Clinical trial NCT03230097
Conditions: Psychotic Disorders
Sponsor: Boehringer Ingelheim
Start date: 2017-09-29; Completion date: 2021-04-07
Enrollment: 50 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a study in people between 16 and 30 years of age who have a specific type of mental illness called attenuated psychosis syndrome (APS). The purpose of this study is to find out whether BI 409306 helps reduce the symptoms of APS.

Participants are in the study for 1 year and 2 months. During this time, they visit the study site about 15 times and get about 10 phone calls. Participants are put into 2 groups by chance. They get either BI 409306 or placebo. Placebo tablets look like BI 409306 tablets but do not contain any medicine. Participants take a BI 409306 or placebo tablet two times a day.

During the study, participants answer questions in interviews and complete questionnaires so the doctors can check whether the APS symptoms change. The doctors also check the general health of the participants.

Detailed description:

Arms: arm 1: Patients meeting Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) diagnostic criteria for attenuated psychosis syndrome (APS) per the Structured Interview for Psychosis-Risk Syndromes (SIPS) took 50 milligrams BI 409306, as a film-coated tablet, orally twice a day at approximately the same time every day in the morning and in the evening (approximately 12 hours apart) with or without food for 52 weeks. arm 2: Patients meeting Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) diagnostic criteria for attenuated psychosis syndrome (APS) per the Structured Interview for Psychosis-Risk Syndromes (SIPS) took placebo matching 50 milligrams BI 409306, as a film-coated tablet, orally twice a day at approximately the same time every day in the morning and in the evening (approximately 12 hours apart) with or without food for 52 weeks.
Interventions: intervention 1: BI 409306 intervention 2: Placebo
Intervention descriptions: intervention 1: 50 milligrams BI 409306, as a film-coated tablet, orally twice a day at approximately the same time every day in the morning and in the evening (approximately 12 hours apart) with or without food for 52 weeks. intervention 2: placebo matching 50 milligrams BI 409306, as a film-coated tablet, orally twice a day at approximately the same time every day in the morning and in the evening (approximately 12 hours apart) with or without food for 52 weeks.

Protocol documents:
Prot_000.pdf: 
001-MCS-40-106-RD-03 (13.0) / Saved on: 05 Aug 2015
Clinical Trial Protocol
TITLE PAGE
Document Number:
c08964447-05
EudraCT No.:
EU Trial No:
2016-004973-42
BI Trial No.:
1289-0032
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 52-week treatment period as an 
early intervention in patients with attenuated psychosis 
syndrome.
Lay Title:
This study tests whether BI 409306 prevents patients with a 
specific type of mental illness (attenuated psychosis syndrome) 
from becoming worse. This study looks at how well patients 
tolerate the medicine and how effective it is over 1 year.
Clinical Phase:
II
Trial Clinical 
Monitor:
Phone:
Email: 
Coordinating 
Investigator:
Phone:
Email:
Status:
Final Protocol (Revised Protocol based on global amendment 3)
Version and Date:
Version: 4.0
Date: 04 Oct 2018
Page 1 of 119
Proprietary confidential information.
2018 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
Name of company:
Boehringer Ingelheim 
Name of finished product:
Not applicable
Name of active ingredient:
BI 409306
Protocol date:
09 Mar 2017
Trial number:
1289-0032
Revision date:
04 Oct 2018
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 52-week treatment period as an early intervention in 
patients with attenuated psychosis syndrome.
Coordinating
Investigator:
Trial site(s):
Multicentre trial 
Clinical phase:
II
Objective(s):
To investigate the efficacy, safety and tolerability of BI 409306 
compared to placebo given for 52 weeks to patients with attenuated 
psychosis syndrome. The study is designed to show superiority of 
BI 409306 over placebo in achieving remission of APS, as well as 
improvement in cognition and functional capacity.
Methodology:
Multinational, multicentre, randomised, double-blind, placebo-
controlled, parallel group study
No. of patients: 
total entered:
300
each treatment:
150 per treatment group
Diagnosis :
Patients meeting Diagnostic and Statistical Manual of Mental 
Disorders, Fifth Edition (DSM-5) diagnostic criteria for Attenuated 


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Name of company:
Boehringer Ingelheim 
Name of finished product:
Not applicable
Name of active ingredient:
BI 409306
Protocol date:
09 Mar 2017
Trial number:
1289-0032
Revision date:
04 Oct 2018
Psychosis Syndrome (APS) per the Structured Interview for 
Psychosis-Risk Syndromes (SIPS).
Main criteria
for inclusion:
Patients who are ≥16 and ≤30 years old who meet diagnostic criteria 
for Attenuated Psychosis Syndrome (APS) per DSM-5 as determined 
by the Structured Interview for Psychosis-Risk Syndromes (SIPS). 
Test product(s):
BI 409306
dose:
50 mg b.i.d.(twice daily dosing)
mode of 
administration:
p.o. (oral)
Comparator products:
Matching placebo
dose:
Not applicable
mode of 
administration:
p.o.
Duration of treatment:
52 weeks
Endpoints
Primary endpoint: 
The primary endpoint is time to remission from APS within a 52 
week timeframe. Remission from APS is defined as a score of <3 on 
all of the P1-P5 Positive Symptom items of the SOPS and maintained
until the end of treatment. 
Secondary endpoints:

Time to first episode of psychosis within a 52 week timeframe 


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Name of company:
Boehringer Ingelheim 
Name of finished product:
Not applicable
Name of active ingredient:
BI 409306
Protocol date:
09 Mar 2017
Trial number:
1289-0032
Revision date:
04 Oct 2018
as adjudicated by the Central Rating Committee. First episode 
of psychosis defined as one or more SOPS P1-P5 rated a 6 
AND either a symptom is seriously disorganizing or 
dangerous OR one of the symptoms above occurred at least 
one hour per day at an average frequency of four days/week 
over the past month. OR a new prescription or increase in dose 
of an ongoing antipsychotic medication. Time of onset of first 
episode psychosis is defined using the rater’s best estimate as 
determined in the SOPS interview or when the patient began 
taking a new prescription or increased the dose of 
antipsychotic medication.

Change from baseline in everyday functional capacity as 
measured by Schizophrenia Cognition Rating Scale (SCoRS) 
total score after 24 and 52 weeks of treatment.

Change from baseline in the Tablet based Brief Assessment of 
Cognition (BAC App) composite T score after 52 weeks of 
treatment.

Change from baseline in Positive and Negative Syndrome 
Scale (PANSS) positive items score, negative items score, and
total score after 52 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 remission from APS, 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 
10% significance level. The model includes the treatment effect and 


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Name of company:
Boehringer Ingelheim 
Name of finished product:
Not applicable
Name of active ingredient:
BI 409306
Protocol date:
09 Mar 2017
Trial number:
1289-0032
Revision date:
04 Oct 2018
categorized NAPLS risk score as covariates and is stratified by 
baseline use of antipsychotics. Time to event endpoints will be 
analysed using Cox proportional hazard model and change from 
baseline endpoints will be analysed using the restricted maximum 
likelihood (REML) based mixed effects model with repeated 
measurements (MMRM).


