child-Pugh B / C).
16. Patients with a history of moderate to severe renal impairment (Stage 3 – 5).
17. Women who are pregnant, nursing, or who plan to become pregnant while in the trial.
18. In the judgment of the investigator, inability of the patient to comply with the clinical trial 
procedures.
19. Currently enrolled in another investigational device or drug study, or less than 6 months 
from Visit 1 since ending another investigational device or drug study(s), or participation 
in > 2 investigational drug clinical trials in the past 2 years.
20. Previous randomisation in any BI 409306 study.
3.3.4
Withdrawal of patients from therapy or assessments
Patients may potentially be withdrawn from trial treatment or from the trial as a whole
(“withdrawal of consent”) with very different implications, please see sections 3.3.4.1 and
3.3.4.2 below. 
An excessive withdrawal rate can have a severe negative impact on the scientific value of the 
trial. Every effort should be made to keep the randomised patients in the trial: if possible on
treatment, or at least to collect important trial data. Measures to control the withdrawal rate 
include careful patient selection, appropriate explanation of the trial requirements and 
procedures prior to randomisation, as well as the explanation of the consequences of 
withdrawal.
The decision to withdraw from trial treatment or from the whole trial as well as the reason
must be documented in the patient files and case report form (CRF).
3.3.4.1
Withdrawal from trial treatment
An individual patient is to be withdrawn from trial treatment if:


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
The patient wants to withdraw from trial treatment, without the need to justify the 
decision.

The patient becomes pregnant during the trial. Patient will be followed up until birth or 
other termination of the pregnancy. 

The patient needs to take concomitant drugs that in the clinical judgment of the 
investigator interfere with the investigational product.

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 has repeatedly shown to be non-compliant with important trial procedures 
and, in the opinion of both the investigator and sponsor representative, is not willing or 
able to stick to the trial requirements in the future. 
Every effort should be made by the site staff to encourage patients to remain in the study and 
on study drug if medically safe. Patients who prematurely discontinue study drug must 
complete the End of Treatment (EOT) procedures as described in the Flow Chart and 
Sections 6.2.2 and 6.2.3. Patients who discontinue study drug prematurely should ideally be 
observed until the end of the trial as if they were still receiving blinded study treatment. For 
all patients the reason for withdrawal from trial treatment (e.g. adverse events) must be 
recorded in the CRF. These data will be included in the trial database and reported.
Patients that are not actively taking study drug may be less motivated to adhere to the study 
visit schedule. Investigators and site staff should work to detect early signs of waning interest 
and readily present such patients with the following options to encourage continued 
participation:
Early D/C 
Option 1:
Continue to conduct regularly scheduled study visits.
Early D/C 
Option 2:
Conduct all remaining study visits over the phone. At the time of planned 
clinic visits, only the following assessments need to be conducted via phone: 
PANSS, CGI-S, C-SSRS, Adverse Events, Concomitant Therapy.
Early D/C 
Option 3:
Discontinue participation in remaining study activities but permit collection 
of the occurrence of psychiatric illness/relapse and vital status approximately 
28 weeks after randomisation through the patient or alternative person 
designated by the patient (e.g., family, spouse, partner, legal representative, 
or physician).
Early D/C 
Option 4:
Same as Option 3 above, but with the possibility of collection of the 
occurrence of psychiatric illness/relapse and vital status approximately 28 
weeks after randomisation through review of patient’s medical information 
from alternative sources (e.g., doctor’s notes, hospital records, etc.).
Patients will be asked to choose the most rigorous form of follow-up that they are willing to 
comply with. Patients who refuse all four of the above are considered to have fully withdrawn 
consent to participate in the study. 


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3.3.4.2
Withdrawal of consent for trial participation
Patients may withdraw their consent for trial participation at any time without the need to 
justify the decision.
This will however mean that no further information may be collected for the purpose of the 
trial and negative implications for the scientific value may be the consequence. Furthermore 
it may mean that further patient follow up on safety cannot occur.
If a patient wants to withdraw consent, the investigator should explain the difference between 
treatment withdrawal and withdrawal of consent for trial participation and explain the options 
for continued follow up after withdrawal from trial treatment. Refer to Section 3.3.4.1 above.
If the patient fully withdraws consent for participation in the study, the study will end for that 
patient. The patient should stop taking study medication and should be asked to complete the 
EOT and Follow-up procedures as described in the Flow Chart and Sections 6.2.2 and 6.2.3. 
Completing these procedures is strongly recommended for the patient’s safety. 
3.3.4.3
Discontinuation of the trial by the sponsor
Boehringer Ingelheim reserves the right to discontinue the trial overall or at a particular trial
site at any time for the following reasons:
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 Good Clinical Practice (GCP), the trial protocol, or the contract impairing 
the appropriate conduct of the trial
The investigator / the trial site will be reimbursed for reasonable expenses incurred in case of 
trial termination (except in case of the third reason).


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4.
TREATMENTS
4.1
INVESTIGATIONAL TREATMENTS
BI 409306, as a film-coated tablet, will be produced by Boehringer Ingelheim Pharma GmbH 
& Co. KG.
Each film-coated tablet contains 10 mg, 25mg or 50 mg BI 409306. 
Eligible patients are randomly assigned to double blind treatment at a ratio of 1:1:1 for the 28 
week treatment period. Patients will be randomised to either slow taper or abrupt withdrawal 
of study medication for 7 days after completing the 28 week treatment period.
4.1.1
Identity of the Investigational Medicinal Products
Table 4.1.1: 1a
Characteristics of the test products-BI 409306
Substance:
BI 409306
Pharmaceutical formulation: Film-coated tablet
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG
Unit strength:
10 mg, 25 mg or 50 mg
Posology:
q.d.
Route of administration:
Oral
Table 4.1.1: 1b
Characteristics of the test products-BI 409306 matching placebo
Substance:
Placebo matching 10 mg, 25mg and 50mg
Pharmaceutical formulation: Film-coated tablet
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG
Unit strength:
N/A
Posology:
q.d.
Route of administration:
Oral


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4.1.2
Selection of doses in the trial
Data from the recent 1289.6 trial in patients with schizophrenia indicate no serious AEs in 
any active dose group (10mg, 25mg, 50mg, and 100mg) [c09340078-01]. Recent preliminary
pharmacometric modelling indicates that at the dose of 25 mg once daily (q.d.) in non-PM 
subjects, the expected therapeutic exposures in the cerebrospinal fluid (CSF) (1xIC50 (half 
maximal inhibitory concentration)) will be achieved in 49% of subjects and will lead to an 
increase of CSF cGMP ≥ 50% above the baseline over a 4 hour duration after dosing. For the
50 mg q.d., about 94% of subjects are expected to reach such a CSF exposure with a 5.9 hour
duration of an increasing CSF cGMP ≥ 50% above the baseline, while for the 10 mg q.d., it is 
clearly sub-therapeutic.  AE data suggest that these doses 25 and 50mg are well-tolerated, and 
similar to placebo.   In line with the proposed mode of action, it is hypothesized that 
compounds which strengthen N-methyl-D-aspartate (NMDA) receptor signalling and LTP, 
exert improvement in vivo outlasting drug exposure, therefore, two doses are planned to 
maximize the therapeutic drug levels in plasma and brain/CSF while providing an acceptable 
level of tolerability.
4.1.3
Method of assigning patients to treatment groups
During Visit 2 eligible patients will be randomised to receive BI 409306 25 mg q.d. or 50 mg 
q.d. or placebo in a 1:1:1 ratio. Additionally, each patient will be randomised up front in a 1:1 
ratio to their method of treatment discontinuation (withdrawal or taper).The assignments will 
occur in a blinded fashion via Interactive Response Technology (IRT) according to a 
randomisation plan.
An IRT will be used to screen and randomise eligible patients, perform subsequent drug 
assignment, manage initial/re-supply ordering of drug supplies and handle emergency un-
blinding. The investigator will receive all necessary instructions to access IRT from the 
Sponsor or chosen provider. Detailed IRT functions/procedures will be documented in the 
user requirement specifications (URS) mutually agreed to by the sponsor and the IRT vendor. 
Note that the medication number is different from the patient number (the latter is assigned 
directly after informed consent is obtained). Site personnel will enter the medication number 
in the eCRF.
4.1.4
Drug assignment and administration of doses for each patient
Following the screening period, patients who qualify according to entry criteria will be 
randomised to one of the three treatment groups to be evaluated as outlined in Table 4.1.4: 1.
Dispensing of kits for the double-blind treatment period will begin at Visit 2. Trial 
medication kits will be provided as described in the Flow Chart. 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.


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To maintain the blind, all treatments will consist of two tablets of BI 409306 or placebo 
during the 28 week treatment period, and 1-4 tablets per day during the withdrawal/taper 
period.
Table 4.1.4: 1
Dosage and treatment schedule for 28 week treatment period
Treatment Group
Dose
Total tablets per daily dose
Placebo
n/a
2 tablets in P.M.
(1 25 mg placebo tablet; 1 50mg placebo tablet)
BI 409306
25 mg
2 tablets in P.M.
(1 25 mg BI 409306 tablet; 1 50mg placebo tablet)
BI 409306
50 mg
2 tablets in P.M.
(1 25 mg placebo tablet; 1 50mg BI 409306 tablet)
Table 4.1.4: 2
Dosage and treatment schedule for 7 day withdrawal/taper period
Administration of study drug tablets will be in the evening, preferably just before going to 
bed. The most common side effects with the use of BI 409306 are visual adverse events 
occurring at maximum concentration (Cmax) (30-40 min post-dose). By taking the study drug 
at bedtime, the negative effect, if any, of experiencing these side effects is expected to be 
minimized.
Patients should be instructed to take their study medication with water at approximately the 
same time in the evening, with or without food. BI 409306 tablets should not be chewed or 
crushed. If a dose is missed by more than 12 hours, that dose should be skipped and the next 
dose should be taken as scheduled.
A dose reduction of BI 409306 is not possible.
Placebo
BI 409306 25 mg
abrupt withdrawal
BI 409306 25 mg
slow taper
BI 409306 50 mg 
abrupt withdrawal
BI 409306 50 mg slow taper
Day 1
4 tablets in P.M. 
4 x 10 mg 
placebo tablets 4 x 10 mg placebo tablets
2 x 10 mg BI 409306 tablets; 
2 placebo tablets
4 x 10 mg placebo tablets 4 x 10 mg BI 409306 tablets
Day 2
3 tablets in P.M. 
3 x 10 mg 
placebo tablets 3 x 10 mg placebo tablets
2 x 10 mg BI 409306 tablets; 
1 placebo tablet
3 x 10 mg placebo tablets 3 x 10 mg BI 409306 tablets
Day 3
3 tablets in P.M. 
3 x 10 mg 
placebo tablets 3 x 10 mg placebo tablets
2 x 10 mg BI 409306 tablets; 
1 placebo tablet
3 x 10 mg placebo tablets 3 x 10 mg BI 409306 tablets
Day 4
2 tablets in P.M. 
2 x 10 mg 
placebo tablets 2 x 10 mg placebo tablets
1 x 10 mg BI 409306 tablet; 
1 placebo tablet
2 x 10 mg placebo tablets 2 x 10 mg BI 409306 tablets
Day 5
2 tablets in P.M. 
2 x 10 mg 
placebo tablets 2 x 10 mg placebo tablets
1 x 10 mg BI 409306 tablet; 
1 placebo tablet
2 x 10 mg placebo tablets 2 x 10 mg BI 409306 tablets
Day 6
1 tablet in P.M. 
1 x 10 mg 
placebo tablet
1 x 10 mg placebo tablet
1 x 10 mg BI 409306 tablet
1 x 10 mg placebo tablet
1 x 10 mg BI 409306 tablet
Day 7
1 tablet in P.M. 
1 x 10 mg 
placebo tablet
1 x 10 mg placebo tablet
1 x 10 mg BI 409306 tablet
1 x 10 mg placebo tablet
1 x 10 mg BI 409306 tablet


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4.1.5
Blinding and procedures for unblinding
4.1.5.1
Blinding
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 randomised treatment 
assignments until after database lock.
The randomisation code will be kept secret by Clinical Trial Support up to database lock.
See Section 4.1.5.2 for rules of breaking the code for patients in emergency situations.
4.1.5.2
Unblinding and breaking the code
Emergency unblinding will be available to the investigator via IRT. It must only be used in
an emergency situation when the identity of the trial drug must be known to the investigator
in order to provide appropriate medical treatment or otherwise assure safety of trial
participants. The reason for unblinding must be documented in the source documents and/or 
appropriate CRF page along with the date and the initials of the person who broke the code.
Each site receives a manual from the IRT provider that contains instructions on how to 
unblind the treatment of a patient via the IRT. 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 CRF page. In case a healthcare 
professional needs to break the code when the investigator cannot be reached, the code can be 
opened by calling the 24-hour Emergency helpline located on the trial identification card 
provided to patients.
Due to the requirements to report Suspected Unexpected Serious Adverse Reactions 
(SUSARs), it may be necessary for a representative from BI’s Pharmacovigilance group to 
access the randomisation code for individual patients during trial conduct. The access to the 
code will only be given to authorised Pharmacovigilance representatives and not be shared
further. 
4.1.6
Packaging, labelling, and re-supply
The investigational products will be provided by BI or a designated Contract Research 
Organization (CRO). They will be packaged and labelled in accordance with the principles of 
Good Manufacturing Practice (GMP). Re-supply to the sites will be managed via an IRT 
system, which will also monitor expiry dates of supplies available at the sites.
For details of packaging and the description of the label, refer to the ISF.


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4.1.7
Storage conditions
Drug supplies will be kept in their original packaging and in a secure limited access storage 
area according to the recommended storage conditions on the medication label. A
temperature log must be maintained for documentation.
If the storage conditions are found to be outside the specified range, the local clinical monitor 
(as provided in the list of contacts) must be contacted immediately.
4.1.8
Drug accountability
The investigator, pharmacist, and/or investigational drug storage manager will receive the 
investigational drugs delivered by the sponsor when the following requirements are fulfilled:

Approval of the clinical trial protocol by the IRB / ethics committee ,

Availability of a signed and dated clinical trial contract between the sponsor and the 
investigational site,

Approval/notification of the regulatory authority, e.g. competent authority,

Availability of the curriculum vitae of the Principal Investigator,

Availability of a signed and dated clinical trial protocol,

Availability of the proof of a medical license for the Principal Investigator,

Availability of FDA Form 1572 (if applicable).
Investigational drugs are not allowed to be used outside the context of this protocol. They 
must not be forwarded to other investigators or clinics. Patients should be instructed to return 
unused investigational drug.
The investigator, pharmacist, and/or investigational drug storage manager must maintain 
records of the product’s delivery to the trial site, the inventory at the site, the use by each 
patient, and the return to the sponsor or warehouse / drug distribution centre or alternative 
disposal of unused products. If applicable, the sponsor or warehouse / drug distribution centre
will maintain records of the disposal. 
These records will include dates, quantities, batch / serial numbers, expiry (‘use- by’) dates, 
and the unique code numbers assigned to the investigational product and trial patients. The 
investigator / pharmacist / investigational drug storage manager will maintain records that 
document adequately that the patients were provided the doses specified by the Clinical Trial 
Protcol (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.


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4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS
4.2.1
Other treatments and emergency procedures
Patients should continue to take their current antipsychotic and concomitant psychotropic 
medications during the treatment period. The dose of these medications should remain 
unchanged unless necessary for the welfare of the patient. These medications will not be 
provided as part of the clinical trial supplies. 
Any change in dose of concomitant antipsychotic medications should be recorded in the 
source documentation and on the appropriate pages of the eCRF. Concomitant psychotherapy 
information should also be recorded in the eCRFs.
Any additional treatment that is considered necessary for the patient’s welfare may be given 
at the discretion of the investigator.
4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
Use of clozapine is not permitted during the study.
Use of medications known to be strong or moderate CYP1A2 inhibitors are not permitted 
unless it is documented that the patient is NOT a CYP2C19 poor metabolizer. Patients taking 
medication known to be strong or moderate inhibitors of CYP1A2 must be prospectively 
genotyped to ensure they are not poor metabolizers of CYP2C19. 
A patient who is a CYP2C19 poor metabolizer may discontinue use of a strong or moderate 
CYP1A2 inhibitor medication prior to randomisation, at the discretion of the Prinicipal 
Investigator (PI).  
Use of strong or moderate CYP1A2 inhibitors taken concomitantly with strong or moderate 
CYP2C19 inhibitors is not permitted. If a patient needs to take strong or moderate CYP1A2 
and CYP2C19 inhibitors during the trial for a short period of time (less than 14 days), study 
drug should temporarily be discontinued. 
A list of strong and moderate CYP1A2 and CYP2C19 inhibitors can be found in the ISF.
Use of St. John’s Wort is prohibited. Use of any traditional/herbal/complimentary medication 
is prohibited during the entire course of study, unless specifically preapproved by the TCM or 
designee. Any such medication must be stopped during the screening period.
Any medication that may interfere with the action of BI 409306 or whose action may be 
altered by concomitant administration of BI 409306 during the treatment period, 
withdrawal/taper period, and the follow-up period, in the clinical judgment of the 
investigator, is not permitted.