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FLOW CHART
Trial Periods
Screening 
Period
Completed
Patients
Early D/C 
Option 1
Early D/C 
Options 2-4
Visit  
1*
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
EOT**
EOT** 
EOT** 
F/U***
End of 
Study****
Study week
-4
0
1
2
3
4
5
6
9
12
15
18
21
24
27
30
33
36
39
42
45
48
52
52
56
Study day
-28
1
 8
15 
22
29
36
43
64
85
106
127
148
169
190
211
232
253
274
295
316
337
365
365
393
Visit window in days
 -28 to -7
N/A
+/- 1 +/- 2
+/- 1 +/- 2
+/- 1 +/- 2
+/- 3
+/- 3
+/- 3
+/- 3
+/- 3
+/- 3
+/- 3
+/- 3
+/- 3
+/- 3
+/- 3
+/- 3
+/- 3
+/- 3
+/- 3
+/- 3
+/- 3
Informed consent
1
X
Demographics
X
Medical history
X
Physical examination
X
X
X
X
X
X
Vital signs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Height
X
X
X
X
Weight
X
X
X
X
X
X
X
X
X
Pregnancy test (urine; females only)
 2
X
X
X
X
X
X
X
X
X
X
X
X
X
X
12 lead-ECG
3
X
X
X
X
X
X
X
X
X
X
X
Safety laboratory tests (urine/blood)
4
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Substance Use Assessment
5
X
Urine drug screen
X
X
X
X
X
X
X
Salivary Cortisol
6
X
X
X
X
X
BDNF, Inflammatory Cytokines Sampling
6
X
X
X
X
X
Pharmacogenomic sampling
X
7
X
8
Optional DNA biobanking (requires separate ICF)
9
X
SIPS
10
X
X
X
SOPS
10
X
X
X
X
X
X
X
X
X
X
X
X
X
Global Functioning: Social 
X
X
X
X
X
X
BACS-SC & HVLT-R
11
X
X
X
X
X
X
BAC App
12
X
X
X
X
X
Phone Visit
13
X
X
X
X
X
X
X
X
X
X
Randomized Treatment Period
Follow-up 
Period


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FLOW CHART (cont.)
Trial Periods
Screening 
Period
Completed
Patients
Early D/C 
Option 1
Early D/C 
Options 2-4
Visit  
1*
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
EOT**
EOT** 
EOT** 
F/U***
End of 
Study****
Study week
-4
0
1
2
3
4
5
6
9
12
15
18
21
24
27
30
33
36
39
42
45
48
52
52
56
Study day
-28
1
 8
15 
22
29
36
43
64
85
106
127
148
169
190
211
232
253
274
295
316
337
365
365
393
Visit window in days
 -28 to -7
N/A
+/- 1 +/- 2
+/- 1 +/- 2
+/- 1 +/- 2
+/- 3
+/- 3
+/- 3
+/- 3
+/- 3
+/- 3
+/- 3
+/- 3
+/- 3
+/- 3
+/- 3
+/- 3
+/- 3
+/- 3
+/- 3
+/- 3
+/- 3
eC-SSRS
14
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
 X
X
X 
X
 X
X
 X
 X
X
X
PANSS
15
X
X
X
X
 
X
X
X
In-/Exclusion Criteria
X
X
16
Randomization (via IRT)
X
17
SCoRS
18
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Brief Supportive Psychoeducation
X
X
X
X
X
X
X
X
Interactive Response Technology Use
19
X
X
X
X
X
X
X
X
X
X
X
X
X
Dispense study drug
X
X
X
X
X
X
X
X
X
Smartphone app training, set-up/
In-clinic drug administration
X
Adverse events/Outcome Events
20
X
X
X
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
X
X
X
Compliance check
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Termination of trial med.
X
X
X
Trial Completion
X
NAPLS Risk Calculator
21
X
X
X
Vital Status
X
22
Randomized Treatment Period
Follow-up 
Period


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*
Screening Visit procedures are not required to be completed on the same day. 
** 
EOT for patients who complete the treatment period should be completed at Visit 23. 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 6.2.3 provide additional information.
Early 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 for both in-clinic and phone visits. Visit 23 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 one year after the patient was randomized.
*** 
Patients who complete the treatment period will be scheduled for a Follow-Up Visit 28 days after Visit 23.  Patients who prematurely discontinue study medication and choose Early D/C Option 1 will not need a Follow-Up Visit.
Patients who prematurely discontinue study medication and choose Early D/C Options 2-4 will be scheduled for a Follow-Up Visit 28 days after the EOT visit. See Sections 3.3.4.1, 6.2.2, and 6.2.3.
****
The End of Study CRFs will be completed at the time of the Follow-Up Visit for completed patients. Patients who prematurely discontinue study drug and remain in the study will have the End of Study CRFs completed one year 
after randomization.
1
Written informed consents/assents 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). Patients who sign the assent and reach the age of majority during the trial must sign the current version of the informed consent. Re-
consenting may become necessary when new relevant information becomes available and should be conducted according to the sponsor’s and IRB/IEC’s instructions.
2
Female patients of childbearing potential must perform urine (dipstick) pregnancy test at in-clinic Visits 1 through Visit 23/EOT.
3
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/assent for main study has been obtained.
4
Routine laboratory tests are hematology, chemistry, coagulation, urinalysis, and endocrine parameters as described in Table 5.3.3:1.  Patients should be fasting for at least 8 hours prior to the blood samples collected at Visit 2 and 
Visit 23/EOT. 
5
Patients will be asked whether they have ever or are currently using/consuming tobacco, alcohol and cannabis.
6
Saliva and blood samples should be collected at approximately the same time of the day at each visit. Baseline samples must be collected prior to first dose. Patients will be instructed to refrain from caffeine, alcohol, dairy products, 
and nonprescription medications the evening before and the morning of saliva sampling.
7
One blood sample will be taken at screening for genotyping of CYP2C19 from all patients taking medication known to be strong or moderate inhibitors of CYP1A2. 
8
One blood sample for the analysis of pre-specified genes will be collected at Visit 2 from all patients. 
9
Collection of a sample for DNA biobanking is optional (See Section 5.5 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. 
10
The Structured Interview for Psychosis-Risk Syndromes (SIPS) and Scale of Prodromal Symptoms (SOPS) interviews will be video-taped for review by 
.
11
The BACS SC and HVLT-R are paper assessments. The paper BACS SC at Visit 23 is a different version than the BACS SC in the BAC App that is also completed at Visit 23.
12
Patients who do not speak English will take the pen-and-paper Brief Assessment of Cognition Schizophrenia (BACS) available in their native language.
13
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 to administer SOPS. See Section 6.2.2. Columns are shaded in grey in the Flow Chart to indicate phone visits.
14
The Columbia Suicide Severity Rating Scale (C-SSRS) Baseline/Screening version will be used at Visit 1 (Screening Visit). At other scheduled visits, the C-SSRS Since Last Visit version will be used. The screening eC-SSRS 
report must be reviewed by the investigator/qualified rater for validity prior to randomization.
15
The PANSS should also be administered at the time conversion to psychosis is diagnosed.
16
To confirm eligibility prior to start of the study treatment.
17
The first dose administration must be done on Day 1 at the site after all baseline assessments are completed.
18
Patients have the option of identifying an informant to provide ratings for the Schizophrenia Cognition Rating Scale (SCoRS). In person ratings are preferred whenever possible. However, if the informant is not available for in 
person ratings, telephone interview is acceptable.
19
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.
20
Psychosis events after randomisation are Outcome Events. See Section 5.3.6.3.
21
The NAPLS risk calculator score will be calculated and data entered by 
. 
22
Patients who have prematurely discontinued study drug and have not continued making regular visits (in person or phone) must have Vital Status collected approximately one year after the patient was randomized.