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4.2.2.2
Restrictions on diet and life style
Because psychoactive drugs may impair thinking, judgment, and/or motor skills, patients will 
be cautioned about operating machinery, including automobiles, until they are reasonably 
certain that the study medication does not adversely affect their ability to engage in such 
activities. It is recommended that patients should exercise caution when driving or operating 
machinery within two hours of drug administration.
Patients should not abuse alcohol or drugs during the study as defined in the fifth edition of 
the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) or ICD-10, or in the 
opinion of the investigator. 
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 drastically changed.
4.2.2.3
Restrictions regarding women of childbearing potential
Women of childbearing potential must use the contraception methods described in the patient
information.
4.3
TREATMENT COMPLIANCE
Study medication will be dispensed to the patient at the study site by designated 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 
in the investigator site file.
This trial will employ a medication adherence monitoring platform. The platform uses 
artificial intelligence on smartphones to confirm study medication ingestion. In addition, 
built-in reminders and a communication system allows real-time intervention in case of drug 
interruptions. Use of this platform will in no way supersede or replace the trial prescribed 
medication protocol of the patients. Because the platform does not change the medication 
protocol of the patients, but rather encourages adherence to the predefined protocol, use of 
this platform presents minimal risk to the patients.
The platform monitors each dose of the medication using a smartphone. The platform will be 
provided to a patient preloaded on a smartphone or the application (app) will be downloaded 
on the patient’s personal smartphone. Patients will receive reminders within predefined time 
windows to take their medication using the platform. Patients will follow a series of 
prescribed steps in front of the front-facing smartphone camera to visually confirm ingestion 
of the medication. The app on the smartphone will make an automated determination of 
whether the patient has properly taken their medication at the prescribed time. There is no 
need for site staff to review the administration, or be available at the time the patient is taking 
their medication. Assistance provided to the patient is automatically reduced as the patient 
becomes more proficient at using the app.


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After local determination by the device of proper medication administration, all video 
recordings are encrypted and then transmitted to a secure centralized location for further 
analysis, including testing for duplicate enrollment. The captured data and video is 
reviewable through a roles and rules restricted Health Insurance Portability and 
Accountability Act (HIPAA) compliant system ensuring privacy of the information. Phone 
numbers of the patients may also be collected and stored in an encrypted manner, allowing 
for direct communication to each patient from the system in an automated manner, or by site 
staff or other study monitoring personnel. At no time is the phone number visible. Individuals 
outside the clinical sites will not know the identity of the study patients and will have not 
have access to any medical or health records of the patients.
The platform will allow for rapid and tailored intervention in case of non-adherence (drug 
interruptions). Site staff will have access to real-time and continuous adherence data without 
having to rely on self-reported data. Patients who are found to regularly not take their 
medication will be contacted by site staff for retraining.
Patients must bring all remaining trial medication including empty package material with 
them when attending visits. Site staff should remind patients of proper drug administration at 
each visit during the treatment period. Study medication usage and return must be 
documented on the respective form and an account must be given for any discrepancies. 
Treatment compliance will also be calculated based on tablet counts as the number of tablets 
taken, divided by the number of tablets which should have been taken according to the 
scheduled period, multiplied by 100. Compliance will be verified by the on-site monitor 
authorised by the sponsor.
Treatment compliance (%) =
Number of tablets actually taken 100
     Number of tablets which should have been taken
Compliance during the treatment period should be between 80% and 120%. If compliance is 
outside this range, the patient should be carefully interviewed and re-informed about the 
purpose and the conduct of the trial. Unreliable patients may be withdrawn from the trial.
The potential for study drug abuse will be closely monitored. Events including overdose, 
misuse, lost and unaccounted for medication must be thoroughly documented in the patients 
source and on the appropriate eCRFs. 


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5.
ASSESSMENTS
5.1
ASSESSMENT OF EFFICACY
Relapse will be measured by the batteries and questionnaires listed below, as well as by 
confirmation of hospitalization, intensive outpatient therapy, or home treatment as an 
alternative to hospitalization:
Positive and Negative Syndrome Scale (PANSS) will be used to assess the severity of 
psychotic symptoms and progression of disease. The PANSS positive and negative symptom 
scales each have 7 items, and the General Psychopathology Scale has 16 items. The patient is 
rated from 1 to 7 on the 30 different items based on the interview as well as reports from an 
informant. The total score is the summation of the 30 item scores [R13-5061].
Clinical Global Impressions-Severity (CGI-S) is a one-item evaluation completed by the 
clinician to measure the severity of psychopathology [R03-0520]. 
Clinical Global Impressions-Improvement (CGI-I) is a one-item evaluation completed by 
the clinician to rate total improvement compared to the patient’s condition at randomisation. 
Patient Global Impressions-Improvement (PGI-I) is a one-item evaluation completed by 
the patient to assess their overall evaluation of his/her status compared to how they felt at 
randomisation. 
The Personal and Social Performance scale (PSP) is a clinician assessment of social 
functioning in patients with schizophrenia. The PSP measures a patient’s functioning in four 
domains over the past month: (1) socially useful activities, (2) personal and social 
relationships, (3) self-care and (4) disturbing and aggressive behaviors. A single overall 
rating score is derived ranging from 1 to 100 with specific criteria for each 10-point interval. 
Higher scores represent better personal and social functioning [R17-2254]. 
5.2
ASSESSMENT OF SAFETY
5.2.1
Physical examination
Physical examinations will be performed at the time points specified in the Flow Chart. It 
includes at a minimum general appearance, neck, lungs, cardiovascular system, abdomen, 
extremities, and skin.
Measurement of height and body weight will be performed at the time points specified in the 
Flow Chart.
The results must be included in the source documents available at the site.
Clinically relevant abnormal findings noticed after baseline assessment will be reported as 
(S)AEs.


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5.2.2
Vital signs
Vital signs (systolic/diastolic blood pressure and pulse rate) will be recorded at the study 
visits as described in the Flow Chart. A similar type of instrument/scale should be used for all 
measurements. Vital signs will be measured after the patient has been sitting for 5 minutes.
5.2.3
Safety laboratory parameters
Safety laboratory test, which will be assessed at the visits as indicated in the Flow Chart, are 
listed in Table 5.2.3: 1. Patients should be fasting for at least 8 hours prior to blood 
collection, except at Visit 1.
Analyses will be performed by a central laboratory, the respective reference ranges will be 
provided in the ISF. 
Instructions regarding sample collection, sample handling/ processing and sample shipping 
are provided in the Laboratory Manual in the ISF. 
The central laboratory will send reports to the investigator. It is the responsibility of the 
investigator to evaluate the laboratory reports. Clinically relevant abnormal findings as 
judged by the investigator will be reported as adverse events (please refer to Section 5.2.6).
In case the criteria for hepatic injury are fulfilled, a number of additional measures will be 
performed (please see Section 5.2.6.1 and the DILI Checklist provided in the electronic data 
capture (EDC) system. The amount of blood taken from the patient concerned will be 
increased due to this additional sampling.
The central laboratory will transfer the results of the analysis to the sponsor.
Table 5.2.3: 1 
Safety laboratory tests
Category
Test name
Haematology  
Hematocrit 
Hemoglobin 
Red Blood Cell (RBC) Count/ Erythrocytes
Reticulocyte Count
White Blood Cells (WBC) / Leukocytes
Platelet Count/ Thrombocytes
Diff. Automatic (manual if 
diff. automatic is abnormal)
- Neutrophils 
- Eosinophils 
- Basophils
- Monocytes
- Lymphocytes 
Coagulation
Partial Thromboplastin Time (=aPTT)
Prothrombin time (Quick and INR)


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Category
Test name
Chemistry
Aspartate aminotransferase (AST/SGOT)
Alanine aminotransferase (ALT/SGPT)
Alkaline Phosphatase (AP)
Albumin
Creatine Kinase (CK)
Creatine kinase myocardial b fraction (CK-MB), 
only if CK is elevated
Gamma-Glutamyl Transferase (GGT/γ-GT)
Lactic Dehydrogenase (LDH)
Calcium
Sodium
Potassium
Chloride
Bicarbonate
Glucose
Creatinine
Blood urea nitrogen (BUN)
Bilirubin Total
Bilirubin Direct
Bilirubin Indirect
Protein, Total
Uric Acid
Cholesterol, total
Triglycerides
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
Urine-Sediment (microscopic 
examination), (only if urine analysis 
abnormal)
Urine Sediment Bacteria
Urine Cast in Sediment
Urine Squamous Epith Cells
Urine Sediment RBC/ Erythrocytes
Urine Sediment WBC/ Leucocytes
Drug screening (urine)
Amphetamines
Cannabis
Cocaine
Methadone
Opiates
Phencyclidine (PCP)


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Category
Test name
Drug assessment in plasma
Refer to lab manual for available antispsychotic 
assays
5.2.4
Electrocardiogram
The 12-lead ECGs will be recorded as scheduled in the Flow Chart after 5 minutes in the 
supine position. The investigator or a designee will evaluate whether the ECG is normal or 
abnormal and whether it is clinically relevant, if abnormal. ECGs may be repeated for quality 
reasons and the repeated recording used for analysis. 
Additional ECGs may be recorded for safety reasons. Dated and signed printouts of ECG 
with findings should be documented in patient’s medical record.
Clinically relevant abnormal findings will be reported either as baseline condition (if 
identified at the screening visit) or otherwise as adverse events and will be followed up 
and/or treated as medically appropriate.
5.2.5
Other safety parameters
5.2.5.1
Assessment of Suicidality
Suicidality should be monitored closely during the study period. Suicidal thoughts and 
behavior will be assessed by the Columbia-Suicide Severity Rating Scale (C-SSRS) (R08-
1147). An electronic version utilizing a tablet solution will be used for this trial.  
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 C-SSRS interview may be administered by any type of physician, psychologist, clinical 
social worker, mental health counselor, nurse, or coordinator with C-SSRS training. It has a 
typical duration of five minutes, and causes only a low burden on subjects. At a minimum, 
the interview consists of 2 screening questions related to suicidal ideation and 4 related to 
suicidal behavior, and may be expanded to up to 17 items in case of positive responses. Free 
text entries are allowed for; the investigator has to directly evaluate the scale and write a 
report.
The C-SSRS has been widely used in large multinational clinical trials. The 
C-SSRS will be administered at the Screening Visit/Visit 1 (using the ‘baseline/ screening’ 
version) with the aim to exclude patients with active moderate or severe symptomatology 


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within a specified time prior to the screening or screening visit. The lifetime history of 
suicidal ideation and behavior will also be recorded.
After the screening visit, the assessment ‘since last visit’ version will be performed at each 
clinic or phone visit. 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. If there is a confirmed positive report of suicidal 
behavior or suicidal ideation type 4 or 5 after start of trial, the investigator is to immediately 
interview the patient, and/or is to consult a psychiatrist. If the positive report is confirmed, 
appropriate actions for the patient’s safety have to be initiated. 
All C-SSRS reports of suicidal ideation type 4 or 5 and all reports of suicidal behavior must 
be reported as separate SAEs by the investigator.
For ‘Self-injurious behavior, without suicidal intent’, standard AE / SAE reporting rules are 
to be applied.
For each negative report (suicidal ideation type 1, 2 or 3) after the 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. Refer to Section 5.2.6.1. 
5.2.6
Assessment of adverse events
5.2.6.1
Definitions of AEs 
Adverse event
An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical 
investigation patient administered a medicinal product and which does not necessarily have to 
have a causal relationship with this treatment.


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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.
Serious adverse event
A serious adverse event (SAE) is defined as any AE which fulfils at least one of the 
following criteria:
-
results in death,
-
is life-threatening, which refers to an event in which the patient was at risk of death at 
the time of the event; it does not refer to an event that hypothetically might have 
caused death if more severe.
-
requires inpatient hospitalisation or 
-
requires prolongation of existing hospitalisation,
-
results in persistent or significant disability or incapacity, or
-
is a congenital anomaly / birth defect,
or
-
is deemed serious for any other reason if it is an important medical event when based 
on appropriate medical judgement which may jeopardise the patient and may require 
medical or surgical intervention to prevent one of the other outcomes listed in the 
above definitions.
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm, blood dyscrasias or convulsions that do not result in 
hospitalisation or development of dependency or abuse. 
For Japan only: the following events will be handled as “deemed serious for any other 
reason”. AEs which possibly lead to disability will be reported as SAEs.
AEs considered “Always Serious”
Cancers of new histology and exacerbations of existing cancer must be classified as a serious 
event regardless of the duration between discontinuation of the drug and must be reported as 
described in 5.2.6.2, subsections “AE Collection” and “AE reporting to sponsor and 
timelines”.
In accordance with the European Medicines Agency initiative on Important Medical Events, 
Boehringer Ingelheim has set up a list of further AEs, which by their nature, can always be 
considered to be “serious” even though they may not have met the criteria of an SAE as 
defined above.
The latest list of “Always Serious AEs” can be found in the EDC system.  These events 
should always be reported as SAEs as described above.
Adverse events of special interest (AESIs)
The term AESI relates to any specific AE that has been identified at the project level as being 
of particular concern for prospective safety monitoring and safety assessment within this trial, 
e.g. the potential for AEs based on knowledge from other compounds in the same class. 


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AESIs need to be reported to the sponsor’s Pharmacovigilance Department within the same 
timeframe that applies to SAEs, please see above.
The following are considered as AESIs:
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 (upper limit of normal) combined with an 
elevation of total bilirubin >2 fold ULN measured in the same blood draw sample, and/or

aminotransferase (ALT, and/or AST) elevations ≥10 fold ULN
These lab findings constitute a hepatic injury alert and the patients showing these lab 
abnormalities need to be followed up according to the “DILI checklist” which can be found 
in the EDC.
In case of clinical symptoms of hepatic injury (icterus, unexplained encephalopathy, 
unexplained coagulopathy, right upper quadrant abdominal pain, etc.) without lab results 
(ALT, AST, total bilirubin) available, the investigator should make sure these parameters are 
analysed, if necessary in an unscheduled blood test. Should the results meet the criteria of 
hepatic injury alert, the procedures described in the DILI checklist should be followed.
Intensity (severity) of AEs
The intensity (severity) of the AE should be judged based on the following:
Mild:
Awareness of sign(s) or symptom(s) that is/are easily tolerated
Moderate:
Sufficient discomfort to cause interference with usual activity
Severe:
Incapacitating or causing inability to work or to perform usual activities
Causal relationship of AEs
Medical judgement should be used to determine the relationship, considering all relevant 
factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge, 
confounding factors such as concomitant medication, concomitant diseases and relevant 
history. 
Arguments that may suggest that there is a reasonable possibility of a causal relationship 
could be:

The event is consistent with the known pharmacology of the drug.

The event is known to be caused by or attributed to the drug class.

A plausible time to onset of the event relative to the time of drug exposure.

Evidence that the event is reproducible when the drug is re-introduced

No medically sound alternative aetiologies that could explain the event (e.g. pre-
existing or concomitant diseases, or co-medications).

The event is typically drug-related and infrequent in the general population not 
exposed to drugs (e.g. Stevens-Johnson syndrome).

An indication of dose-response (i.e. greater effect size if the dose is increased, smaller 
effect size if dose is diminished).


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Arguments that may suggest that there is no reasonable possibility of a causal relationship 
could be:

No plausible time to onset of the event relative to the time of drug exposure is evident 
(e.g. pre-treatment cases, diagnosis of cancer or chronic disease within days / weeks 
of drug administration; an allergic reaction weeks after discontinuation of the drug 
concerned)

Continuation of the event despite the withdrawal of the medication, taking into 
account the pharmacological properties of the compound (e.g. after 5 half-lives).
Of note, this criterion may not be applicable to events whose time course is prolonged 
despite removing the original trigger.

Additional arguments amongst those stated before, like alternative explanation (e.g. 
situations where other drugs or underlying diseases appear to provide a more likely 
explanation for the observed event than the drug concerned).

Disappearance of the event even though the trial drug treatment continues or remains 
unchanged.
5.2.6.2
Adverse event collection and reporting
AE Collection
Patients will be required to report spontaneously any AEs as well as the time of onset, 
duration and intensity of these events. 
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 to be reported in the eCRF (and SAE 
form if applicable). A local ophthalmology assessment will be required if any visual AE is 
rated as severe by the patient or at the discretion of the Principal Investigator. The 
ophthalmologist will act as a consultant to the investigator and may offer advice on the 
proper management and treatment for the reaction.
The potential for study drug abuse-related adverse events will be closely monitored and 
narratives provided in the Clinical Trial Report (CTR). Narratives will include standard AE 
data collection, including time of onset, duration, severity and outcome.
The investigator shall maintain and keep detailed records of all AEs in the patient files.
The following must be collected and documented on the appropriate CRF(s) by the 
investigator:
•
From signing the informed consent onwards until the individual patient’s end of trial: 
-all AEs (serious and non-serious) and all AESIs.
•
After the individual patient’s end of trial: 
the investigator does not need to actively monitor the patient for AEs but should only 
report related SAEs and related AESIs of which the investigator may become aware of by 
any means of communication, e.g. phone call. Those AEs should however, not be 
reported in the CRF.