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TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS .....................................................................2
FLOW CHART........................................................................................................................6
TABLE OF CONTENTS ........................................................................................................9
ABBREVIATIONS................................................................................................................13
1.
INTRODUCTION...............................................................................................16
MEDICAL BACKGROUND.............................................................................16
1.1
DRUG PROFILE................................................................................................18
1.2
2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK ASSESSMENT .....21
RATIONALE FOR PERFORMING THE TRIAL.........................................21
2.1
TRIAL OBJECTIVES........................................................................................22
2.2
BENEFIT - RISK ASSESSMENT.....................................................................22
2.3
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.........................25
OVERALL TRIAL DESIGN AND PLAN .......................................................25
3.1
3.1.1 
Administrative structure of the trial .................................................................26
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
3.2
CONTROL GROUP(S)......................................................................................27
SELECTION OF TRIAL POPULATION .......................................................27
3.3
3.3.1
Main diagnosis for trial entry ............................................................................28
3.3.2
Inclusion criteria .................................................................................................29
3.3.3
Exclusion criteria ................................................................................................30
3.3.4
Removal of patients from therapy or assessments...........................................31
3.3.4.1
Removal of individual patients .............................................................................31
3.3.4.2
Discontinuation of the trial by the sponsor...........................................................33
4.
TREATMENTS...................................................................................................34
INVESTIGATIONAL TREATMENTS ...........................................................34
4.1
4.1.1 
Identity of the Investigational Medicinal Products..........................................34
4.1.2
Selection of dose in the trial ...............................................................................35
4.1.3
Method of assigning patients to treatment groups...........................................35
4.1.4
Drug assignment and administration of doses for each patient......................35
4.1.5
Blinding and procedures for unblinding...........................................................36
4.1.5.1
Blinding.................................................................................................................36
4.1.5.2
Unblinding and breaking the code ........................................................................36
4.1.6
Packaging, labelling, and re-supply...................................................................37
4.1.7
Storage conditions...............................................................................................37
4.1.8
Drug accountability.............................................................................................37
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
4.2
RESTRICTIONS ................................................................................................38
4.2.1
Other treatments and emergency procedures..................................................38


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4.2.2
Restrictions ..........................................................................................................38
4.2.2.1
Restrictions regarding concomitant treatment ......................................................38
4.2.2.2
Restrictions on diet and life style..........................................................................39
4.2.2.3
Restrictions regarding women of childbearing potential ......................................39
TREATMENT COMPLIANCE........................................................................40
4.3
5.
VARIABLES AND THEIR ASSESSMENT ....................................................42
TRIAL ENDPOINTS..........................................................................................42
5.1
5.1.1
Primary Endpoint ...............................................................................................42
5.1.2
Secondary Endpoints..........................................................................................42
ASSESSMENT OF EFFICACY........................................................................43
5.2
ASSESSMENT OF SAFETY.............................................................................46
5.3
5.3.1
Physical examination ..........................................................................................46
5.3.2
Vital Signs............................................................................................................46
5.3.3
Safety laboratory parameters ............................................................................46
5.3.4
Electrocardiogram ..............................................................................................48
5.3.5
Other safety parameters.....................................................................................48
5.3.5.1
Assessment of suicidality......................................................................................48
5.3.6
Assessment of adverse events.............................................................................50
5.3.6.1
Definitions of AEs ................................................................................................50
5.3.6.2
Adverse event collection and reporting ................................................................52
5.3.6.3
Exemptions to SAE reporting ...............................................................................55
DRUG CONCENTRATION MEASUREMENTS AND 
5.4
PHARMACOKINETICS...................................................................................55
ASSESSMENT OF BIOMARKERS.................................................................55
5.5
5.5.1
Biobanking...........................................................................................................55
Methods and Timing of Pharmacogenomic Sample Collection ...........................56
5.5.1.1
5.5.2
Pre-specified Pharmacogenomic Analysis ........................................................56
5.5.3
Cortisol and Inflammatory Cytokines ..............................................................57
5.5.4
BDNF Levels........................................................................................................57
5.5.5
Automated Speech Analysis...............................................................................57
OTHER ASSESSMENTS...................................................................................58
5.6
APPROPRIATENESS OF MEASUREMENTS..............................................58
5.7
6.
INVESTIGATIONAL PLAN.............................................................................59
VISIT SCHEDULE.............................................................................................59
6.1
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS .................59
6.2
6.2.1
Screening period..................................................................................................59
6.2.2
Treatment period ................................................................................................60
6.2.3
Follow Up Period and Trial Completion...........................................................62
7.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE
...............................................................................................................................63
STATISTICAL DESIGN - MODEL.................................................................63
7.1
NULL AND ALTERNATIVE HYPOTHESES ...............................................63
7.2
PLANNED ANALYSES.....................................................................................63
7.3


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7.3.1
Primary endpoint analyses.................................................................................63
7.3.2
Secondary endpoint analyses .............................................................................64
7.3.4
Safety analyses.....................................................................................................65
7.3.5
Pharmacokinetic and pharmacodynamic analyses..........................................66
INTERIM ANALYSES ......................................................................................66
7.4
HANDLING OF MISSING DATA ...................................................................66
7.5
RANDOMISATION ...........................................................................................67
7.6
DETERMINATION OF SAMPLE SIZE .........................................................67
7.7
8.
INFORMED CONSENT, TRIAL RECORDS, DATA PROTECTION, 
PUBLICATION POLICY..................................................................................69
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED 
8.1
CONSENT ...........................................................................................................69
DATA QUALITY ASSURANCE ......................................................................70
8.2
RECORDS...........................................................................................................70
8.3
8.3.1
Source documents ...............................................................................................70
8.3.2
Direct access to source data and documents.....................................................71
8.3.3
Storage period of records ...................................................................................71
EXPEDITED REPORTING OF ADVERSE EVENTS ..................................71
8.4
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY........72
8.5
TRIAL MILESTONES.......................................................................................72
8.6
9.
REFERENCES....................................................................................................73
PUBLISHED REFERENCES............................................................................73
9.1
UNPUBLISHED REFERENCES......................................................................79
9.2
10.
APPENDICES.....................................................................................................81
BIOMARKER SUB-STUDY: EEG...................................................................81
10.1
10.1.1
Flowchart.............................................................................................................81
10.1.2
Background and Objectives...............................................................................81
10.1.2.1 
Background of Biomarker sub-study: EEG ..........................................................81
10.1.2.2
Objectives of Biomarker Sub-study: EEG............................................................84
10.1.3
Selection of Study Population ............................................................................84
10.1.3.1
Inclusion Criteria...................................................................................................85
10.1.3.2
Exclusion Criteria .................................................................................................85
10.1.4
Sub-study Design.................................................................................................85
10.1.5
Methods and Testing procedure........................................................................85
10.1.6
Endpoint...............................................................................................................87
10.1.8
Statistical Considerations...................................................................................88
10.1.8.1
Stastistical Design – Model...................................................................................88
10.1.8.2
Null and Alternative Hypotheses ..........................................................................88
10.1.8.3
Planned Analyses ..................................................................................................89
OCULAR SAFETY SUB-STUDY.....................................................................90
10.2
10.2.1
Flowchart.............................................................................................................90
10.2.2
Background and Objective.................................................................................90
10.2.3
Selection of Study Population ............................................................................90


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10.2.4
Sub-study Design.................................................................................................90
10.2.5
Methods and Testing procedure........................................................................91
10.2.6
Endpoint...............................................................................................................91
10.2.8
Statistical Considerations...................................................................................92
11.
DESCRIPTION OF GLOBAL AMENDMENT..............................................93


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ABBREVIATIONS
AD
Alzheimer’s Disease
AE
Adverse Event
AESI
Adverse Event of Special Interest
 
ALT
Alanine transaminase (SGPT)
ANOVA
Analysis of variance
APS
Attenuated Psychosis Syndrome
ARMS
At Risk Mental State
ASSR
Auditory steady-state response 
AST
Asparatate transaminase (SGOT)
BAC App
Tablet based Brief Assessment of Cognition
BACS
Brief Assessment of Cognition in Schizophrenia
BACS SC
Brief Assessment of Cognition in Schizophrenia: Symbol Coding
BCVA
Best Corrected Visual Acuity 
BDNF
Brain-derived neurotrophic factor
BI
Boehringer Ingelheim.
b.i.d.
bis in die (twice daily dosing)
Bpm
Beats per minute
CA
Competent Authority
CHR
Clinical High Risk
CI
Confidence Interval
cGMP
Cyclic guanosine monophosphate
CML
Local Clinical Monitor 
CNS
Central Nervous System
COPS
Criteria Of Psychosis-risk Syndromes 
CRA
Clinical Research Associate
CRF
Case Report Form
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
DALY
Disability adjusted life year
dB
decibel
DDI
Drug-drug interaction
DEDP
Drug exposure during pregnancy
DILI
Drug Induced Liver Injury
DMC
Data Monitoring Committee
DNA
Deoxyribonucleic acid
DSM
Diagnostic and Statistical Manual of Mental Disorders
ECG
Electrocardiogram


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eC-SSRS
Electronic Columbia Suicide Severity Rating Scale
EDC
Electronic Data Capture
EEG
Electroencephalogram/Electroencephalography
EM
Extensive metabolizers 
EOT
End of treatment
ERP
Event related potential
EudraCT
European Clinical Trials Database
FAS
Full Analysis Set
FDA
Food and Drug Administration
FEP
First episode of psychosis
Fluency
Category Fluency: Animal Naming 
F-M 100
Farnsworth-Munsell 100 hue test 
GABAA
gamma-aminobutryic acid 
GAF
Global Assessment of Functioning 
GCP
Good Clinical Practice
GF: Social
Global Functioning: Social
GMP
Good Manufacturing Practice
HIPAA
Health Insurance Portability and Accountability Act
HrQoL
Health related quality of life
HVLT-R
Hopkins Verbal Learning Test-Revised
HZ
Hertz (frequency)
IB
Investigator’s Brochure
ICC
Intra-class correlation coefficient
ICF
Informed Consent Form
ICH
International Conference on Harmonization
IEC
Independent Ethics Committee
IL-6
Interleukin 6
IL 1β
Interleukin 1 beta
IQ
Intelligence Quotient
IRB
Institutional Review Board
IRT
Interactive Response Technology
ISF
Investigator Site File
IPEG
International Pharmaco-EEG Society
ITC
Inter-trial phase coherence
IUD
Intrauterine device
IUS
Intrauterine hormone releasing system
LNS
Letter-Number Span 
LTP
Long term potentiation
MATRICS
Measurement And Treatment Research to Improve Cognition in 
Schizophrenia
MCCB
MATRICS Consensus Cognitive Battery
MedDRA
Medical Dictionary for Drug Regulatory Activities
MEG
Magneto-encephalography
MMN
Mismatch negativity
MMRM
Mixed effects model with repeated measurements


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MoA
Mechanism of Action
Ms
millisecond
NAPLS
North American Prodromal Longitudinal Study
NIMH
National Institute of Mental Heath
NMDA
N-methyl-D-aspartate
OPU
Operative Unit
PANSS
Positive and Negative Syndrome Scale 
PCP
Phencyclidine
PD
Pharmacodynamics
PDE9
Phosphodiesterase-9
PI
Principal Investigator 
PK
Pharmacokinetics
PM
Poor metabolizers
p.o.
per os (oral)
POPS
Presence Of Psychosis Scale 
q.d.
quaque die (once a day)
qEEG
Quantitative EEG
REML
Restricted maximum likelihood 
REP
Residual effect period, after the last dose of medication with measureable 
drug levels or pharmacodynamic effects still likely to be present
RON
Reorienting negativity
SAE
Serious Adverse Event
SCoRS
Schizophrenia Cognition Rating Scale
SIPS
Structured Interview for Psychosis-Risk Syndromes
SOP
Standard Operating Procedure
SOPS
Scale of Prodromal Symptoms
SPET
Single photon emission tomography 
SUSAR
Suspected Unexpected Serious Adverse Reaction 
TCM
Trial Clinical Monitor
TES
Total error score
TNFα
Tumor necrosis factor alpha
TS
Treated set
TSAP
Trial Statistical Analysis Plan
TMT
Trail Making Test TMT
UHR
Ultra High Risk
ULN
Upper limit of normal
URS
User Requirement Specifications
VAS
Visual analogue scale
WHO
World Health Organization
YLD
Years lived with disability