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Figure 5.2.6.2: 1
AE Collection
Patients who discontinue trial medication prematurely and agree to be contacted further, 
should be followed up as described in Section 3.3.4.1, withdrawal from trial treatment. From 
then on until the individual patient’s end of the trial the investigator must report:

All AEs/SAEs/AESIs collected by the investigator as instructed in Section 3.3.4.1 for 
patients who choose Options 1 and 2.

All AEs/SAEs/AESIs the investigator becomes aware of for patients who choose 
Options 3 and 4. 
After the individual patient’s end of the trial the investigator does not need to actively 
monitor the patient for AEs but should report related SAEs and related AESIs of which the 
investigator may become aware of by any means of communication, e.g. phone call. Those 
AEs should however, not be reported in the CRF.
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.
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 
eCRF pages and the BI SAE form, if applicable. The investigator should determine the causal 
relationship to the trial medication.
The following should also be recorded as an (S)AE in the CRF and BI SAE form (if 
applicable):


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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 to trial inclusion they will be considered as 
baseline conditions and should be collected in the eCRF only. All (S)AEs, including those 
persisting after individual patient’s end of trial must be followed up until they have resolved, 
have been assessed as “chronic” or “stable” , or no further information can be obtained.
Pregnancy
In rare cases, pregnancy might occur in a clinical trial. Once a patient has been enrolled in the 
clinical trial and has taken trial medication, the investigator must report any drug exposure 
during pregnancy in a trial participant immediately (within 24 hours) by means of Part A of 
the Pregnancy Monitoring Form to the sponsor’s unique entry point.
The outcome of the pregnancy associated with the drug exposure during pregnancy must be 
followed up and reported to the sponsor’s unique entry point on the Pregnancy Monitoring 
Form for Clinical Trials (Part B).
The ISF will contain the Pregnancy Monitoring Form for Clinical Trials (Part A and B).
As pregnancy itself is not to be reported as an AE, in the absence of an accompanying SAE 
and/or AESI, only the Pregnancy Monitoring Form for Clinical Trials and not the SAE form 
is to be completed. If there is an SAE and/or AESI associated with the pregnancy an SAE 
form must be completed in addition.
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS
5.3.1
Assessment of Pharmacokinetics
BI 409306:
Blood samples will be collected as indicated in the Flow Chart to measure plasma 
concentrations of BI 409306 and metabolites.
From the data collected after first dose, the following individual pharmacokinetic parameters 
will be reported:
- C0:45h: measured plasma concentration of BI 409306 in plasma 0:45 h after single dose of BI 
409306.
- C1.5h: measured plasma concentration of BI 409306 in plasma 1.5 h after single dose of BI 
409306. 
- C2h: measured plasma concentration of BI 409306 in plasma 2 h or more after single dose of 
BI 409306.
From the individual pharmacokinetic parameters C0:45h and C1.5h, mean pharmacokinetic 
parameters will be calculated by descriptive statistics if data allow.


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At the post-randomisation visits, the following pharmacokinetic parameters will reported for 
each analyte:
- Cpress: residual concentration of BI 409306 and metabolites CD 13896 and CD 14084 in 
plasma measured after last dose of BI 409306.
See Section 10 for additional information.
5.3.2
Methods of sample collection
5.3.2.1
Plasma sampling for analysis of BI 409306 and metabolites 
At Visit 2 blood samples of 3 mL each will be collected from each patient at pre-dose and at 
2 post-dose sampling timepoints within the first 1.5 hours after drug intake. One additional 
blood sample of 3 mL will be collected from each patient at the end of Visit 2 only after all 
other scheduled procedures have been performed. See Table 10.3:1.
The two metabolites CD 13896 and CD 14084 will be analysed if BI 409306 plasma 
concentration is BLQ (below the limit of quantification) in the trough samples from Visits 8 
and 16, and, if BI 409306 plasma concentrations are above BLQ in two of the samples from 
Visit 2.
Detailed instructions for obtaining, handling and shipping PK samples are provided in the 
laboratory manual.
Special attention must be directed to exact timing and instant recording of plasma sampling 
and drug administration as well as to the correct handling, labelling and storage of samples.
At Visit 2, the clock time of the administration of the first BI 409306 dose (during the study 
visit) and of the actual PK sampling times will be recorded in the eCRF.
At Visits 8 and 16, the clock time of the administration of the last BI 409306 dose (at home) 
and of the actual PK sampling times will be recorded in the eCRF.
5.3.4
Pharmacokinetic – pharmacodynamic relationship
The relationship between the BI 409306 plasma concentrations and efficacy response and AE 
may be assessed descriptively.


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5.4
ASSESSMENT OF BIOMARKER(S)
5.4.1
Biobanking
Participation in sampling for biobanking (including DNA) is voluntary and not a prerequisite 
for participation in the trial. A sample for DNA biobanking will be taken only after a separate 
biobanking informed consent has been given in accordance with local ethical and regulatory 
requirements. Banked samples may be analysed in the future for scientific evaluations or to 
further, for example, the mechanistic understanding of drug effects and/or to identify genetic 
or other factors associated with response to therapy or the risk of adverse drug reactions. 
Measures are in place to comply with the applicable rules for the collection, biobanking and 
future use of biological samples and clinical data, in particular
Sample and data usage has to be in accordance with the separate biobanking informed consent.
The BI-internal facilities storing biological samples from clinical trial participants as well as 
the external banking facility are qualified for the storage of biological samples collected in 
clinical trials. 
An appropriate sample and data management system, including audit trail for clinical data and 
samples to identify and destroy such samples according to the informed consent form (ICF) is 
in place 
A fit for the purpose documentation (biomarker proposal, analysis plan and report) ensures 
compliant usage 
A fit for purpose approach will be used for assay/equipment validation depending on the 
intended use of the biomarker data
Samples and/or data may be transferred to third parties and other countries as specified in the 
biobanking ICF
5.4.1.1
Methods and Timing of Pharmacogenomic Sample Collection
Sampling will be performed at the time points specified in the Flow Chart. Approximately 8.5 
mL of blood will be drawn into a PAXgene Blood DNA tube, preferably at Visit 2. If not 
feasible at Visit 2, the sample can also be taken at a later visit during the treatment period. 
Detailed instructions on sampling, preparation, processing, shipment and storage are provided 
in the laboratory manual. DNA, extracted from the original whole blood sample, will be 
stored at the Sponsor. 
5.4.2
Pre-specified Pharmacogenomic Analysis
One blood sample will be taken at the screening visit for genotyping of CYP2C19 from all 
patients taking medication known to be strong or moderate inhibitors of CYP1A2. Patients
classified as poor metabolizers (poor metabolizers defined as presence of two non-functional 


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alleles (*2 and *3) of the CYP2C19 gene) may be excluded from enrollment (see Section 
3.3.3 (Exclusion criteria) and Section 4.2.2.1 (Restrictions regarding concomitant treatment)).
In addition, all randomised patients will be asked for one mandatory blood sample for pre-
specified pharmacogenomic analyses at Visit 2. If not feasible at Visit 2, the sample can also 
be taken at a later visit during the treatment period. In case of a positive study outcome, the 
sample may be used for DNA extraction and subsequent genotyping for variants in genes 
involved in absorption, distribution, metabolism and elimination of the compound. It is not 
intended to include these data in the final report. However, the data may be part of the report 
if necessary.
All remaining samples will be destroyed no later than two years after the end of the trial.
Detailed instructions on sampling, preparation, processing, shipment and storage of the 
samples are provided in the laboratory manual.
5.6
APPROPRIATENESS OF MEASUREMENTS
All measurements performed during this trial are acceptable measurements and commonly 
used in monitoring safety aspects or assessing treatment response in patients meeting 
diagnostic criteria for schizophrenia. 


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The scheduled measurements are appropriate to see drug induced changes in physical 
examination, vital signs, ECG and standard laboratory values. The primary and secondary 
efficacy endpoints and safety endpoints are standard and accepted for evaluation of safety 
and tolerability of an oral drug.


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6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
All patients are to adhere to the visit schedule as specified in the Flow Chart. If any visit 
needs to be rescheduled, subsequent visits should follow the original visit date schedule by 
referring to the date of randomisation (Visit 2).
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
Study procedures to be performed at each visit are listed in the Flow Chart. Additional details 
regarding visit procedures are provided in Section 5 and below. 
The members of the site staff that will be administering the assessments have to be properly 
trained (either at the investigator meeting or individually), and training documentation must 
be filed 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 assessments.
6.2.1
Screening Period
No trial procedures should begin until the patient has signed the informed consent. After a 
patient has signed the informed consent, the patient is enrolled in the trial and has begun 
screening. The patient should be recorded on the enrolment log and be registered in the IRT 
as a screened patient. The Screening procedures are not required to be completed on the same 
day. 
Additional written informed consent for the unspecified pharmacogenomics sample must be 
obtained if the patient is willing to provide the blood sample for DNA banking.
Patients who have a laboratory test value outside the range that would jeopardize patients’ 
safety while participating in this clinical trial may have the test repeated once to determine 
eligibility; however, the result must be available prior to Visit 2 (Day 1). The site should 
inform the authorized monitors (CML/Clinical Research Associate (CRA)) of their intent to 
redraw a sample(s) and receive the approval from the CML before they send out the retest 
sample to the central laboratory. 
Patients who are not eligible for randomisation should be entered as a screen failure in IRT.
Patients who failed screening may repeat the screening phase once after discussion between 
the investigator and sponsor, providing the reasons for screening failure were reversible and 
have been resolved. Permission to rescreen patients must be obtained from the TCM or CML, 
and documentation of approval filed in the ISF. The patient who will be rescreened needs to 
be re-consented and be given a new patient number. All the study procedures for the 
Screening Visit (Visit 1) must be repeated upon rescreen.


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6.2.2
Treatment period(s)
Eligible patients will be trained and set-up with the smartphone medication adherence 
monitoring Platform at Visit 2 prior to taking their first dose of study drug. Please refer to the 
manual in the ISF.
Study medication will be allocated via IRT and dispensed at visits specified in the Flow Chart. 
Patients will be assigned a new medication number(s) at each of these visits. The first dose of 
study drug will be administered at the site after all baseline assessments have been completed
and trial eligibility confirmed at Visit 2. 
See Sections 5.3.2 and Section 10.3 for the sampling methods and time schedule for PK 
blood sampling.
Phone Visits are to be conducted at the time points specified in the Flow Chart to assess the 
overall status of the patient, assess suicidality, check compliance, and to collect new AE and 
concomitant medication information. If symptom worsening is suspected, an unscheduled in-
clinic visit should be scheduled to further assess the patient for relapse. During the 
unscheduled visit, information should be gathered to determine whether any criteria for 
relapse have been met. PANSS and CGI-S should be assessed, as well as any other 
assessments necessary to assess the patient’s condition, in the judgment of the investigator.
Relapse of Schizophrenia
If the criteria for relapse (See Section 2.1.2) have been met, additional treatment considered 
necessary for the patient’s welfare may be given. The patient may continue in the trial at the 
discretion of the investigator. 
A blood sample should be collected at the time relapse is diagnosed to measure for detectable 
levels of antipsychotic medication. 
Patients prematurely discontinuing study drug:
Patients who discontinue study drug prematurely should ideally be observed until study end 
as if they were still receiving blinded study treatment. There are 4 Options for observing 
patients after premature drug discontinuation. See Section 3.3.4.1
Early D/C Option 1: For patients who prematurely discontinue taking study drug who are 
willing to conduct the remaining visits, the following should be performed:

EOT Visit must be performed within 7 days of last intake of study drug, or as soon as 
possible.

Thereafter, patients should be followed up according to the regular visit schedule 
through Visit 16. 

A Follow-Up Visit is not necessary if the patient discontinued >4 weeks prior to Visit 
16. If a patient discontinues <4 weeks prior to Visit 16, a Follow-up Visit will be 
performed 28 days after the EOT Visit. 


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Early D/C Option 2: For patients who prematurely discontinue taking study drug who are 
willing to conduct the remaining visits over the phone, the following should be performed: 

EOT Visit must be performed within 7 days of last intake of study drug, or as soon as 
possible.

A Follow-up Visit will be performed 28 days after the EOT Visit.

Thereafter, patients should be followed up over the phone according to the regular 
visit schedule through Visit 16. See Section 3.3.4.1 for Early D/C Option 2 which 
details the assessments to be conducted via phone.
Early D/C Options 3 and 4: For patients who prematurely discontinue study drug and agree 
to be contacted or have information collected from an alternative source at the end of the 
study, the following should be performed:

EOT Visit must be performed within 7 days of last intake of study drug, or as soon as 
possible.

A Follow-up visit will be performed 28 days after the EOT Visit.

Occurrence of psychiatric illness/relapse and vital status must be collected 
approximately 28 weeks after the patient was randomised.
6.2.2.1
Withdrawal/Taper Period
Patients who complete the 28 week treatment period will enter the withdrawal/taper period. 
When patients are randomised at Visit 2, they are also randomised to either abrupt 
withdrawal or slow taper of study drug. Vital signs, suicidality and adverse events will be 
closely monitored during this period.
Refer to Section 7.3.4 for the withdrawal/taper analysis strategy.


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6.2.3
Follow up period and trial completion
Patients who complete the treatment and withdrawal/taper periods will have a Follow-Up 
Visit performed at Week 32.  Patients who enter the withdrawal/taper period, but discontinue 
taking their study drug will have a Follow-up Visit as planned at Week 32.
For patients who prematurely discontinue taking study drug who are willing to conduct the 
remaining in-clinic and phone visits (Early D/C Option 1), a Follow-Up Visit is not
necessary if the patient discontinued >4 weeks prior to Visit 16. If a patient discontinues <4 
weeks prior to Visit 16, a Follow-up Visit should be performed 28 days after the EOT Visit.
A Follow-Up Visit will be performed 28 days after the EOT Visit for patients who 
prematurely discontinue taking study drug and agree to conduct the remaining visits over the 
phone or who agree to be contacted or have information collected from an alternative source 
at the end of the study (Early D/C Options 2-4).
Occurrence of AEs since last visit will be documented and will be managed in accordance 
with Section 5.2.6. All AEs and/or SAEs persisting after trial completion must be followed 
up until they have resolved, have been sufficiently characterized, or no further information 
can be obtained.


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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
7.1
STATISTICAL DESIGN - MODEL
This is a randomised, double-blind, parallel group, multi-centre trial aiming to show 
superiority of BI 409306 to placebo as an intervention to prevent relapse in patients with 
schizophrenia.  All patients will be treated for 28 weeks. 
The primary objective of the statistical analysis is to determine whether BI 409306 
significantly reduces the risk of relapse in comparison to placebo.
The estimand of primary efficacy interest is the test of the hazard ratio of BI 409306 (25 mg 
q.d. and 50 mg q.d. pooled) vs. placebo using the Wald test for the treatment effect in a 
stratified Cox proportional hazards model stratified by country, on the full analysis set using 
the ITT follow-up analysis period.  Refer to Sections 7.2 and 7.3 for more details.
7.2
NULL AND ALTERNATIVE HYPOTHESES
The trial will follow a hierarchical testing strategy. The first hypothesis for the superiority 
testing of the primary endpoint time to first relapse is (HR = hazard ratio):
Ho: HRBI 409306 / placebo = 1
vs. 
Ha: HRBI 409306 / placebo ≠ 1, where HRBI 409306 is the 
hazard ratio for the pooled active treatment arms (i.e. BI 409306 50 mg q.d. and BI 
409306 25 mg q.d.), over 28 weeks (excluding the withdrawal/taper period)
Superiority will be declared if the hazard ratio between BI 409306 vs. placebo is statistically 
significantly less than 1 at the two-sided type I error level α = 0.05.
If the first hypothesis test is determined to be statistically significant, the individual doses 
will be tested for superiority using Hochberg’s step-up test. The method will be to perform 
the statistical tests and rank the p-values for the individual doses vs. placebo.  Let p(1) ≥ p(2)
be the two-sided p-values.  The corresponding null hypotheses are H0(1) and H0(2).
H0(1): HRBI 409306 / placebo = 1
vs. 
Ha(1): HRBI 409306 / placebo ≠ 1, where HRBI 409306 is 
the hazard ratio for the BI 409306 dose with the highest p-value
H0(2): HRBI 409306 / placebo = 1
vs. 
Ha(2): HRBI 409306 / placebo ≠ 1, where HRBI 409306 is 
the hazard ratio for the BI 409306 dose with the lowest p-value
Step 1: If p(1) ≤ 0.05 then both hypotheses are rejected and both doses are declared 
statistically significant and testing ends.  If p(1) > 0.05, then H0 (1) is not rejected and the 
testing proceeds to Step 2.
Step 2: If p(2) ≤ 0.025, then H0 (2) is rejected and this dose is declared statistically significant.  
If p(2) > 0.025, then all doses fail.  


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The remaining alpha after the testing of the primary endpoint (Steps 1 and 2) will be used to 
test the key secondary endpoint of change from baseline in PANSS positive symptoms. The 
hypotheses to be tested are:
H0(3): Mean change from baseline of PANSS positive symptom score after 28 weeks of 
treatment with BI 409306
≥Mean change from baseline of PANSS positive symptom score after 28 weeks of 
treatment with placebo
Ha(3): Mean change from baseline of PANSS positive symptom score after 28 weeks of 
treatment with BI 409306
< Mean change from baseline of PANSS positive symptom score after 28 weeks of 
treatment with placebo
The first of the key secondary hypothesis to be tested will be based on the pooled active 
treatment arms (i.e. BI 409306 50 mg q.d. and BI 409306 25 mg q.d.), over 28 weeks 
(excluding the withdrawal/taper period).
Similar to the primary endpoint, if the first hypothesis test (on the pooled doses) is 
determined to be statistically significant, the individual doses will be tested for superiority 
using Hochberg’s step-up test as described above.
7.3
PLANNED ANALYSES
Two patient populations are defined:

The treated set (TS) includes all patients who were dispensed study medication and 
were documented to have taken at least one dose of investigational treatment

The full analysis set (FAS) includes all patients in the treated set with at least one 
post-baseline measurement of any type
No per protocol population will be used for analyses; however protocol violations will be
identified and listed.
Analysis sets will be fully defined in TSAP.
Three analysis periods are defined:

Intent to Treat (ITT) follow-up: from treatment start date until the end of the 
intended complete treatment period:
For patients who complete the trial according to the flow chart, the 
withdrawal/taper period is not included. Additionally, if a patient happens to 
take drug for 29 weeks (i.e. 1 week longer than the planned 28 weeks) and 
then begin the withdrawal/taper period, the withdrawal/taper period will not be 
included.


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For patients who discontinue prior to the 28 week treatment period, e.g. at 
week 25, the follow-up period until the end of week 28, is included.

Full follow-up: from randomisation until the end of the trial, including all 
observed time on and off trial medication until the follow-up visit or the last 
date of contact:
For patients who discontinue trial medication according to the flow chart, the 
withdrawal/taper period is included. Additionally, if a patient happens to take 
drug for 29 weeks (i.e. 1 week longer than the planned 28 weeks) and then 
begin the withdrawal/taper period, the withdrawal/taper period is included.
For patients who discontinue prior to the 28 week treatment period, e.g. at 
week 25, the follow-up period until the last contact date is included. 
The full follow-up analysis period will be used as a sensitivity analysis to the 
ITT follow-up analysis.

On-treatment: from treatment start date until the date of discontinuation of 
trial medication + 7 days:
For all patients this analysis period includes only the time on trial medication
+ 7 days after taken off trial medication. 
For patients randomised to the withdrawal period, this will include 28 weeks 
of treatment, or for early discontinued patients, the time period on active 
treatment  prior to discontinuation + 7 days, which corresponds to the 7 days 
abrupt withdrawal period.
For patients randomised to the taper period, this will include 28 weeks of 
treatment + the tapering period (of 7 days) + 7 days, or for early discontinued 
patients, simply the time period on randomised active treatment  prior to 
discontinuation + 7 days (because tapering will not be done for patients 
discontinued early).
The on-treatment analysis period will be used to analyse safety.
7.3.1
Primary endpoint analyses
The primary endpoint is the time to first relapse as defined in Section 2.1.2 over the ITT 
follow-up period (see definition in Section 7.3).
The treatment comparison strategy is specified in Section 7.2.  The treatment arms will be 
pooled according to dose, i.e. no distinction will be made between treatment arm randomised 
to taper or treatment arm randomised to withdrawal.


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The equality of the hazard rates will be tested by the Wald test for the treatment effect in a 
stratified Cox proportional hazards model at the two-sided 5% significance level. The model 
includes the treatment effect as the only covariate and is stratified by country. Breslow’s 
method for handling ties will be used.
The same stratified Cox proportional hazards model will be used to estimate the hazard ratio 
of BI 409306 vs. placebo and the asymptotic 95% Wald confidence interval. A hazard ratio 
of less than one favors BI 409306.  The analysis will be implemented using SAS® PROC 
PHREG.  Cox proportional hazard model assumptions will be verified.
In early discontinued patients, if the occurance of a relapse cannot be determined between the 
time of discontinuation and last contact, it is assumed that no relapse has occurred.
Patients who discontinue study medication will be followed until the end of the trial for the 
primary endpoint.  Patients who are lost-to-follow up will be censored for the primary 
endpoint at the date of last known patient contact. 
A sensitivity analysis will be conducted on the primary endpoint, using the Full Follow-up 
period (see definition above).
7.3.2
Secondary endpoint analyses
Key secondary analysis
The key secondary analysis is a restricted maximum likelihood (REML) based approach 
using a mixed model with repeated measurements (MMRM) comparing the change from 
baseline of PANSS positive symptoms score after 28 weeks of treatment (Section 7.2).
The analysis will include the fixed, categorical effects of treatment at each visit, and the fixed 
continuous effects of baseline at each visit. Visit will be treated as the repeated measure with 
an unstructured covariance structure used to model the within-patient measurements.
The statistical model will be as follows: 
yijkm=βjSi + τjk + ϕm + eij
eij~NZ (0, Σ).
yijkm  = response variable for subject i in country m at visit j receiving treatment k
Si = the baseline measurement of subject i, i=1,2,…
βj = coefficient of baseline effect at visit j
τjk = the effect of treatment k at visit j, j=1,…,Z and k=1,…,Y
ϕm = the effect of country m, m=1,…,X
eij = the random error associated with the jth visit of the ith subject. Errors are 
independent between subjects.
Σ = an unstructured covariance matrix.
The Kenward-Roger approximation will be used to estimate denominator degrees of freedom 
and adjust standard errors. Significance tests will be based on least-squares means using a 
two-sided α = 0.05 or the remaining alpha (two-sided ((1- α )% confidence intervals).The 
treatment comparison will be the contrast between treatments at the endpoint visit.


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The key secondary analysis will be performed on the FAS. Patients will be analysed 
according to the stratum to which they belong (regardless of any mis-assignment to treatment 
based on identification of the wrong stratum), as such an error occurs before randomisation 
and is therefore consistent with regulatory guidance. 
Procedures to follow if the analysis fails to converge will be described in the TSAP.
To assess the homogeneity of the treatment effect on the primary endpoint across the levels 
of the country stratification, the same MMRM model will be fitted but replacing the 
treatment-by-visit term by a treatment-by-country-by-visit term. A descriptive p-value of 
treatment effect homogeneity at 28 weeks will be calculated. No overall treatment effect will 
be estimated from this model as it is not interpretable.
Secondary analysis
Time to change in antipshychotic medication will be analysed in the same manner as the 
primary endpoint using the stratified Cox proportional hazards model.
Additionally, the analyses for suicidal ideation and behaviour as assessed by C-SSRS will be 
analysed by calculating a relative risk reduction and providing a 95% confidence interval 
around the RRR. 
The PGI-I score, change in CGI-S and PSP will be summarized descriptively. 
7.3.4
Safety analyses
Adverse events will be coded using the Medical Dictionary for Regulatory Activities
(MedDRA). Standard BI summary tables and listings will be produced. All adverse events 
with an onset between start of treatment and end of the residual effect period (REP), a period 
of 7 days after the last dose of trial medication, will be assigned to the on-treatment period
(see above) for evaluation.
All treated patients will be included in the safety analysis. In general, safety analyses will be 
descriptive in nature and will be based on BI standards. No hypothesis testing is planned.
Statistical analysis and reporting of adverse events will concentrate on treatment-emergent 
adverse events, i.e. all adverse events occurring between start of treatment and end of the 


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residual effect period. 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 MedDRA at 
the database lock.
Laboratory data will be analysed both quantitatively as well as qualitatively. The latter will 
be done via comparison of laboratory data to their reference ranges. Values outside the 
reference range as well as values defined as clinically relevant will be summarised. Treatment 
groups will be compared descriptively with regard to distribution parameters as well as with 
regard to frequency and percentage of patients with abnormal values or clinically relevant 
abnormal values.
Vital signs, physical examinations, or other safety-relevant data observed at screening, 
baseline, during the course of the trial and at the end-of-trial evaluation will be assessed with 
regard to possible changes compared to findings before start of treatment.
Withdrawal/taper period
As described in Section 3.1, during the initial randomisation phase, patients will be 
randomised to either BI 409306 50 mg qd and either abrupt withdrawal or slow taper, or BI 
409306 25 mg qd and either abrupt withdrawal or slow taper, or Placebo. This 7-day, post 28-
week treatment, withdrawal/taper period will assess the impact of abrupt withdrawal versus 
slow taper of study drug to assess drug dependency, and does not affect the primary 28-week 
analysis, for which the doses will be pooled and the assignment to taper vs. withdrawal 
during randomisation will not be taken into account.
Contrary to the primary analysis, in which the randomisation to a withdrawal/taper group will 
be ignored, this safety analysis will assess the following:
-
Change in vital signs 
-
Change in suicidality
-
Adverse events
The analyses will be descriptive only and will be performed only on patients who were 
randomised to an active treatment arm and will include three different comparisons, which 
will analysed hierarchically:
1. the effect of tapering versus abrupt withdrawal when both doses are pooled.
If an effect is apparent, then the next evaluation will be:
2. the effect of dose dependency
and finally,
3. the interaction between dose dependency and the withdrawal/taper.
All these analyses will only use the data obtained during the withdrawal/taper period. 


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7.3.5
Pharmacokinetic and pharmacodynamic analyses
The relationship between the BI 409306 plasma concentrations and efficacy response and AE 
may be assessed descriptively.
In case the primary analysis demonstrates a drug effect, PK analysis on all plasma 
concentrations will be performed by population PK and PK/PD modelling (i.e. exposure-
response). These pharmacometric analyses, if performed, will be reported separately.
7.4
INTERIM ANALYSES
No interim analysis is planned but blinded evaluation of the relapse rate will be conducted on 
an ongoing basis and blinded sample size re-calculations may be performed.  
7.5
HANDLING OF MISSING DATA
All patients will be followed up for relapse to the greatest possible extent as described in 
Section 3.3.4.1. Any patient who has not relapsed will be censored in the analysis of the 
primary endpoint at the time of last patient contact.  For any secondary analysis using RRR, 
all patients in the FAS will be included in the calculation of the RRR, regardless of dropout. 
For the key secondary analyses, if a patient misses a visit, the data will not be imputed. The 
mixed effects model will handle missing data based on a likelihood method under the 
“missing at random” assumption.
Further details about handling missing data will be specified in the TSAP.
7.6
RANDOMISATION
Patients will be randomised in blocks to double-blind treatment equally to three treatment 
arms (25 mg q.d. BI 409306, 50 mg q.d. BI 409306 or placebo).  Additionally, patients will 
be randomised equally to a one-week taper or withdrawal period immediately after the 28 
week treatment discontination.  The randomisations will occur together using the IRT in a 
1:1:1:1:1:1 ratio.  The randomisation will be stratified by country.
BI will arrange for the randomisation and the packaging and labelling of trial medication. The 
randomisation 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 Clinical Trial Report. Access to the 
codes will be controlled and documented.
7.7
DETERMINATION OF SAMPLE SIZE
Sample size considerations are given in Table 7.7: 1 based on background placebo relapse 
rates of 25% and 30% and for hazard redeductions for the combined BI 409306 groups vs. 


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placebo ranging from 45% to 55%, 80% power, a two-sided alpha = 0.05, and 20% dropout 
after six months.
Table 7.7: 1
Trial sample sizes for selected assumptions of hazard ratios and 
proportions of placebo failures, with 20% dropout, 80% power, and 
α=0.05
Hazard reductiona for BI 409306 (both groups combined) to 
placebo
Placebo failure rate
55%a
50%a
45%a
30%
305
385
494
25%
372
470
603
a 55% hazard reduction is the same as a hazard ratio of 0.45; 45% hazard reduction is the same as a hazard ratio of 0.55
The sample size selected was 385 under the assumption that the relapse rate for placebo is 
30% and the hazard reduction for BI 409306 is 50%.  One hundred twenty-nine (129) patients 
will be randomised per treatment group in a 1:1:1, making the target total number of 
randomised patients to be 387.
Seventy-four (74) events (relapses) are needed to be observed to meet the trial objective of
80% power for the comparison of BI 409306 (N=258 for 25 mg q.d. and 50 mg q.d. 
combined) to placebo (N=129).  This will not be an event driven trial, so the trial will end 
when all randomised patients have reached 6 months exposure, regardless of number of 
conversions observed.  
Calculations were performed using ADDPLAN® 6.1.1 statistical package by 
.


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8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY, AND 
ADMINISTRATIVE STRUCTURE
The trial will be carried out in compliance with the protocol, the ethical principles laid down 
in the Declaration of Helsinki, in accordance with the ICH Harmonized Tripartite Guideline 
for Good Clinical Practice (GCP), relevant BI Standard Operating Procedures (SOPs), the EU 
regulation 536/2014  the Japanese GCP regulations (Ministry of Health and Welfare 
Ordinance No. 28, March 27, 1997) and other relevant regulations.
Standard medical care (prophylactic, diagnostic and therapeutic procedures) remains the 
responsibility of the treating physician of the patient.
The investigator will inform the sponsor immediately of any urgent safety measures taken to 
protect the trial patients against any immediate hazard, as well as of any serious breaches of 
the protocol or of ICH GCP.
The Boehringer Ingelheim transparency and publication policy can be found on the following 
web page: trials.boehringer-ingelheim.com. The rights of the investigator and of the sponsor
with regard to publication of the results of this trial are described in the investigator contract. 
As a rule, no trial results should be published prior to finalization of the Clinical Trial Report.
The certificate of insurance coverage is made available to the investigator and the patients, 
and is stored in the ISF.
8.1
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED CONSENT
This trial will be initiated only after all required legal documentation has been reviewed and 
approved by the respective Institutional Review Board (IRB) / Independent Ethics Committee 
(IEC) and competent authority (CA) according to national and international regulations. The 
same applies for the implementation of changes introduced by amendments.
Prior to patient participation in the trial, written informed consent must be obtained from each 
patient (or the patient’s legally accepted representative) according to ICH / GCP and to the 
regulatory and legal requirements of the participating country. Each signature must be 
personally dated by each signatory and the informed consent and any additional patient-
information form retained by the investigator as part of the trial records. A signed copy of the 
informed consent and any additional patient information must be given to each patient or the 
patient’s legally accepted representative.
The investigator must give a full explanation to trial patients based on the patient information 
form. A language understandable to the patient should be chosen, technical terms and 
expressions avoided, if possible. 


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The patient must be 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. 
For Japan only: 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. The consent and re-consenting 
process should be properly documented in the source documentation.
8.2
DATA QUALITY ASSURANCE
A quality assurance audit/inspection of this trial may be conducted by the sponsor, sponsor’s 
designees, or by IRB / IEC or by regulatory authorities. The quality assurance auditor will 
have access to all medical records, the investigator’s trial-related files and correspondence, 
and the informed consent documentation of this clinical trial.
8.3
RECORDS
CRFs for individual patients will be provided by the sponsor. See Section 4.1.5.2 for rules 
about emergency code breaks. For drug accountability, refer to Section 4.1.8.
8.3.1
Source documents
In accordance with regulatory requirements the investigator should prepare and maintain 
adequate and accurate source documents and trial records that include all observations and 
other data pertinent to the investigation on each trial patient. Source data as well as reported 
data should follow good documentation practices and be attributable, legible, 
contemporaneous, original and accurate. Changes to the data should be traceable (audit trail).
Data reported on the CRF must be consistent with the source data or the discrepancies must 
be explained.
The current medical history of the patient may not be sufficient to confirm eligibility for the 
trial and the investigator may need to request previous medical histories and evidence of any 
diagnostic tests. If medical records cannot be obtained prior to randomization, a phone call 
with the treating physician(s) detailing eligibility information must be conducted and 
documented, and the documentation filed with the subject’s source records. If medical 
records cannot be obtained and a call with the treating physician cannot be conducted, the 
TCM or CML should be contacted for further discussion.
During the site visit the sponsor’s CRA or auditor must be granted access to the original 
patient file (please see Section 8.3.2). The investigator must ensure that all patient identifiers 
(e.g. patient’s name, initials, address, phone number, social security number) have properly 


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been removed or redacted from any copy of the patients’ source documents before sending 
them to the sponsor.
If the patient is not compliant with the protocol, any corrective action e.g. re-training must be 
documented in the patient file.
For the CRF, data must be derived from source documents, for example:

Patient identification: gender, year of birth (in accordance with local laws and 
regulations)

Patient participation in the trial (substance, trial number, patient number, date patient was 
informed)

Dates of patient’s visits, including dispensing of trial medication

Medical history (including trial indication and concomitant diseases, if applicable)

Medication history

Adverse events (onset date (mandatory), and end date (if available))

Serious adverse events (onset date (mandatory), and end date (if available))

Concomitant therapy (start date, changes)

Originals or copies of laboratory results and other imaging or testing results, with proper 
documented medical evaluation (in validated electronic format, if available)

Completion of patient’s participation in the trial (end date; in case of premature 
discontinuation document the reason for it).