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1.
INTRODUCTION
BI 409306 is a Phosphodiesterase-9 (PDE9) inhibitor under development for the prevention 
of relapse in persons with schizophrenia, and for the treatment of patients with attenuated 
psychosis syndrome (APS) [c01694347-08].
MEDICAL BACKGROUND
1.1
Over the past decade, research into the factors that contribute to the development of 
psychosis has led to the awareness that subgroups of patients can be identified, including 
individuals <18 years of age, in whom conversion to overt psychosis is likely to occur [R15-
1442, R15-1790]. Moreover, the presence of non-specific psychosis spectrum symptoms has 
indicated that incidence rates for comorbid mental disorders in adolescents are almost twice 
the incidence found among the general U.S. population [R15-1442].   The American 
Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders, Fifth 
Edition  (DSM-5), proposes the classification of Attenuated Psychosis Syndrome (APS) as a 
condition for further study, identifying a vulnerable group of individuals suffering from 
"manifest pathology and impaired function and distress” [R15-4424].  This subgroup of 
clinically high risk (CHR) individuals exhibits discernible motor, emotional, cognitive, and 
behavioral alterations that are intermediate between those of healthy individuals and those 
with schizophrenia [R15-1442] (Figure 1.1:1).  These at-risk individuals represent a 
population who stand to benefit from early detection and treatment of the aforementioned 
symptoms as well as possible prevention of subsequent psychotic conversion.  Such 
symptoms as well as the occurrence of psychotic episodes are the focus of the investigation 
plan for BI 409306.
Figure 1.1:1 Computerized Neurocognitive Battery profiles of psychosis spectrum and non-
spectrum physically healthy youths1.
1ABF – abstraction/flexibility, ATT – attention, WM – working memory, VME – verbal memory, FME – face memory, SME – spatial 
memory, LAN – language, NVR – non-verbal reasoning, SPA – spatial processing, EMI – emotion identification, EMD – emotion 
differentiation, AGD – age discrimination, MOT – motor, SM – sensorimotor


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The clinically high risk (CHR) state has been the focus of extensive research over the last 
decade and was described in the DSM-5 as Attenuated Psychosis Syndrome (APS), 
alternatively called “ultra-high risk” (UHR) and “at-risk mental state” (ARMS). There is 
broad consensus of the existence of a prodromal, at-risk syndrome as well as hypotheses 
regarding potential intervention [R15-1790, R15-1792].
Community based-epidemiology data were published from the Philadelphia 
Neurodevelopmental Cohort, a collaborative investigation of clinical and neurobehavioral 
phenotypes in a prospectively accrued cohort of youths (ages 11-21; N=7,054).   Among 
medically healthy youths, 3.7% reported threshold psychotic symptoms (delusions and/or 
hallucinations). An additional 12.3% reported significant sub-psychotic positive symptoms, 
with odd/unusual thoughts and auditory perceptions, followed by reality confusion, being the 
most discriminating and widely endorsed attenuated symptoms [R15-1442].  These data 
suggest not only that psychosis is substantially prevalent among youth, but in addition, the 
vulnerability for psychosis and dysfunction associated with high-risk symptoms, is widely 
present.
Data from a recent analysis of a large US insurance claims database (R18-0654) 
demonstrated that as far back as five years before an incident diagnosis of schizophrenia 
subjects presented for care and utilized healthcare resources at a rate twice that of age and 
region matched controls.  The data demonstrated that these individuals are prescribed a 
number of medications including antipsychotics and antidepressants, suggesting that their 
level of symptomatology has already become problematic in their lives.
Recently, several studies have evaluated the potential applicability of methods to detect and 
prevent psychosis [R15-1790, R15-1442, R15-1792]. New psychometric instruments have 
been developed to better predict the appearance of FEP in a CHR population. Recently, the 
North American Prodromal Longitudinal Study (NAPLS) consortium has reported 
development and validation of prodromal risk syndrome criteria which predict a 35% risk of 
conversion to psychosis within 2 ½ years of ascertainment [R15-1441, R15-1440]. The 
results have been used to develop a pilot, web-based individualized risk prediction tool that 
can be used to predict conversion risk based on profiles of risk factors for newly ascertained 
cases.  Similar studies (e.g., ongoing
 initiative in EU [www.
.eu]; 
Personalised Prognostic Tools for Early Psychosis Management) have shown slightly 
different conversion rates, mainly due to aspects of diagnosis and definitions, which has led 
the United States (US) National Institute of Mental Health (NIMH) to initiate a project called 
HARMONY to align the different initiatives (www.nimh.nih.gov).
In the Global Burden of Disease 2000 study, published in the World Health Report 2001,
schizophrenia is the 7th leading cause of years lived with disability (YLD) at a global level, 
accounting for 2.8% of total global YLD.  Further, the Disability Adjusted Life Years 
(DALYs), reflecting the sum of years of potential life lost due to premature mortality and the 
years of productive life lost due to disability is estimated at 15.6 million [R16-5173]. In the 
“Global Burden of Disease Study 2010”, 1160 sequelae of over 220 diseases were studied:  
the health state with the highest disability weight was acute schizophrenia [R13-0284].  No 
treatment exists that is shown to reduce the annual incidence of this devastating illness.


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DRUG PROFILE
1.2
BI 409306 is a new chemical entity intended for oral administration. Film coated immediate 
release tablets of 50 mg 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 was 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) [c01694347-08]).
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 
(for details please refer to section 5.2 of the IB [c01694347-08].
BI 409306 was tested in a comprehensive panel of in vitro and in vivo General Pharmacology 
tests (non-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 [c01694347-08].
Clinical Summary
In all 10 healthy volunteer trials, the most frequent drug related adverse events were visual 
side effects that occurred shortly after dosing, mostly resolved within 1 hour, i.e., in close 
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. 


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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 [c01694347-08]. 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 350 mg in CYP2C19 extensive metabolizers (EM); up to 100 mg in CYP2C19 
poor metabolizers (PM)) in healthy young volunteers and multiple doses (14 days up to 100
mg EM/50 mg 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 [c01694347-08]. 
Study 1289.18 was conducted to assess safety, tolerability, PK and pharmacodynamics (PD)
of BI 409306 25 mg, 50 mg, or 100 mg QD 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 cognitive 
impairment associated with schizophrenia) 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 adverse event (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 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 subject 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 [c01694347-08; c09991178-01].
Subsequent  pharmacometric modelling was conducted simulating PK and PD in 2000 
subjects and showed that a dose of 50 mg  b.i.d. would provide exposures of >65 nM 
(1xIC50) in 93% of subjects for 5.9 hours twice a day compared with 49% of subjects for 4 
hours in subjects receiving the 25 mg QD dose.  Therefore we conclude that a dose of 50 mg 


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b.i.d. provides optimal exposure levels within the CSF while demonstrating acceptable 
tolerability.
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) [c01694347-08].