Prior to allocation of a patient to a treatment into a clinical trial, there must be 
documented evidence in the source data (e.g. medical records) that the trial participant 
meets all inclusion criteria and does not meet any exclusion criteria. The absence of 
records (either medical records, verbal documented feedback of the patient or testing 
conducted specific for a protocol) to support inclusion/exclusion criteria does not make 
the patient eligible for the clinical trial.
8.3.2
Direct access to source data and documents
The sponsor will monitor the conduct of the trial by regular on-site monitoring visits and in-
house data quality review. The frequency of site monitoring will be determined by assessing 
all characteristics of the trial, including its nature, objective, methodology and the degree of 
any deviations of the intervention from normal clinical practice.
The investigator /institution will allow site trial-related monitoring, audits, IRB / IEC review 
and regulatory inspections. Direct access must be provided to the CRF and all source 
documents/data, including progress notes, copies of laboratory and medical test results, which 
must be available at all times for review by the CRA, auditor and regulatory inspector 
(e.g. FDA). They may review all CRFs and informed consents. The accuracy of the data will 
be verified by direct comparison with the source documents described in Section 8.3.1. The 
sponsor will also monitor compliance with the protocol and GCP.


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8.3.3
Storage period of records
Trial site(s):
The trial site(s) must retain the source and essential documents (including ISF) according to 
contract or the local requirements valid at the time of the end of the trial (whatever is longer).
Sponsor:
The sponsor must retain the essential documents according to the sponsor’s SOPs.
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS
BI is responsible to fulfil their legal and regulatory reporting obligation in accordance with 
regulatory requirements. 
8.5
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY
Individual patient data obtained as a result of this trial is considered confidential and 
disclosure to third parties is prohibited with the exceptions noted below. Patient privacy will 
be ensured by using patient identification code numbers.
Data protection and data security measures are implemented for the collection, storage and 
processing of patient data in accordance with the principles 6 and 12 of the World Health 
Organization (WHO) GCP handbook.
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.
8.5.1
Collection, storage and future use of biological samples and corresponding 
data 
Measures are in place to comply with the applicable rules for the collection, storage and 
future use of biological samples from clinical trial participants and the corresponding data, in 
particular

A Quality Management System has been implemented to ensure the adherence with 
the Principles of Good Clinical Practice as outlined in 'Note For Guidance On Good 
Clinical Practice' (CPMP/ICH/13 5/95)

The BI-internal facilities storing and analysing biological samples and data from 
clinical trial participants as well as the laboratories' activities for clinical trials 
sponsored by Boehringer Ingelheim are regularly audited. The analytical groups and 
the banking facility are therefore assessed to be qualified for the storage and use of 
biological samples and data collected in clinical trials.

Samples and data are used only if an appropriate informed consent is available.


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8.6
TRIAL MILESTONES
The start of the trial is defined as the date when the first patient in the whole trial signs 
informed consent.
The end of the trial is defined as the date of the last visit of the last patient in the whole trial
(“Last Patient Completed”). The “Last Patient Last Treat” date is defined as the date on 
which the last patient at an individual trial site ends trial medication (as scheduled per 
protocol or prematurely). Individual investigators will be notified of SUSARs occurring with 
the trial medication until 30 days after “Last Patient Last Treat” at their site.
Early termination of the trial is defined as the premature termination of the trial due to any 
reason before the end of the trial as specified in this protocol.
Temporary halt of the trial is defined as any unplanned interruption of the trial by the 
sponsor with the intention to resume it.
Suspension of the trial is defined as an interruption of the trial based on a Health Authority 
request.
The IEC / competent authority in each participating EU member state will be notified about 
the trial milestones according to the respective laws.
A final report of the clinical trial data will be written only after all patients have completed 
the trial in all countries (EU or non-EU) to incorporate and consider all data in the report.
The sponsor will submit to the EU database a summary of the final trial results within one 
year from the end of a clinical trial as a whole, regardless of the country of the last patient
(EU or non-EU).
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL
The trial is sponsored by Boehringer Ingelheim (BI).
A Coordinating Investigator is responsible to coordinate investigators at the different sites 
participating in this trial. Tasks and responsibilities are defined in a contract. Investigators 
will be selected to participate who have experience with conducting trials in patients with 
schizophrenia.
Relevant documentation on the participating (Principal) Investigators (e.g. their curricula 
vitae) will be filed in the (Investigator Site File) ISF. The investigators will have access to the 
BI clinical trial portal (Clinergize) to facilitate document exchange and maintain electronic 
ISF. 
BI 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,


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-
ensure appropriate training and information of Local Clinical Monitors (CML), 
Clinical Research Associates (CRAs), and investigators of participating countries.
The organisation of the trial in the participating countries will be performed by the respective 
local or regional BI-organisation (Operative Unit, OPU) in accordance with applicable 
regulations and BI SOPs, or by a Contract Research Organisation (CRO) with which the 
responsibilities and tasks will have been agreed and a written contract filed before initiation 
of the clinical trial.
Data Management and Statistical Evaluation will be done by BI according to BI SOPs.
Tasks and functions assigned in order to organise, manage, and evaluate the trial are defined 
according to BI SOPs. A list of responsible persons and relevant local information can be 
found in the ISF.
A service provider has been selected to provide a tablet-based solution for select instruments 
and scales for patient assessment. This vendor will also support tasks related to rater 
prequalification, rater training, provision of rater materials, and central review of PANSS 
assessments for quality. These responsibilities and tasks will be defined in a written contract 
before initiation of the clinical trial.
A central laboratory service and an IRT vendor will be used in this trial. Details will be 
provided in the IRT Manual and Central Laboratory Manual, available in the ISF. In addition, 
a vendor will be used to to monitor medication adherence using a smartphone application.


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9.
REFERENCES
9.1
PUBLISHED REFERENCES
P17-01959 
Ince B, Eskazan E, Hurdogan O, Koseoglu L, Ferhanoglu B. Diffuse large B-
cell lymphoma and multifocal ischemic stroke. 23rd Eur Stroke Conf and 8th 
Stroke Mtg for Nurses, Physiotherapists, Speech and Occupational Therapists, 
Study Research Assistants, Nice, 6 - 9 May 2014. Cerebrovasc Dis 
2014;37(Suppl 1): 600.
R03-0520 
028 CGI clinical global impressions. GuyW. ECDEU Assessment Manual for 
Psychopharmacology. Rockville: U.S. Department of Health, Education, and 
Welfare, Public Health Service, Alcohol, Drug Abuse, and Mental Health 
Administration , 218 - 222 (1976)
R08-1147 
Posner K. State of the science: measurement of suicidal adverse events and the
Columbia Suicide Severity Rating Scale. 47th NCDEU Ann Mtg, Boca Raton, 
11 -14 Jun 2007. 2007:15.
R12-3534
Lieberman JA, Stroup TS, McEvoy JP, Swartz MS, Rosenheck RA, Perkins 
DO, et al. Clinical Antipsychotic Trials of Intervention Effectiveness 
(CATIE) Investigators. Effectiveness of antipsychotic drugs in patients with 
chronic schizophrenia. N Engl J Med 2005;353(12):1209-1223.
R13-5061
Kay SR, Fiszbein A, Opler LA. The positive and negative syndrome scale 
(PANSS) for schizophrenia. Schizophr Bull. 1987;13(2):261-76.
R15-1782
Lieberman JA, Perkins D, Belger A, Chakos M, Jarskog F, Boteva K, et al.   
The early stages of schizophrenia: speculations on pathogenesis,   
pathophysiology, and therapeutic approaches. Biol Psychiatry 
2001;50(11):884-  897.
R16-1601  
Mizrahi R, Addington J, Rusjan PM, Suridjan I, Ng A, Boileau I, et al. 
Increased stress-induced dopamine release in psychosis. Biol Psychiatry 
2012;71(6):561-567.
R16-2785
Kleiman RJ, Chapin DS, Christoffersen C, Freeman J, Fonseca KR, 
Geoghegan KF, et al. Phosphodiesterase 9A regulates central cGMP and 
modulates responses to cholinergic and monoaminergic perturbation in vivo. J 
Pharmacol Exp Ther 2012;341(2):396-409.
R17-0563
Stahl SM, editor. Stahl's essential psychopharmacology: neuroscientific basis
  
and practical application. 4th ed. Cambridge: Cambridge University Press;
  
2013.


Boehringer Ingelheim
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Page 71 of 81
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (14.0) / Saved on: 17 Oct 2016
R17-0969
Kapur S. How antipsychotics become anti-'psychotic' - from dopamine to
  
salience to psychosis. Trends Pharmacol Sci 2004;25(8):402-406.
R17-0970
Kapur S. Psychosis as a state of aberrant salience: a framework linking
biology, phenomenology, and pharmacology in schizophrenia. Am J 
Psychiatry 2003;160(1):13-23.
R17-0971
Remington G, Foussias G, Agid O, Fervaha G, Takeuchi H, Hahn M. The
neurobiology of relapse in schizophrenia. Schizophr Res 2014;152(2/3):381-
390.
R17-0972
Emsley R, Chiliza B, Asmal L, Harvey BH. The nature of relapse in
schizophrenia. BMC Psychiatry 2013;13:50
R17-0973
Howes OD, Kambeitz J, Kim E, Stahl D, Slifstein M, Abi-Dargham A, et al. 
The nature of dopamine dysfunction in schizophrenia and what this means for
  
treatment: meta-analysis of imaging studies. Arch Gen Psychiatry 2012;69(8):
  
776-786.
R17-2075 
Wolter A, Preuss U, Krischke N, Wong JW, Langosch JM, Zimmermann J. 
Recovery and remission in schizophrenia: results from a naturalistic 2-year 
follow-up inpatient study. Fortschr Neurol Psychiatr 2010;78(8):468-474.
R17-2077 
Lafeuille MH, Frois C, Cloutier M, Duh MS, Lefebvre P, Pesa J, et al. Factors
associated with adherence to the HEDIS quality measure in medicaid patients
  
with schizophrenia. Am Health Drug Benefits 2016;9(7):399-410.
R17-2078 
Chi MH, Hsiao CY, Chen KC, Lee LT, Tsai HC, Lee IH, et al. The 
readmission rate and medical cost of patients with schizophrenia after first
  
hospitalization - a 10-year follow-up population-based study. Schizophr Res
2016;170(1):184-190.
R17-2079 
Ascher-Svanum H, Zhu B, Faries DE, Salkever D, Slade EP, Peng X. The cost 
of relapse and the predictors of relapse in the treatment of schizophrenia. BMC
  
Psychiatry 2010;10:2
R17-2080 
Hong J, Windmeijer F, Novick D, Haro JM, Brown J. The cost of relapse in
  
patients with schizophrenia in the European SOHO (Schizophrenia Outpatient
  
Health Outcomes) study. Prog Neuropsychopharmacol Biol Psychiatry 
2009;33:835-841.
R17-2081 
Boyer L, Millier A, Perthame E, Aballea S, Auquier P, Toumi M. Quality of 
life is predictive of relapse in schizophrenia. BMC Psychiatry 2013;13:15


Boehringer Ingelheim
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Page 72 of 81
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001-MCS-40-106-RD-03 (14.0) / Saved on: 17 Oct 2016
R17-2082 
Kohler O, Horsdal HT, Baandrup L, Mors O, Gasse C. Association between 
Global Assessment of Functioning scores and indicators of functioning, 
severity, and   prognosis in first-time schizophrenia. Clin Epidemiol 
2016;8:323-332.
R17-2083 
Xiao J, Mi W, Li L, Shi Y, Zhang H. High relapse rate and poor medication 
adherence in the Chinese population with schizophrenia: results from an 
observational survey in the People's Republic of China. Neuropsychiatr Dis  
Treat 2015;11:1161-1167.
R17-2254
Nasrallah H, Morosini PL, Gagnon DD. Reliability, validity and ability to
  
detect change of the Personal and Social Performance scale in patients with
  
stable schizophrenia. Psychiatry Res 2008;161:213-224.
R17-2735
Wu J, He X, Liu L, Ye W, Montgomery W, Xue H, et al. Health care resource 
use  and direct medical costs for patients with schizophrenia in Tianjin, 
People's Republic of China. Neuropsychiatr Dis Treat 2015;11:983-990.
9.2
UNPUBLISHED REFERENCES
U12-1034-01
 A randomised, double-blind,
placebo-controlled (within dose groups) Phase I study to assess the safety,
tolerability and pharmacokinetics of single rising doses 0.5 mg to 500 mg of
BI 409306 administered orally in healthy male volunteers 1289.1 19-Jan-2012.
U12-2165-01
 Randomised, double
blind, placebo-controlled, parallel-group proof of mechanism study to assess 
the pharmacokinetics and to evaluate the pharmacodynamic effect of different 
single oral doses of BI 409306 in healthy male volunteers. 1289.3. 17-Sep-
2012.
U13-1182-01
 Safety, tolerability,
pharmacokinetics, and pharmacodynamics of multiple-rising doses of BI 
409306 film-coated tablets given orally q.d. or bid for 14 days in young 
healthy and elderly healthy male/female volunteers (randomised, double-blind, 
placebo-controlled within dose groups Phase I study). 1289.2. 20 Feb 2013.
U13-1303-01
 Safety, tolerability,
pharmacokinetics, and pharmacodynamics of multiple rising doses of BI
409306 film-coated tablets given orally q.d. for 14 days in young and elderly
healthy male/female volunteers (randomized, double-blind, placebo controlled
within dose groups Phase I study). 1289.17. 22 Feb 2013.
c03808525-01
 A randomized, double-blind, double
dummy, placebo controlled, three-way crossover study to assess cardiac


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effects after single oral doses of BI 409306 under resting and exercise
conditions in healthy male volunteers. 1289.28. 17 June 2016.
c09168615-01 
 Other Clinical Report. Randomized, parallel-group, double-blind 
study of systemic and ocular safety and pharmacokinetics of BI 409306 in 
patients with schizophrenia, Alzheimer’s disease, and age-comparable healthy 
volunteers: interim analysis on patients with schizophrenia and age-
comparable healthy volunteers. 1289.27. 27 Oct 2016
c09340078-01 
 A phase II randomised, double-
blinded, placebo-controlled study to evaluate the efficacy, safety, and 
tolerability of four orally administrated doses of BI 409306 during a 12-week 
treatment period in patients with schizophrenia on stable antipsychotic 
treatment. 1289.6. 10Jan2017.
c01694347-09 Investigator’s Brochure: BI 409306 in Alzheimer’s Disease, Prevention of 
first episode psychosis in subjects with Attenuated Psychosis Syndrome, 
Reduction of relapse in patients with Schizophrenia.


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10.
APPENDICES
10.1
PHARMACOKINETIC ANALYSES
For pharmacokinetic analysis and displays, concentrations will be used in the same format as 
reported in the bioanalytical report. Only concentrations within the validated concentration 
range and actual sampling times will be used for the reporting of pharmacokinetic 
parameters. Plasma concentrations will be plotted graphically versus time for all subjects as 
listed in the drug plasma concentration-time tables.
For the presentation of the mean profiles, the arithmetic and geometric mean and the planned 
blood sampling times will be used.
10.1.1
Handling of missing data
Concentration data identified with NOS (no sample available), NOR (no valid result), NOA 
(not analysed), BLQ (below the limit of quantification), and NOP (no peak detectable) will be 
ignored. Descriptive statistics of concentrations at specific time points will be calculated only 
when at least 2/3 of the individuals have concentrations within the validated concentration 
range. The overall sample size to decide whether the “2/3 rule” is fulfilled will be based on 
the total number of samples intended to be drawn for that time point (i.e. BLQ, NOR, NOS,
NOA, NOP are included).
10.2
HANDLING PROCEDURE OF BLOOD SAMPLES FOR PLASMA 
CONCENTRATION-TIME MEASUREMENTS
After completion of the study the plasma samples may be used for further methodological 
investigations, e.g. for stability testing. However, only data related to the analyte(s) and/or its 
metabolite(s) will be generated by these additional investigations. The study samples will be 
discarded after completion of the additional investigations but not later than 3 years after the 
final study report has been signed.
Refer to the lab manual for detailed instructions for obtaining, handling and shipping PK 
samples. 


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10.3
TIME SCHEDULE FOR PHARMACOKINETIC (PK) BLOOD 
SAMPLING
Table 10.3: 1
Time schedule for PK blood sampling (BI 409306)
Visit
Day
Time Point 
[hh:min]
CRF Time
/PTM1
Event
Sample 
No.
2
1
Just before drug 
administration
-0:05
PK Blood
1
0:00
0:00
Drug 
administr.
---
0:45 minutes
(15 minutes – 1:00 h)
0:45
PK Blood
2
1:30 
(1:00 to 2:00 h)
1:30
PK Blood
3*
End of study 
procedures/visit 
(After 2 hour post 
dose.  No upper time 
window applied)
2:00
PK Blood
4*
8
85
8:00-24:00
8:00-24:00
PK Blood
5
16
197
8:00-24:00
8:00-24:00
PK Blood
6
1.
Planned time
*Due to wide sampling window, the 3nd and 4rd samples must be at least 30 minutes 
from the previous collected sample (i.e. all PK samples are to be collected within their 
respective sampling window, plus they will be at least 30 minutes apart from each 
other).
The two metabolites CD 13896 and CD 14084 will be analysed if BI 409306 plasma 
concentration is BLQ in the through samples from Visits 8 and 16, and, if BI 409306 plasma 
concentrations are above BLQ in two of the samples from Visit 2. 


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
Number of global amendment
1
Date of CTP revision
08 Nov 2017
EudraCT number
2017-002369-23
BI Trial number
1289-0049
BI Investigational Product(s)
BI 409306
Title of protocol
A phase II randomised, double-blind, placebo-
controlled study to evaluate the efficacy, safety, and 
tolerability of orally administered BI 409306 during a 
28-week treatment period as adjunctive therapy to 
antipsychotic treatment for the prevention of relapse 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
Synopsis
Description of change
Secondary efficacy endpoints:
Key secondary endpoint:

Change from baseline in Positive and 
Negative Symptom Score (PANSS) positive 
symptoms score after 28 weeks of 
treatment.
Secondary endpoints:

Time to new prescription or increase in 
dose of an ongoing antipsychotic 
medication.

Change from baseline in Clinical Global 
Impressions–Severity (CGI-S) scale score 
after 28 weeks of treatment.

Patient Global Impressions-Improvement 
(PGI-I) scale score after 28 weeks of 


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treatment.

Suicidal ideation and behaviour as assessed 
by C-SSRS after 28 weeks of treatment.

Change from baseline in Personal and 
Social Performance scale (PSP) score after 
28 weeks of treatment.
Rationale for change
Key secondary endpoint added
Section to be changed
2.1.3 Secondary Endpoints
Description of change
Secondary efficacy endpoints:
Key secondary endpoint:

Change from baseline in Positive and 
Negative Symptom Score (PANSS) positive 
symptoms score after 28 weeks of 
treatment.
Secondary endpoints:

Time to new prescription or increase in 
dose of an ongoing antipsychotic 
medication.

Change from baseline in Clinical Global 
Impressions–Severity (CGI-S) scale score 
after 28 weeks of treatment.

Patient Global Impressions-Improvement 
(PGI-I) scale score after 28 weeks of 
treatment.

Suicidal ideation and behaviour as assessed 
by C-SSRS after 28 weeks of treatment.
Change from baseline in Personal and Social 
Performance scale (PSP) score after 28 weeks of 
treatment.
Rationale for change
Key secondary endpoint added
Section to be changed
Description of change
Rationale for change
 
Section to be changed
3.3.2
Inclusion criteria
Description of change
3. Patients currently taking a stable dose of 
antipsychotic medication(s) for at least 8 12 weeks 


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prior to randomisation.
4. Detectable level of current antipsychotic 
medication(s) in plasma or serum from blood 
drawn at Visit 1 (unless no assay is available for 
the antipsychotic(s) currently prescribed).
6. CGI-S score ≤4 at Visits 1 and 2.
7. PANSS total score <80 and a score of ≤ 4 on all
individual PANSS items conceptual 
disorganization, hallucinatory behavior, 
suspiciousness, and unusual thought content at 
Visit 1.
Rationale for change
#3 and #6: To ensure clinical stability of patients 
entering the study.
#4: Updated to reflect that the lab will analyse
plasma.
#7: Clarification that the four items listed in this 
criterion must be ≤ 4.
Section to be changed
7.2
NULL AND ALTERNATIVE 
HYPOTHESES
Description of change
Step 1: If p(1) ≤ 0.05 then both hypotheses are 
rejected and both doses are declared statistically 
significant and testing ends.  If p(1) > 0.05, then 
H0(1) is accepted not rejected and the testing 
proceeds to Step 2.  
Step 2: If p(2) ≤ 0.025, then H0(2) is rejected and this 
dose is declared statistically significant.  If p(2) > 
0.025, then all doses fail.  
The remaining alpha after the testing of the primary 
endpoint (Steps 1 and 2) will be used to test the key 
secondary endpoint of change from baseline in 
PANSS positive symptoms. The hypotheses to be 
tested are:
H0(3): Mean change from baseline of PANSS 
positive symptom score after 28 weeks of 
treatment with BI 409306
≥ Mean change from baseline of PANSS 
positive symptom score after 28 weeks of 
treatment with placebo
Ha(3): Mean change from baseline of PANSS 


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positive symptom score after 28 weeks of 
treatment with BI 409306
< Mean change from baseline of PANSS 
positive symptom score after 28 weeks of 
treatment with placebo
The first of the key secondary hypothesis to be 
tested will be based on the pooled active treatment 
arms (i.e. BI 409306 50 mg q.d. and BI 409306 25 
mg q.d.), over 28 weeks (excluding the 
withdrawal/taper period).
Similar to the primary endpoint, if the first 
hypothesis test (on the pooled doses) is determined 
to be statistically significant, the individual doses 
will be tested for superiority using Hochberg’s 
step-up test as described above. 
Rationale for change
Key secondary endpoint added
Section to be changed
7.3.2
Secondary endpoint analyses
Description of change
Key secondary analysis
The key secondary analysis is a restricted 
maximum likelihood (REML) based approach 
using a mixed model with repeated measurements 
(MMRM) comparing the change from baseline of 
PANSS positive symptoms score after 28 weeks of 
treatment (Section 7.2).
The analysis will include the fixed, categorical 
effects of treatment at each visit, and the fixed 
continuous effects of baseline at each visit. Visit 
will be treated as the repeated measure with an 
unstructured covariance structure used to model the 
within-patient measurements.
The statistical model will be as follows: 
yijkm=βjSi + τjk + ϕm + eij
eij~NZ (0, Σ).
yijkm  = response variable for subject i in 
country m at visit j receiving treatment k
Si = the baseline measurement of subject i, 
i=1,2,…
βj = coefficient of baseline effect at visit j
τjk = the effect of treatment k at visit j, 
j=1,…,Z and k=1,…,Y
ϕm = the effect of country m, m=1,…,X
eij = the random error associated with the jth


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visit of the ith subject. Errors are 
independent between subjects.
Σ = an unstructured covariance matrix.
The Kenward-Roger approximation will be used to 
estimate denominator degrees of freedom and 
adjust standard errors. Significance tests will be 
based on least-squares means using a two-sided α = 
0.05 or the remaining alpha (two-sided ((1- α )% 
confidence intervals).The treatment comparison 
will be the contrast between treatments at the 
endpoint visit.
The key secondary analysis will be performed on 
the FAS. Patients will be analysed according to the 
stratum to which they belong (regardless of any 
mis-assignment to treatment based on identification 
of the wrong stratum), as such an error occurs 
before randomisation and is therefore consistent 
with regulatory guidance. 
Procedures to follow if the analysis fails to 
converge will be described in the TSAP.
To assess the homogeneity of the treatment effect 
on the primary endpoint across the levels of the 
country stratification, the same MMRM model will 
be fitted but replacing the treatment-by-visit term 
by a treatment-by-country-by-visit term. A 
descriptive p-value of treatment effect homogeneity 
at 28 weeks will be calculated. No overall 
treatment effect will be estimated from this model 
as it is not interpretable.
Secondary analysis
Rationale for change
Key secondary endpoint added
Section to be changed
Description of change
Rationale for change
Section to be changed
7.5
HANDLING OF MISSING DATA
Description of change
For the key secondary analyses, if a patient misses 


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a visit, the data will not be imputed. The mixed 
effects model will handle missing data based on a 
likelihood method under the “missing at random” 
assumption.
Rationale for change
Key secondary endpoint added
Section to be changed
8.1 TRIAL APPROVAL, PATIENT 
INFORMATION, INFORMED CONSENT
Description of change
For Japan only: 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. These two sentences are only 
applicable in Japan.
Rationale for change
These two sentences are only applicable in Japan.


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c14883409
2.0
clinical-trial-protocol-version-02
A phase II randomised, double-blind, placebo-controlled study to evaluate the
efficacy, safety, and tolerability of orally administered BI 409306 during a 28-week
treatment period as adjunctive therapy to antipsychotic treatment for the prevention
of relapse in patients with schizophrenia.
Author-Trial Clinical Monitor
08 Nov 2017 15:00 CET
Approval-Biostatistics
08 Nov 2017 16:45 CET
Approval-Team Member Medicine
08 Nov 2017 18:02 CET
Approval-Clinical Pharmacokinetics
09 Nov 2017 15:17 CET
Approval-Therapeutic Area 
09 Nov 2017 15:38 CET
Verification-Paper Signature
Completion
09 Nov 2017 22:46 CET


Boehringer Ingelheim 
Page 2 of 2
Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c14883409
2.0

SAP_001.pdf: 
Reference Document “Template Trial Statistical Analysis Plan – template”
001-MCS-40-415_RD-02 (1.0) / Saved on: 25 Jul 2016
TITLE PAGE
TRIAL STATISTICAL ANALYSIS PLAN
c20537098-04
BI Trial No.:
1289-0049
Title:
A phase II randomised, double-blind, placebo-controlled study to 
evaluate the efficacy, safety, and tolerability of orally administered BI 
409306 during a 28-week treatment period as adjunctive therapy to 
antipsychotic treatment for the prevention of relapse in patients with 
schizophrenia. [c14883409-02]
Investigational
Product(s):
BI 409306
Responsible trial 
statistician(s):
Telephone: 
Date of statistical 
analysis plan:
17 MAR 2021 SIGNED
Version:
V4
Page 1 of 35
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2021 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(S) ..................................................................................9
5.2
SECONDARY ENDPOINT(S) ..........................................................................10
5.2.1
Key secondary endpoint .....................................................................................10
5.2.2
Secondary endpoints...........................................................................................10
5.4
OTHER VARIABLES........................................................................................11
5.4.1 
Demographic and other baseline characteristics .............................................11
5.4.2 
Treatment compliance and treatment exposure ..............................................12
5.4.3 
Pharmacokinetic assessments ............................................................................12
5.4.4 
Pharmacogenomic evaluation............................................................................13
6.
GENERAL ANALYSIS DEFINITIONS ..........................................................15
6.1
TREATMENT(S)................................................................................................15
6.2
IMPORTANT PROTOCOL DEVIATIONS....................................................17
6.3
SUBJECT SETS ANALYZED ..........................................................................17
6.5
POOLING OF CENTRES .................................................................................18
6.6
HANDLING OF MISSING DATA AND OUTLIERS....................................18
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS ...................19
7.
PLANNED ANALYSIS......................................................................................21
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS.........21
7.2
CONCOMITANT DISEASES AND MEDICATION .....................................21
7.3
TREATMENT COMPLIANCE........................................................................21
7.4
PRIMARY ENDPOINT(S) ................................................................................22
7.4.1
Primary efficacy analysis...................................................................................22
7.4.2
Sensitivity analysis .............................................................................................25
7.5
SECONDARY ENDPOINT(S) ..........................................................................26
7.5.1
Key secondary endpoint(s).................................................................................26
7.5.2
(Other) Secondary endpoint(s) ..........................................................................28
7.7
EXTENT OF EXPOSURE.................................................................................29
7.8
SAFETY ANALYSIS..........................................................................................29
7.8.1
Adverse events.....................................................................................................29
7.8.2
Laboratory data ..................................................................................................30


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7.8.3
Vital signs.............................................................................................................30
7.8.4
ECG......................................................................................................................30
7.8.5
Others...................................................................................................................31
8.
REFERENCES....................................................................................................32
9.3
ADDITIONAL ANALYSIS FOR IMPACT OF THE COVID-19 
PANDEMIC ON THE TRIAL ..........................................................................34
9.3.1
Start and end of COVID-19 disruption.............................................................34
9.3.2
Additional analysis..............................................................................................34
10.
HISTORY TABLE..............................................................................................35


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LIST OF TABLES
Table 6.1: 1
Treatments and their labels per randomization list ..........................................15
Table 6.1: 2
Treatments and their labels in specified analyses ............................................15
Table 6.3: 1
Subject sets analyzed........................................................................................17
Table 6.7: 1
Visit calculation relative to study start.............................................................19
Table 10: 1
History table .....................................................................................................35


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2.
LIST OF ABBREVIATIONS
Term
Definition / description
AE
Adverse Event
AR(1)
Autoregressive covariance matrix of order 1
BI 
Boehringer Ingelheim
CGI-I
Clinical Global Impressions – Improvement
CGI-S
Clinical Global Impressions – Severity
C-SSRS
Columbia- Suicide Severity Rating Scale
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
CYP
Cytochrome P450
EC
Exclusion Criteria
ECG
Electrocardiogram
EOS
End of Study
EOT
End of Treatment
eCRF
Electronic Case Report Form
FAS
Full Analysis Set
FU
Follow Up
H0
Null Hypothesis
Ha
Alternative Hypothesis
HR
Hazard Ratio
IC
Inclusion Criteria
ICD-10
International Statistical Classification of Diseases and Related Health 
Problems, 10th Revision
ICF
Informed Consent Form
ICH E9
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human use, E9-Statistical Principles for 
Clinical Trials
IPD
Important Protocol Deviation
ITT
Intent To Treat


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Term
Definition / description
LLT
Lower Level Term
LTFU
Lost to Follow-up
Max
Maximum
Min
Minimum
MINI
Mini-International Neuropsychiatric Interview
MMRM
Mixed Model with Repeated Measurements
N
Sample Size
PANSS
Positive and Negative Syndrome Scale
PGI-I
Patient Global Impressions-Improvement
PK
Pharmacokinetic
PSP
Personal and Social Performance
PT
Preferred Term
RRR
Relative Risk Reduction
RS
Randomized Set
SD
Standard deviation
SOC
System Organ Class
TOEPH
Toeplitz with Heterogeneous Variances
TOEP
standard Toeplitz matrix
TS
Treated Set
TSAP
Trial Statistical Analysis Plan
T/W
Taper/Withdrawal
VAS
Visual Analogue Scale


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3.
INTRODUCTION
As per ICH E9, 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 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, randomization.
SAS® Version 9.4 or higher will be used for all analyses.


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4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY
CTP section 7.5 specifies: All patients will be followed up for relapse […]. Any patient who 
has not relapsed will be censored in the analysis of the primary endpoint at the time of last 
patient contact. In fact, the primary endpoint analysis is the ITT analysis, which is indicated 
in CTP section 7.3 to include relapses only during the 28-week planned on-treatment period. 
See Section 6.6 for corrections.
The following additional analyses, which were not mentioned in the CTP, were added:

Time to Discontinuation was added as a further endpoint. 

Time to Treatment Discontinuation or Relapse was added as a sensitivity 
analysis to the primary endpoint 
Recruitment to this study was stopped early by the Sponsor due to slow enrolment. As a 
result, statistical power is reduced because of sample size reduction, analyses remain the 
same as planned, see more details in Section 7.4. A fast-track approach will be taken in order 
to expedite decision making and for preparation of the planned phase III trials, see more 
details in Section 9.2.
Details surrounding the planned assessment of the impact of the COVID-19 pandemic on the 
trial, are specified in section 9.3.
Hazard ratio calculated from the Cox proportional hazard model and a 95% confidence 
interval around the HR will be provided for primary and secondary endpoint; relative risk 
reduction and a 95% confidence interval around the RRR will be provided for further 
endpoints.
Due to the fact that there were cases where the site was not able to enter the data into the iPad
in a timely manner and
was unable to confirm with the site the actual date the 
assessment was completed, visit start date as recorded on the CRF will be used as the analysis 
date.
confirmed that all assessments started on the visit date and therefore it is a 
reasonable assumption to use the CRF recorded visit date as the analysis date.


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5.
ENDPOINTS
The overall objective of this study is to evaluate the efficacy and safety of BI 409306 during 
a 28-week period in patients with schizophrenia, who are on stable background antipsychotic 
treatment. Refer to Sections 2 and 7 of the CTP for more details on the endpoints of the 
study.
5.1
PRIMARY ENDPOINT(S)
The primary endpoint will be used as defined in the revised CTP, Section 2.1.2:
The primary endpoint is time to first relapse until study end (planned at 28 weeks). Time of 
relapse will be obtained by selecting the earliest date from any, or all of the following 6 
criteria:

Time to hospitalization (involuntary or voluntary admission), intensive outpatient therapy 
or use of home treatment, as an alternative to hospitalization, for decompensation of  
schizophrenia symptoms

Time to an assessment on the Clinical Global Impressions - Severity (CGI-S) of ≥ 5 
(markedly ill) and either:
-
an increase on any of the following individual PANSS items: conceptual 
disorganization, hallucinatory behavior, suspiciousness, unusual thought content -
to a score > 4 with an absolute increase of ≥2 on that specific item since 
randomisation 
or 
-
an increase on any of the following individual PANSS items: conceptual 
disorganization, hallucinatory behavior, suspiciousness, unusual thought content -
to a score > 4 and an absolute increase of ≥4 on the combined 4 PANSS items  
since randomisation
or
-
PANSS total score increase of ≥25% relative to baseline score or an increase of 
≥10 points if baseline score was ≤40

Time to a prescription for a new antipsychotic or time to an increase in dose of an 
ongoing antipsychotic medication for significant worsening of schizophrenia symptoms

Time to clinically significant homicidal ideation, in the investigator’s judgement 

Time to suicidal behavior, or time to assessment of suicidal ideation type 4 or 5 on the 
Columbia Suicide Severity Rating Scale (C-SSRS) 

Time to deliberate self-injury and/or violent behaviour resulting in suicide or in clinically 
significant injury to the patient or another person or property damage, in the 
investigator’s judgement


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5.2
SECONDARY ENDPOINT(S)
5.2.1
Key secondary endpoint
The key secondary endpoint as described in Section 2.1.3 in the revised CTP is:
Change from baseline in Positive and Negative Symptom Score (PANSS) positive symptoms 
score after 28 weeks of treatment.
See section 6.7 for details regarding the definition of “baseline”.
5.2.2
Secondary endpoints
The secondary endpoints are described in Section 2.1.3 in the revised CTP:

Time to new prescription or increase in dose of an ongoing antipsychotic medication.