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2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT
RATIONALE FOR PERFORMING THE TRIAL
2.1
PDE9 inhibition is hypothesized to improve the N-methyl-D-asparate acid (NMDA)-receptor 
signaling cascade by increasing cyclic guanosine monophosphate (cGMP) levels with 
subsequent lead to strengthening of synaptic plasticity as measured by enhanced hippocampal 
long-term potentiation (LTP) [c01694347-08]. Increasing evidence suggests that 
glutamatergic dysfunction may play a key role in mediating risk for conversion to psychosis 
[P15-03385, R15-3282, R15-1561]. Reorganization of synapses occurs extensively during 
postnatal and adolescent brain development until young adulthood, and one of the major 
changes is reorganization of glutamatergic synapses in which the NMDA receptor plays a key 
role. This important neurodevelopmental process results in changes in brain plasticity and 
synaptic transmission, known as synaptic pruning, since synapses are reorganized into more 
efficient configurations and weak connections are being eliminated [R15-1457, R15-3301]. 
Consistent with this, total gray matter volume in cortical areas was found to increase at earlier 
ages, followed by sustained loss starting around puberty as revealed in magnetic resonance 
imaging studies [R15-1783, R15-3396]. Regarding schizophrenia, plausible scenarios of its 
genesis includes “faulty” over-pruning later during adolescence [R15-1563, R15-3331] which 
is in-line with changes in NMDA receptor density (especially NR1 subunit decrease) seen in 
post-mortem brain from patients with schizophrenia [R15-1784, R15-1789] and in single 
photon emission tomography (SPET) studies in patients [R15-1786].
Synaptic over-pruning (i.e. elimination of important as well as less-relevant synaptic 
connections likely due to NMDA receptor dysfunction) during synaptic reorganization of the 
brain in adolescence remains an untested candidate pathogenic mechanism underlying 
transition from states of attenuated psychosis syndrome to frank psychosis. Synaptic pruning 
targets weak synapses, but synapses are strengthened with experience via mechanisms of 
synaptic plasticity, including NMDA receptor dependent signaling LTP. Thus, it is 
hypothesized that synaptic over-pruning compromises synaptic plasticity/LTP, which may 
further exacerbate deficient plasticity and intensify over-pruning [R15-1457]. Regarding 
strengthening of synaptic plasticity, BI 409306 [c01694347-08] and other PDE9 inhibitors 
such as PF-04447943 [R15-3303] showed an enhancement of hippocampal LTP. Moreover, 
studies of exposure of hippocampal neurons to the PDE9 inhibitor PF-04447943 
demonstrated both enhanced neurite outgrowth and an increase in the number of synapses per 
neurons [R15-3303], providing evidence of a putative mechanism of action (MoA) for 
alleviating synaptic over-pruning in addition to strengthening of synaptic plasticity, thus 
suggesting a rational target for early intervention in APS, as well as that for cognitive 
impairment associated with schizophrenia. 
In conclusion, these preclinical and clinical findings suggest that inhibition of PDE9 by 
BI 409306 represents a rational approach for improvement and potentially normalization of 
those processes dysfunctional in individuals with attenuated psychosis syndrome, leading to 
reduction or remission of the symptoms, and the delay or even prevention of FEP in 


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individuals with attenuated psychosis syndrome via decreasing synaptic over-pruning and 
strengthening the NMDA-receptor signaling and synaptic plasticity.
This trial is a proof of concept study designed to investigate the effect of BI 409306 on early 
intervention in patients with APS. Adolescents (>16 years old) will be included in this trial 
based on the recognition that the clinically high-risk state is already apparent in this age 
group and the criteria and symptomatology in adolescents under 18 is identical to the 
presentation of the older (>18) individuals.
TRIAL OBJECTIVES
2.2
The objective of this study is to investigate the efficacy, safety and tolerability of BI 409306 
compared to placebo given for 52 weeks to patients with attenuated psychosis syndrome. The 
study is designed to show superiority of BI 409306 over placebo in achieving remission of 
APS as well as improvement in cognition and functional capacity.
Exploratory biomarkers will be evaluated including NMDA-R signaling genotyping, salivary 
cortisol, brain-derived neurotrophic factor (BDNF), inflammatory cytokines in the blood, and 
automated speech analysis to explore their association with clinical outcome in patients with 
attenuated psychosis syndrome.
An optional electroencephalogram (EEG) sub-study will investigate the clinical utility of 
quantitative EEG, and auditory and visual event related potential (ERP) biomarkers for risk 
stratification and targeted intervention. See Section 10.1.
A subset of patients will complete ocular safety tests to further characterize the ocular safety
of BI 409306. See Section 10.2.
BENEFIT - RISK ASSESSMENT
2.3
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 10 mg, 25 mg and 50 mg 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 [c09991178-01].  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.   All adverse effects 
generally were restricted to high dose levels and were reversible [U12-1034; U13-1182; U12-
2165; U13-1303]. Cardiac function will be monitored during the study according to the Flow 
Chart.


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It is expected that the metabolic clearance of BI 409306 will be similar for adolescents and 
adults.  Any possible effects on sexual maturation will be monitored clinically via appropriate 
endocrine markers. Inclusion of adolescents in this trial is based on the recognition that the 
clinically high-risk state is already apparent in these adolescents and the criteria and 
symptomatology in adolescents under 18 is identical to the presentation of the older
individuals.
As with all drugs, the potential for hypersensitivity and allergic reactions have to be taken 
into consideration when BI 409306 is administered. Other risks are inherent to any clinical 
trial such as unexpected adverse clinical or laboratory events. 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 
5.3.6.1.
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 
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 [c01694347-08].
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 [c01694347-08].
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. This must be balanced with an effort to ensure that the population under study is 
representative to the extent possible, of the population intended to be prescribed the 
compound, should it ever receive regulatory approval.  Since suicidality is known to be 
common in the CHR population, the exclusion criteria for this study allow for an assessment 
of past suicidal behaviour by the investigator while excluding recent significant suicidal 
ideation. 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.
NAPLS has constructed an algorithm to estimate the risk of conversion to psychosis 
depending on several risk factors. When applied, this algorithm predicts the conversion rates 
for patients without treatment [R16-3564].  This algorithm will be utilized to assess the 
sample of eligible patients to better quantify risk for conversion.  Patients who convert to 
psychosis will continue to be followed in the trial.


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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. All randomised patients will 
receive Brief Supportive Psychoeducation, which was developed for use within the NAPLS 
studies and demonstrated statistically significant improvement in positive symptoms over six 
months compared to baseline [R16-1547]. Patients are also permitted to remain on any 
psychotropic medications and new concomitant medications may be prescribed as necessary 
to ensure the welfare of the patient. 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.