Change from baseline in Clinical Global Impressions–Severity (CGI-S) scale score
after 28 weeks of treatment.

Patient Global Impressions-Improvement (PGI-I) scale score after 28 weeks of 
treatment.

Suicidal ideation and behaviour as assessed by C-SSRS after 28 weeks of treatment.

Change from baseline in Personal and Social Performance scale (PSP) score after 28 
weeks of treatment.
See section 6.7 for details regarding the definition of “baseline”.


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5.4
OTHER VARIABLES
5.4.1 
Demographic and other baseline characteristics
Demographics:

Sex

Race

Ethnicity

Region (North America, Europe, Asia)

Country (Canada, USA, France, Japan, Taiwan, South Korea)

Age [years]

Age in classes (18-<35; 35-<50; >=50)

Weight (kg) 

Height (cm)

Body Mass Index [kg/m2]: Weight [kg]/(Height[m]*Height[m]), as continuous 
variable and in classes (<18.5; >=18.5 to <25; >=25 to <30; >=30)

Ethnicity

Smoking history 

Alcohol Consumption 

Cannabis usage

Time since diagnosis of schizophrenia [years]


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
Education (self) [years]

Education (childrearing mother) [years]

Student (within past 6 months) 

Living arrangements 

Employment status
Other baseline characteristics:

Baseline conditions/Medical history

Baseline clinical assessments (CGI-S, C-SSRS, PANSS (total, conceptual 
disorganization, hallucinatory behavior, suspiciousness, unusual thought content
positive, negative, general), PSP (total, socially useful activity, personal and social 
relationships, self-care, disturbing and aggressive behaviour) AIMS, EQ-5D-5L)

Concomitant Antipsychotic Medication

Concomitant Medication

Concomitant Non-Drug Therapy

Psychotherapy
Pharmacogenomic data:

CYP2C19 (UM, EM, IM, PM, ND, Missing)
5.4.2
Treatment compliance and treatment exposure
Treatment compliance:
Treatment compliance is assessed via the use of the AICURE device and the eCRF. Average 
adjusted compliance will be calculated and displayed. Compliance will be categorized into 
classes: <80%, >=80% to <=100%, >100%.
Treatment exposure:

Exposure is calculated as (drug stop date) – (drug start date) +1

Treatment exposure classes (<=102 days, 103 days to <=204 days, >204 days)
The Taper/Withdrawal (T/W) period is included in the treatment exposure calculation.
Study observation periods:

Each patient’s observation time contribution, for the Intent to Treat (ITT) follow-up, 
and Full follow-up period, will be summarized, for more details see Section 6.1.
5.4.3 
Pharmacokinetic assessments
As described in Section 5.3.1 of the CTP:

C0:45h: measured plasma concentration of BI 409306 in plasma 0:45h after a single 
dose of BI 409306


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
C1.5h: measured plasma concentration of BI 409306 in plasma 1.5h after a single dose 
of BI 409306

C2h: measured plasma concentration of BI 409306 in plasma 2h or more after a single 
dose of BI 409306
From the individual pharmacokinetic parameters C0:45h and C1.5h, mean pharmacokinetic 
parameters will be calculated by descriptive statistics if data allow.
At the post-randomisation visits, the following pharmacokinetic parameters will reported for 
each analyte:

Cpress: residual concentration of BI 409306 and metabolites CD 13896 and CD 14084 
in plasma after last dose of BI 409306
Per CTP flow-chart, pharmacokinetic sampling will be performed at Visits 8 and 16.
5.4.4 
Pharmacogenomic evaluation
As specified in the Section 5.4.2 of the CTP: 
One blood sample will be taken at the screening visit for genotyping of CYP2C19 from all 
patients taking medication known to be strong or moderate inhibitors of CYP1A2.
[…]
In case of a positive study outcome, the sample may be used for DNA extraction and
subsequent genotyping for variants in genes involved in absorption, distribution, metabolism 
and elimination of the compound. It is not intended to include these data in the final report. 
However, the data may be part of the report if necessary.
In case of a positive study outcome as determined based on topline results, samples from all 
subjects will be genotyped for CYP2C19. The influence of CYP2C19 variations on 
pharmacokinetics will be explored descriptively and if applicable by population 
pharmacokinetic methods. The parameters C0.45h and C1.5h of BI 409306 in plasma will be 
compared in exploratory figures by CYP2C19 diplotype and predicted phenotype, if 
applicable; these analyses will be presented in section 15.6 of the CTR.


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENT(S)
As described in Section 3 of the revised CTP, patients will be randomized in equal allocation 
to one of three treatment dosage groups (50 mg, 25 mg and placebo) for analysis purposes.
For randomization purposes 6 arms have been defined: 

BI 409306 50 mg q.d  for 28 weeks and 7 days of withdrawal from treatment

BI 409306 50 mg q.d  for 28 weeks and 7 days of tapering from treatment

BI 409306 25 mg q.d  for 28 weeks and 7 days of withdrawal from treatment

BI 409306 25 mg q.d  for 28 weeks and 7 days of tapering from treatment

Placebo for 28 weeks and 7 days of withdrawal from treatment

Placebo for 28 weeks and 7 days of tapering from treatment
Table 6.1: 1
Treatments and their labels per randomization list
Treatment 
Short label 
BI 409306 50 mg q.d. taper
BI 409306 50 mg 
taper
BI 409306 50 mg q.d. withdraw
BI 409306 50 mg 
withdraw
BI 409306 25 mg q.d. taper
BI 409306 25 mg 
taper
BI 409306 25 mg q.d. withdraw
BI 409306 25 mg 
withdraw
Placebo taper
Placebo taper
Placebo withdraw
Placebo withdraw
The treatment period is defined as 28 weeks, hence for most analyses the taper/withdrawal 
period will not be considered and the arms corresponding to the same doses of treatment will 
be pooled, resulting in the following treatment labels for displays.
Table 6.1: 2
Treatments and their labels in specified analyses
Treatment (per rand list)
Short label (in displays)
BI 409306 50 mg q.d. taper
BI 409306 50 mg 
BI 409306 50 mg q.d. withdraw
BI 409306 25 mg q.d. taper
BI 409306 25 mg 
BI 409306 25 mg q.d. withdraw


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Treatment (per rand list)
Short label (in displays)
Placebo taper
Placebo 
Placebo withdraw
The trial consists of a 28 day screening period, followed by a 28 week treatment period (after 
randomization), followed by a 7 day taper/withdraw (T/W) period and a 21day follow-up. 
For analysis purposes three periods have been defined in section 7.3.1 of the CTP:

Intent to Treat (ITT) follow-up
This is the intended 28 week treatment period. It does not include the T/W period. For 
patients who discontinue early, their follow-up information until the end of the 
planned 28 week treatment period is included.

Full follow-up
This is the entire study period, beginning with randomization until the end of the 
follow-up period (or date of last contact), including the T/W period and follow-up
period. (Sensitivity for ITT follow-up analysis)

On-treatment
This includes the time period from treatment start date until drug discontinuation + 7 
days.
o
Patients randomized to withdrawal period/early discontinued patients:
Time on treatment prior to withdrawal (or early discontinuation) + 7 days
o
Patients randomized to taper period:
Time on treatment + 7 days taper period + 7 days
Patients who discontinue early will be followed up according to the CTP.


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6.2
IMPORTANT PROTOCOL DEVIATIONS
Handling of iPDs in analysis is included in the DV domain specifications and stored within 
the Trial Master File (TMF) in the electronic Document Management System (eDMS). 
6.3
SUBJECT SETS ANALYZED
Screened Set
The screened set includes all patients who were screened for the trial, gave informed consent 
and had at least one screening procedure at Visit 1.
Randomized Set (RS)
The RS consists of all patients who were screened for the trial and who were randomized to 
study drug, regardless of whether any study drug was taken.
Treated Set (TS)
The TS includes all patients who were randomized and were documented to have taken at 
least one dose of study drug.
Full Analysis Set (FAS)
The FAS includes all patients in the TS with at least one baseline and post-baseline 
measurement of any type. The FAS will be used for the primary and secondary analyses.
The screened set, and treated set will be used to populate patient disposition and the TS will 
be used for demographics, baseline characteristics, treatment exposure and safety analyses 
(including adverse events, laboratory measurements, and vital signs). Safety analyses will 
assign patients to the treatment group based on the treatment they received at the time the AE 
occurred.
Efficacy data will always be analyzed according to the randomized treatment following the 
intention-to-treat (ITT) principle. If a patient erroneously received a medication kit that 
included a treatment different from what they were randomized to, the patient’s efficacy data 
will be analyzed according to the treatment they were originally randomized to.
Table 6.3: 1
Subject sets analyzed
Subject set
Class of endpoint
TS
FAS
Primary and key secondary 
endpoints 
X
(other) Secondary and further 
endpoints 
X
Safety endpoints 
X
Demographic/baseline 
endpoints
X


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Analysis periods are defined in the revised CTP and in Section 6.1.
6.5
POOLING OF CENTRES
The randomization was stratified by country. 
6.6
HANDLING OF MISSING DATA AND OUTLIERS
Assessment of relapse data (primary endpoint):
All patients will be followed up for relapse […]. Any patient who has not relapsed will be 
censored in the analysis of the primary endpoint at the time of their planned complete 28-
week treatment period. This does not include the T/W period. For AEs that meet the primary 
endpoint criteria, missing or incomplete AE dates are imputed according to BI standards.
The sensitivity analysis will use the Full Follow-up period to demonstrate the robustness of 
the results of the main analysis. See revised CTP Section 7.3 
PANSS positive symptoms (key secondary analysis)
Change from baseline in PANSS positive symptoms will be evaluated using Mixed effect 
Model for Repeated Measures (MMRM) approach. This approach allows for missing data, 
assuming they are missing at random.  All patients can be included in the model and missed 
visits will not be imputed. If a PANSS item is missing, the missing score on that individual
PANSS item will not be imputed; if individual PANSS item is missing within a PANSS 
subscale, this subscale cannot be included in the calculation of the overall PANSS total score. 
Therefore, patients with missing individual PANSS items will also have a missing PANSS 
total score at that visit. However, subscale scores will be used for analysis if none of the 
individual items are missing.
Relative Risk Reduction (RRR)
Per revised CTP Section 7.5.:
All patients in the FAS will be included […] regardless of drop-out.


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For
AE dates
Missing or incomplete AE dates are imputed according to BI standards (see “Handling of 
missing and incomplete AE dates”) (3).
PK data
Missing data and outliers of PK data are handled according to Reference (2) and as described 
in Section 10 of the revised CTP.
In December 2019, during the conduct of the trial, a Visit 8 eCRF page was added to capture 
the date and time of the last dose of BI drug intake before the PK sampling performed at Visit 
8. For patients who had completed the trial at that time, or patients for whom the visit 8 date 
had passed, the
data will be used to inform the date and time of the last BI drug 
intake.
Sensitivity analysis: the date and time of the last dose of BI drug intake at Visit 8 collected in 
the eCRF will be compared to the information recorded in 
 This will be done for 
patients for whom both sources of information are available (eCRF and 
. 
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
For all efficacy endpoints, “baseline” is defined as the assessments done at Visit 2, prior to 
administration of first dose. If this value is not available, the latest measurement prior to 
treatment administration will be used. 
For demographics, medical history, concomitant antipsychotic medication, AEs, concomitant 
therapies, vital signs and C-SSRS, Visit 1 (screening) will be considered as “baseline”. If this 
value is not available, the earliest value prior to treatment administration will be used.
Visit will be labelled according to the flow chart in the protocol: Visit 1 (for screening), Visit
2 (randomization and start of treatment), Visits 3-19, End of Treatment (EOT), Follow Up 
(FU) (28 days after Visit 16 for completed patients; 28 days after EOT for early discontinued 
patients). Planned and actual test days will be calculated relative to the beginning of study as 
indicated in the following table.
Table 6.7: 1
Visit calculation relative to study start
Visit
Relative to study start
Planned test day
(every 14 days)
Actual test day
2
1
1


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Visit
Relative to study start
Planned test day
(every 14 days)
Actual test day
3
15
Visit 3 date – first dose date +1
4
29
Visit 4 date – first dose date +1
5
43
Visit 5 date – first dose date +1
Etc...
...
...
16
197
Visit 16 date – first dose date +1
T/W 17
Visit 16 + 2 days
T/W 17 date – first dose date + 1
T/W 18
Visit 16 + 4 days
T/W 18 date – first dose date + 1
EOT
(T/W 19)
Visit 16 + 7 days
EOT (T/W 19 date) – first dose 
date + 1
FU
Visit 16 + 28 days
FU date – first dose date + 1
All time to event analyses will use the visit start date as recorded on the CRF as the analysis 
date.    


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7.
PLANNED ANALYSIS
For End-Of-Text (EoT) tables, the set of summary statistics is: N / Mean / SD / Min / Median 
/ Max.
For tables that are provided for endpoints with some extreme data, median, quartiles and 
percentiles should be preferred to mean, standard deviation, minimum and maximum. 
Tabulations of frequencies for categorical data will include all possible categories and will 
display the number of observations in a category as well as the percentage (%) relative to the 
respective treatment group (unless otherwise specified, all subjects in the respective subject 
set whether they have non-missing values or not). 
The precision for percentages should be one decimal point, unless the denominator is smaller 
than 100 (in all treatment columns), in which case percentages are given in integer numbers.
The category missing will be displayed only if there are actually missing values. 
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Only descriptive statistics are planned for this section of the report based on the treated set.
7.2
CONCOMITANT DISEASES AND MEDICATION
Only descriptive statistics are planned for this section of the report, based on the treated set.
A summary of concomitant diseases will be provided by treatment group, System Organ
Class (SOC) and Preferred Term (PT).
Concomitant medications will be summarized by two groups: schizophrenia and non-
schizophrenia. And depending on if concomitant medication is started before or after trial 
medication, baseline and on-treatment concomitant medication use will be summarized
separately.
7.3
TREATMENT COMPLIANCE
Only descriptive statistics are planned for this section of the report. Summary statistics will 
be given for percent compliance along with the number (%) of patients with compliance in
the categories <80%, 80% - 100%, >100%, see more details in Section 5.4.2.


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7.4
PRIMARY ENDPOINT(S)
The hypothesis testing strategy for primary and key secondary endpoints is described in 
Section 7.2 of the CTP:
The trial will follow a hierarchical testing strategy. The first hypothesis for the superiority 
testing of the primary endpoint time to first relapse is (HR = hazard ratio):
Ho: HRBI 409306 / placebo = 1
vs. 
Ha: HRBI 409306 / placebo ≠ 1, where HRBI 409306 is the 
hazard ratio for the pooled active treatment arms (i.e. BI 409306 50 mg q.d. and BI 
409306 25 mg q.d.), over 28 weeks (excluding the withdrawal/taper period)
Superiority will be declared if the hazard ratio between BI 409306 vs. placebo is statistically 
significantly less than 1 at the two-sided type I error level α = 0.05.
If the first hypothesis test is determined to be statistically significant, the individual doses will 
be tested for superiority using Hochberg’s step-up test. The method will be to perform the 
statistical tests and rank the p-values for the individual doses vs. placebo.  Let p(1) ≥ p(2) be 
the two-sided p-values.  The corresponding null hypotheses are H0(1) and H0(2).
H0(1): HRBI 409306 / placebo = 1
vs. 
Ha(1): HRBI 409306 / placebo ≠ 1, where HRBI 409306 is 
the hazard ratio for the BI 409306 dose with the highest p-value
H0(2): HRBI 409306 / placebo = 1
vs. 
Ha(2): HRBI 409306 / placebo ≠ 1, where HRBI 409306 is 
the hazard ratio for the BI 409306 dose with the lowest p-value
Step 1: If p(1) ≤ 0.05 then both hypotheses are rejected and both doses are declared 
statistically significant and testing ends.  If p(1) > 0.05, then H0 (1) is not rejected and the 
testing proceeds to Step 2.
Step 2: If p(2) ≤ 0.025, then H0 (2) is rejected and this dose is declared statistically significant.  
If p(2) > 0.025, then all doses fail.  
7.4.1
Primary efficacy analysis
The primary analysis will be conducted on the FAS using the ITT follow-up period as 
defined in Section 6.1. Because the ITT covers the 28 weeks of planned treatment and not the 
T/W period, the treatment arms will be pooled according to dose and disregarding the T/W 
randomization.
Revised CTP in Section 7.3.1:
The equality of the hazard rates will be tested by the Wald test for the treatment effect in a 
stratified Cox proportional hazards model at the two-sided 5% significance level. The model 
includes the treatment effect as the only covariate and is stratified by country. Breslow’s 
method for handling ties will be used.