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
OVERALL TRIAL DESIGN AND PLAN
3.1
This is a multicentre, multinational, randomised, double-blind, placebo-controlled parallel 
group trial. In total, 300 patients with Attenuated Psychosis Syndrome (APS) are planned for 
randomisation in this study.  
Patients are included in the study once informed consent/assent has been signed. Patients 
suitable after screening will be randomised to the 52 week treatment period assigned at a ratio 
of 1:1 to one of two treatment groups as shown in Figure 3.1: 1. Randomisation will be 
stratified by baseline use of antipsychotics (see Section 7.6 for details). After completion of 
the treatment period, or following early discontinuation, patients will complete the 4 week 
follow-up period. 
Screening       Randomisation
Figure 3.1: 1
Overview of trial design
Additionally, exploratory biomarkers will be assessed for structural and functional measures
of brain plasticity. These objective markers of brain physiology may help interpretation of the 
data or may help identify subgroups of patients that are better responders. The Biomarker 
Plan is described in Section 5.5.
BI 409306 50 mg b.i.d.
Day 1
Week 56 
Screening
Day -28
Treatment period
Week 52 
Follow-up
R
S
Placebo b.i.d.
R
S


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3.1.1 
Administrative structure of the trial
The trial is sponsored by Boehringer Ingelheim (BI). Boehringer Ingelheim has appointed a 
Trial Clinical Monitor (TCM), responsible for coordinating all required activities, in order to:
-
manage the trial in accordance with applicable regulations and internal standard 
operation procedures (SOPs)
-
direct the clinical trial team in the preparation, conduct, and reporting of the trial
-
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 internal 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. For 
these activities, a Trial Data Manager and Trial Statistician have been appointed. 
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 Coordinating Investigator is responsible to coordinate Investigators at different centres 
participating in this multicentre trial. Tasks and responsibilities are defined in a contract. 
Relevant documentation on the participating (Principal) Investigators and other important 
participants, including 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 an electronic ISF.
A data-monitoring committee (DMC) independent of the sponsor will be established to assess 
the progress of the clinical trial and to ensure there is no imbalance in safety endpoints. The 
DMC will meet three times per year. An unblinded safety and efficacy assessment is planned
to recommend to the sponsor whether to continue, modify, or stop the trial. Measures are in 
place to ensure blinding of the sponsor and all other trial participants. The tasks and 
responsibilities of the DMC will be specified in a charter. The DMC will maintain written 
records of all its meetings, which will be stored as per the charter.  
 has been selected as a service provider to support the following tasks related 
to the instruments and scales for patient assessment: rater prequalification, rater training, 
provision of rater materials, and central review of assessments for quality (SIPS/ SOPS, 
HVLT-R, BACS SC, BAC App, SCoRS). These responsibilities and tasks will be defined in 
a written contract before initiation of the clinical trial.


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 will confirm each patient’s diagnosis of Attenuated Psychosis Syndrome 
(APS) after review of the video-taped Structured Interview for Psychosis-Risk Syndromes 
(SIPS) during the screening period. A Central Rating Committee will adjudicate conversions
to psychosis after 
’ review of the video-taped Scale of Prodromal Symptoms 
(SOPS) interviews. After the video and source document review has been completed, site and 
sponsor personnel will receive feedback on the interview quality and ratings. The tasks and 
responsibilities of 
 and the Central Rating Committee will be specified in the 
Assessment Procedures Binder, including documentation specifications regarding the 
SIPS/SOPS review.
A central laboratory service and an IRT vendor will be used in this trial. Details will be 
provided in an IRT Manual and Central Laboratory Manual, filed in the ISF. Vendors will 
also be used to administer the suicidality assessment (eC-SSRS) via telephone and to monitor 
medication adherence using a smartphone application.
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
3.2
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 on the remission of APS symptoms as well as 
improvement in cognition and functional capacity.  The primary efficacy analysis is planned 
to be conducted after 52 weeks of treatment.  The 4-week 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 indicated for the treatment of symptoms of APS or 
for the prevention of first episode of psychosis. 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 
their concomitant psychotropic medications, will receive Brief Supportive Psychoeducation, 
and are permitted to receive a new or increased dose of antipsychotic medication if the 
Principal Investigator (PI) feels the patient has experienced a first episode of psychosis. The 
risk to the control group is discussed in Section 2.3.
SELECTION OF TRIAL POPULATION
3.3
It is planned that approximately 50 trial centres in up to four countries will be participating in 
this trial to randomise 300 patients.  Eligible patients will be randomised to the 52 week 
treatment period assigned at a ratio of 1:1 (BI 409306 50 mg b.i.d. (twice daily dosing), 
placebo). 
It is expected that approximately 6 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 TCM.


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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 CML, and 
documentation of approval filed in the 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/assent) 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 meeting the following diagnostic criteria for attenuated psychosis syndrome (APS) 
as defined in DSM-5 will be included:
A. At least one of the following of symptoms is present in attenuated form, with 
relatively intact reality testing and is of sufficient severity or frequency to warrant 
clinical attention:

Delusions

Hallucinations

Disorganized speech.
B. Symptom(s) must have been present at least once per week in the last 1 month
C. Symptom(s) must have begun or worsened in the past year
D. Symptom(s) is sufficiently distressing and disabling to the individual to warrant 
clinical attention
E. Symptom(s) is not better explained by another mental disorder, including: Depressive 
or bipolar disorder with psychotic features and is not attributable to physiological 
effects of a substance or another medical condition
F. Criteria for any psychotic disorder have never been met.
A diagnosis of Attenuated Positive Symptom Syndrome is defined by the presence of recent 
attenuated positive symptoms that meet ALL of 5 criteria: sufficient severity (criterion A), 
sufficient  frequency (criterion B), recency of onset or worsening (criterion C), associated 
with sufficient distress or disability to warrant clinical attention (“warrant attention
criterion,” criterion D), and not have been likely due to another disorder (“attribution
criterion,” criterion E).


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Patients may be enrolled if they are currently taking antipsychotic medication (See Section 
4.2.1). If a patient discontinues an antipsychotic medication, they can be randomized two 
weeks after discontinuation.
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. Meet diagnostic criteria for attenuated psychosis syndrome as defined in DSM-5 
and determined by SIPS administered at screening and diagnosis confirmed by 
after review of video-taped SIPS interview.
2. Inclusion criterion 2 removed in global amendment 3. Numbering of subsequent 
criteria was not changed. 
3. Age ≥16 and ≤ 30 years at the time of consent/assent.
4. Male or female patients willing to use highly effective methods of contraception. 
-
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.
5. Signed and dated written informed consent in accordance with Good Clinical 
Practice (GCP) and local legislation prior to any study-related procedures OR 
signed and dated informed consent provided by the patient’s parent(s) (or legal 
guardian) and assent by the patient prior to any study-related procedures in 
accordance with GCP and local legislation2. If the patient has a legal 
representative, then this legal representative must give written informed consent 
as well.
____________________________________________
1. Females of childbearing potential are defined as:
-
fertile, following menarche and until becoming post-menopausal unless permanently sterile.
-
not postmenopausal (12 months with no menses without an alternative medical cause) and 
-
not permanently sterilised (e.g., hysterectomy, bilateral oophorectomy or bilateral salpingectomy).
2. Patients who sign the assent and reach the age of majority during the trial must sign the current version of the informed 
consent.