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The same stratified Cox proportional hazards model will be used to estimate the hazard ratio 
of BI 409306 vs. placebo and the asymptotic 95% Wald confidence interval. A hazard ratio of 
less than one favors BI 409306.  The analysis will be implemented using SAS® PROC 
PHREG.  Cox proportional hazard model assumptions will be verified.
In early discontinued patients, if the occurance of a relapse cannot be determined between 
the time of discontinuation and last contact, it is assumed that no relapse has occurred.
Patients who discontinue study medication will be followed until the end of the trial for the 
primary endpoint.  Patients who are lost-to-follow up will be censored for the primary 
endpoint at the date of last known patient contact. 
According to the CTP, we have specified more details regarding efficacy analysis using ITT 
FU and Full FU:
Definition of last at-risk date:
The last at-risk date determined as the latest date among: the date of first dose of study 
medication, the date of last drug administration, all the visit start dates (including phone 
contact dates in which the patient was reached and follow-up contact dates) and start or stop 
dates of events reported on the adverse event forms. 
If a patient dies, the date of death is their last at-risk date.
Definition of Visit 16 date:
The date of Visit 16 for the determination of the ITT FU period end date will be the start date 
recorded on eCRF.
Time to event calculations:
A.
Patients completing treatment period and study period (for ITT analysis): 
Events (relapses) are counted in the ITT time to event analysis whenever they occur between 
the first dose of randomized treatment and the patient’s Visit 16 date or the date of last dose if 
this occurred after visit 16. (In SDTM this is EPOCH=TREATMENT1) 

Patients with event counted: <date of event> – <date of first drug administration> +1 
day

Patients without event counted: <date of last dose of study drug or date of Visit 16> –
<date of first drug administration >+1 day
B.
Patients completing treatment period and study period (for Full FU analysis): 
Events (relapses) are counted in the FU time to event analysis whenever they occur between 
the first dose of randomized treatment and the patient’s EOS date.

Patients with event counted: <date of event> – <date of first drug administration> +1 
day


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
Patients without event counted: <date of EOS> – <date of first drug administration 
>+1 day
C.
Patients who chose Early Discontinuation Option 1 or Option 2 per CTP (ITT and 
Full FU analysis): 
1.
And completed required study period: Events (relapses) are counted in the time to 
event analysis whenever they occur between the first dose of randomized treatment and the 
patient’s EOS date.

Patients with event counted: <date of event> – <date of first drug administration> +1 
day

Patients without event counted: <date of EOS> – <date of first drug administration 
>+1 day 
2.
And discontinued or did not complete required study period: Events (relapses) are 
counted in the time to event analysis whenever they occur between the first dose of 
randomized treatment and the patient’s last at-risk date. 

Patients with event counted: <date of event> – <date of first drug administration> +1 
day

Patients without event counted: <date of last at-risk date > – <date of first drug 
administration >+1 day 
D.
Patients who chose Early Discontinuation Option 3 or Option 4 per CTP (ITT and 
Full FU analysis): 
1.
And completed required study period: Events (relapses) are counted in the time to 
event analysis whenever they occur between the first dose of randomized treatment and the 
patient’s End of Study Date. 

Patients with event counted: <date of event> – <date of first drug administration> +1 
day

Patients without event counted: < date of EOS > – <date of first drug administration 
>+1 day 
2.
And discontinued or did not complete required study period: Events (relapses) are 
counted in the time to event analysis whenever they occur between the first dose of 
randomized treatment and the date of last at-risk date.

Patients with event counted: <date of event> – <date of first drug administration> +1 
day

Patients without event counted: < date of last at-risk date > – <date of first drug 
administration >+1 day 
E.
Patients who chose Early Discontinuation Option 5, i.e. withdrew consent per CTP 
(for ITT and Full FU analysis): Events (relapses) are counted in the time to event analysis 
whenever they occur between the first dose of randomized treatment and the patient’s date of 
consent withdrawal. 

Patients with event counted: <date of event> – <date of first drug administration> +1 
day

Patients without event counted: <date of consent withdrawal> – <date of first drug 
administration >+1 day 
F.
Patients who are Lost-to-Follow-up (for ITT analysis): Events (relapses) are counted 
in the time to event analysis whenever they occur between the first dose of randomized 
treatment and the last at-risk date.


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
Patients with event counted: <date of event> – <date of first drug administration> +1 
day

Patients without event counted: <date of last at-risk> – <date of first drug 
administration >+1 day 
*Please note: Patients who are LTFU during the study (regardless of initial Early 
Discontinuation choice), but were successfully found towards the end of study via a vital 
status call, will be included in the Full-FU analysis period by replacing as follows: 

Patients without event counted: <date of vital status/date of EOS> – <date of first 
drug administration >+1 day
The following SAS code will be used:
proc phreg data= primary;
   CLASS &trt.(ref="Placebo") / order=internal;
   model aval*cnsr(1) = &trt./ties=breslow;
   strata countrdc;
   hazardratio 'HR' &trt. /diff=ref cl=both ;
run;
Subgroup analyses will be performed on the subgroups specified in Section 6.4. Definition of 
Japanese patients is provided in Section 9.1. The same model as described above for the 
primary efficacy analysis, will be used for these analyses.
The following SAS code will be used for survival plot:
proc lifetest data=primary method=km plots=survival(failure test 
atrisk);
time aval*cnsr(1);
id usubjid;
strata &trt. /test=logrank;
run;
7.4.2
Sensitivity analysis
The sensitivity analysis to the primary analysis, will be performed on the Treated Set (TS)
using the Full follow-up period. 
An additional sensitivity analysis of Time to Treatment Discontinuation or Relapse will be 
performed using the same model as the primary analysis and using the same subject sets, i.e. 
FAS using the ITT follow-up period. This endpoint is a composite endpoint as defined above 
in the primary analysis, however it includes discontinuation as an outcome event.


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7.5
SECONDARY ENDPOINT(S)
7.5.1
Key secondary endpoint(s)
The hypothesis testing strategy for key secondary endpoints is described in Section 7.2 of the
revised CTP:
The remaining alpha after the testing of the primary endpoint (Steps 1 and 2) will be used to 
test the key secondary endpoint of change from baseline in PANSS positive symptoms. The 
hypotheses to be tested are:
H0(3):
Mean change from baseline of PANSS positive symptom score after 28 weeks 
of treatment with BI 409306 ≥ Mean change from baseline of PANSS positive 
symptom score after 28 weeks of treatment with placebo
vs.
Ha(3):
Mean change from baseline of PANSS positive symptom score after 28 weeks 
of treatment with BI 409306 < Mean change from baseline of PANSS positive 
symptom score after 28 weeks of treatment with placebo
The first of the key secondary hypothesis to be tested will be based on the pooled active 
treatment arms (i.e. BI 409306 50 mg q.d. and BI 409306 25 mg q.d.), over 28 weeks 
(excluding the withdrawal/taper period).
Similar to the primary endpoint, if the first hypothesis test (on the pooled doses) is 
determined to be statistically significant, the individual doses will be tested for superiority 
using Hochberg’s step-up test as described above.
The key secondary analysis will be performed on the FAS, and is described in Section 7.3.2 
of the revised CTP:
The key secondary analysis is a restricted maximum likelihood (REML) based approach 
using a mixed model with repeated measurements (MMRM) comparing the change from 
baseline of PANSS positive symptoms score after 28 weeks of treatment (Section 7.2).
The analysis will include the fixed, categorical effects of treatment at each visit, and the fixed 
continuous effects of baseline at each visit. Visit will be treated as the repeated measure with 
an unstructured covariance structure used to model the within-patient measurements.
The statistical model will be as follows: 
yijkm=βjSi + τjk + ϕm + eij
eij~NZ (0, Σ).
yijkm  = response variable for subject i in country m at visit j receiving treatment k
Si = the baseline measurement of subject i, i=1,2,…
βj = coefficient of baseline effect at visit j
τjk = the effect of treatment k at visit j, j=1,…,Z and k=1,…,Y


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ϕm = the effect of country m, m=1,…,X
eij = the random error associated with the jth visit of the ith subject. Errors are 
independent between subjects.
Σ = an unstructured covariance matrix.
The Kenward-Roger approximation will be used to estimate denominator degrees of freedom 
and adjust standard errors. Significance tests will be based on least-squares means using a 
two-sided α = 0.05 or the remaining alpha (two-sided ((1- α )% confidence intervals).The 
treatment comparison will be the contrast between treatments at the endpoint visit.
The key secondary analysis will be performed on the FAS. Patients will be analysed 
according to the stratum to which they belong (regardless of any mis-assignment to treatment 
based on identification of the wrong stratum), as such an error occurs before randomisation 
and is therefore consistent with regulatory guidance. 
[…]
To assess the homogeneity of the treatment effect on the key secondary endpoint across the 
levels of the country stratification, the same MMRM model will be fitted but replacing the 
treatment-by-visit term by a treatment-by-country-by-visit term. A descriptive p-value of 
treatment effect homogeneity at 28 weeks will be calculated. No overall treatment effect will 
be estimated from this model as it is not interpretable.
The following SAS code will be used:
ODS OUTPUT LSMEANS=lsmeans DIFFS=diffs TESTS3=tests3; 
PROC MIXED DATA=alldata cl method=reml order=formatted; 
CLASS ptno treatment country timepoint; 
MODEL ept = country treatment*timepoint baseline*timepoint
/ ddfm=kr solution; 
REPEATED timepoint / subject=ptno type=un r rcorr; 
LSMEANS timepoint*treatment / pdiff=all om cl alpha=0.05 
slice=timepoint; 
RUN; 
ODS OUTPUT CLOSE;
In case the model described in the revised CTP fails to converge, the following methods will 
be attempted (in order) to overcome it:
1. Add the ‘singular=1e-10’ option in the model statement – This raises the threshold at 
which columns are declared linearly dependent (from typically 1e-12). 
2. Set ‘maxiter=100’ in the Proc Mixed statement – This increases the number of 
convergence iterations used from a default of 50. 
3. Set ‘scoring=4’ to specify use of the Fisher scoring algorithm in the first 4 iterations. 
4. Include the statement ‘performance nothread’ – this removes multi-threading from the 
calculations. 


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5. Provide starting values for covariance parameters using a ‘parms’ statement. 
6. Use a simpler covariance matrix: Should none of the previous methods work, the 
covariance matrix will be changed from unstructured to Toeplitz with heterogeneous 
variances (TOEPH). Should this also not converge, a standard Toeplitz matrix 
(TOEP) will be fitted. Finally, if convergence still does not occur, then an order-1 
autoregressive matrix (AR(1)) will be fitted. 
In this case, the final choice of covariance matrix will be documented in the CTR.
7.5.2
(Other) Secondary endpoint(s)
Secondary endpoints will be analyzed as described in section 7.3.2 in the revised CTP:
Time to change in antipsychotic medication will be analysed in the same manner as the 
primary endpoint using the stratified Cox proportional hazards model.
Additionally, the analyses for suicidal ideation and behaviour as assessed by C-SSRS will be 
analysed by calculating a relative risk reduction and providing a 95% confidence interval 
around the RRR. 
The following SAS code will be used for RRR:
proc freq data=patdata;
tables trtp*avalc /chisq
RELRISK ;
ods output
RelativeRisks=rr(where=(lowcase(STUDYTYPE)=’ Cohort (Col1 Risk)')
rename=(value=compestimate lowercl=complower uppercl=compupper))
ChiSq=chi(where=(lowcase(STATISTIC)='chi-square') rename=prob=comppvalue);
run;
The PGI-I score, change in CGI-S and PSP will be summarized descriptively. 
For the secondary endpoints summary, the worse case scenario data will be analyzed if 
multiple assessments are completed during the same visit window.


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7.7
EXTENT OF EXPOSURE
Exposure will be analyzed on the treated set. Extent of exposure will be summarized using
descriptive statistics for days of exposure as well as number (%) of patients whose total
exposure falls in the categories specified in Section 5.4.2.
7.8
SAFETY ANALYSIS
All safety analyses will be performed on the treated set. Analyses are specified in section 
7.3.4 of the CTP.
7.8.1
Adverse events
Unless otherwise specified, the analyses of adverse events 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.
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 (LLT, intensity, action taken, therapy required, seriousness, 
reason for seriousness, relationship, outcome, AE of special interest )
•
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 summarization of AE data, please refer to (3, 4).
The analysis of adverse events will be based on the concept of treatment emergent adverse 
events. That means that all adverse events occurring between first drug intake till last drug 
intake + residual effect period will be assigned to the randomised treatment. All adverse 
events occurring before first drug intake will be assigned to ‘screening’ and all adverse events 
occurring after the residual effect period will be assigned to ‘post-treatment’ (for listings 
only). For details on the treatment definition, see Section 6.1.
According to ICH E3 (5), AEs classified as ‘other significant’ need to be reported and will 
include those non-serious and non-significant adverse events with:
(i) ‘action taken = discontinuation’ or ‘action taken = reduced’, or


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(ii) marked haematological and other lab abnormalities or lead to significant 
concomitant therapy as identified by the Clinical Monitor/Investigator at a Medical 
Quality Review Meeting.
An overall summary of adverse events will be presented.
The frequency of subjects with adverse events will be summarized by treatment, primary 
system organ class and preferred term. Separate tables will be provided for subjects with 
other significant adverse events according to ICH E3 (5), for subjects with adverse events of 
special interest (detailed in section 5.2.6.1 of the revised CTP) and for subjects with serious 
adverse events.
The system organ classes will be sorted alphabetically, preferred terms will be sorted by 
frequency (within system organ class).
7.8.2
Laboratory data
The analyses of laboratory data will be descriptive in nature and will be based on BI 
standards (6). Planned analyses are detailed in section 7.3.4 of the revised CTP.
Baseline for safety laboratory parameters will be the last available measurement before the 
start of randomized treatment.
Laboratory measurements taken up to 7 days after the last administration of randomized 
treatment will be considered as on-treatment.
Only patients with at least one available on-treatment value will be included in the analysis of 
an individual laboratory parameter. All individual data will be presented in listings.
If there are multiple safety laboratory values at one visit, the worst of these will be assigned 
to that visit date measurement.
7.8.3
Vital signs
Only descriptive statistics are planned for this section of the report. The latest measurement 
will be analyzed if multiple assessments are completed during the same visit window.
See section 7.3.4 of the revised CTP.
7.8.4
ECG
Any clinically significant new findings in the ECG measurement after the first ECG will be 
considered as AE and analyzed as planned in Section 7.8.1.


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7.8.5
Others
Taper/withdrawal (T/W) period
The 7-day, post 28 week treatment T/W period will not be analyzed as part of the primary 
analyses. Planned analyses on the T/W period will be descriptive only 
Vital signs, suicidality and adverse events will be closely monitored during this period T/W.
Only data obtained during the T/W period will be included in the analyses, and only of those 
patients randomized to the active treatment arms will be included in comparisons, which 
include all tapering comparing to all withdrawal as well as comparisons between the
individual doses.


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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.
001-MCS 36-472: "Standards and processes for analyses performed within Clinical 
Pharmacokinetics/Pharmacodynamics", current version; IDEA for CON.
3.
001-MCG-156_RD-01: "Handling of missing and incomplete AE dates", current version; 
IDEA for CON.
4.
001-MCG-156: "Handling and summarization of adverse event data for clinical trial
reports and integrated summaries", current version; IDEA for CON.
5.
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
6.
001-MCG-157: "Handling, Display and Analysis of Laboratory Data", current version; 
IDEA for CON.


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9.3
ADDITIONAL ANALYSIS FOR IMPACT OF THE COVID-19 
PANDEMIC ON THE TRIAL 
9.3.1
Start and end of COVID-19 disruption 
The trial specific start date of COVID-19 disruption is defined as the date of earliest COVID-
19 related event, including COVID-19 related protocol deviation, discontinuation of a 
subject’s treatment with study drug or trial participation due to COVID-19, or onset of a 
SARS-CoV-2 related AE. In this trial, start date of COVID-19 disruption is 13-Mar-2020 as 
it is the date of first occurrence of COVID-19 related protocol deviation.
As of now, end of the impact is not foreseeable so it will not be defined for this trial.
9.3.2
Additional analysis
Additional outputs will be included in CTR to assess the impact of COVID-19 on the trial, 
and it will include analyses of the following:

Disposition

Premature discontinuation

COVID-19 related iPD

Study medication exposure

Compliance with study medication

Adverse events 


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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
01-DEC-17
 
Initial
This is the initial TSAP with 
necessary information for trial 
conduct
V2
27-NOV-18
 
Initial sections were  
only modified to 
change “iPV” to “iPD”;
All other sections were 
populated
This is the final TSAP 
V3
26-Feb-2021
Updated version to reflect 
sponsor’s decision to stop trial 
earlier, implement fast-track 
approach to expedite decision 
making and for preparation of the 
planned phase III trials. and add
more analysis to assess COVID-
19 impact.
V4
17-Mar-2021
Updated a typo in the date of
signature