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3.3.3
Exclusion criteria
1. Present or past diagnosis of schizophrenia, schizophreniform, schizoaffective disorder, 
bipolar disorder I, major depressive disorder with psychotic features, delusional
disorder, brief psychotic disorder, other specified schizophrenia spectrum and other 
psychotic disorder (except attenuated psychosis syndrome), and unspecified 
schizophrenia spectrum and other psychotic disorder, according to DSM-5.
2. Patients taking antipsychotic medication for less than 8 weeks, or patients taking 
antipsychotic medication for a longer duration but who have not been on a stable dose 
for 8 weeks prior to informed consent. 
3. Patients who begin taking an antipsychotic between Visit 1 and Visit 2.
4. Patients who have discontinued an antipsychotic medication less than two weeks prior 
to randomization.
5. Patients taking Clozapine.
6. Suicidal behavior in the past 2 years reported in the Columbia Suicide Severity Rating 
Scale (C-SSRS) with a lethality of attempt ≥1, or with a lethality of 0 but a potential 
lethality of 2, or that in the judgement of the investigator would jeopardize the 
patient’s safety while participating in the trial. The investigator/qualified rater must 
review all screening C-SSRS reports prior to randomization, documenting an 
additional interview assessing lethality of the behavior history when appropriate.
7. 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).
8. 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.
9. Known diseases of the central nervous system (including but not limited to any kind 
of seizures or stroke).
10. History of significant head injury (>5 minutes without consciousness).
11. A serious developmental disorder that in the judgement of the investigator would 
inhibit the patient’s ability to comply with all study procedures, or mental retardation
(documented IQ <70), or acute attenuated symptoms exclusively related to
intoxication from a psychotropic substance. 
12. 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.
13. Planned elective surgery requiring general anesthesia, or hospitalization for more than 
1 day during the study period.
14. Meets criteria for Substance Use Disorder (DSM-5) within the six months prior to 
informed consent/assent. 
15. 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.
16. Patients taking strong or moderate CYP1A2 inhibitors who are also a CYP2C19 Poor 
Metabolizer (PM). Patients taking medication known to be a strong or moderate 
inhibitor of CYP1A2 must be prospectively genotyped to ensure they are not poor 


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metabolizers of CYP2C19. (A list of CYP1A2 and CYP2C19 inhibitors can be found 
in the ISF.). 
17. 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.)
18. Patients with a history of moderate to severe hepatic impairment (Child-Pugh B / C).
19. Patients with a history of moderate to severe renal impairment (Stage 3 – 5).
20. Women who are pregnant, nursing, or who plan to become pregnant while in the trial.
21. In the judgment of the investigator, inability of the patient to comply with the clinical 
trial procedures.
22. Currently enrolled in another investigational device or drug study, or less than 30 days 
since ending another investigational device or drug study(s), or receiving other 
investigational treatment(s).
23. Previous participation in any BI 409306 study.
24. Known hypersensitivity to the drug product excipients (lactose monohydrate, 
pregelatinized starch, hydroxypropylcellulose, croscarmellose sodium, magnesium 
stearate, hypromellose, propylene glycol, titanium dioxide, talc and iron oxide 
yellow).
3.3.4
Removal of patients from therapy or assessments
3.3.4.1
Removal of individual patients
An excessive withdrawal rate can have a severe negative impact on the scientific value of the 
trial. Every effort should be made to keep patients in the trial as scheduled. This includes 
careful patient selection and appropriate explanation of the trial requirements and procedures 
prior to enrolment as well as an explanation of the consequences of premature withdrawal.
An individual patient is to be withdrawn from trial treatment if:

The patient withdraws consent for trial treatment or trial participation, 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 adhere to the trial requirements in the future.

The patient exhibits suicidality, in the clinical judgement of the Investigator or according 
to criteria below: 

Any suicidal behavior (i.e. actual attempt, interrupted attempt, aborted attempt, or 
preparatory acts or behavior)


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
Any suicidal ideation of type 4 or 5 in the C-SSRS (i.e. active suicidal thought 
with intent but without specific plan, or active suicidal thought with plan and 
intent)
Patients who discontinue participation after signing the informed consent/assent form but 
prior to randomisation (Visit 2) will be considered screening failures. 
Patients who discontinue or withdraw from the study after randomisation (Visit 2) will be 
considered as “early discontinuations” and the reason for premature discontinuation must be 
recorded in the electronic case report forms (eCRFs). Patients who withdraw or discontinue 
from the trial after randomisation will not be replaced. The data will be included in the trial 
database and will be reported.
Premature study drug discontinuation
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 Section 
6.2.2. Patients who discontinue study drug prematurely should ideally be observed until the
end of the study (week 52) as if they were still receiving blinded study treatment. 
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 (in-clinic 
and phone 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: the SOPS Positive 
Symptom items, eC-SSRS, AEs, concomitant therapy (including 
change in dose or new dose of antipsychotic medication).
Early D/C Option 3
Discontinue participation in remaining study activities but permit 
collection of the occurrence of psychiatric illness and vital status
approximately one year after randomization from 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 and vital status 
approximately one year after randomization through review of 
patient’s medical information from alternative sources (e.g., 
doctor’s notes, hospital records, etc.).


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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. In this case, the patient does not need to justify the 
decision and should be withdrawn from the study and all follow-up assessments. 
If the patient refuses all four options and elects to immediately discontinue the trial, the 
patient should complete the same EOT and follow-up procedures as those patients who 
choose Early D/C Options 3 and 4.  Completing these procedures is strongly recommended 
for the patient’s safety.
The discussion with the patient and the outcome regarding follow up, psychiatric and vital 
status collection, discontinuation of trial medication, and withdrawal of consent must be
documented in the patient’s medical records.
3.3.4.2
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 GCP, the clinical trial protocol (CTP), or the contract disturbing the 
appropriate conduct of the trial
The Investigator / the trial site will be reimbursed for reasonable expenses incurred in case of 
trial termination (except in case of the third reason).


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4.
TREATMENTS
INVESTIGATIONAL TREATMENTS 
4.1
BI 409306, as a film-coated tablet, will be produced by Boehringer Ingelheim Pharma GmbH 
& Co. KG.
Each film-coated tablet contains 50 mg BI 409306.
Eligible patients are randomly assigned to double blind treatment at a ratio of 1:1 of placebo 
or 50 mg b.i.d. BI 409306 (c.f. Section 4.1.4 and Table 4.1.4:1).
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:
50 mg
Posology
b.i.d.
Route of administration:
Oral
Table 4.1.1: 1b
Characteristics of the test products-BI 409306 matching placebo
Substance:
Placebo matching 50 mg
Pharmaceutical formulation:
Film-coated tablet
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG
Unit strength:
N/A
Posology
b.i.d.
Route of administration:
Oral


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4.1.2
Selection of dose in the trial
Based on the effective doses in the T-maze spontaneous alternation test,  the novel object 
recognition test in mice and clinical data of a cerebrospinal fluid (CSF) study in healthy 
volunteers, the therapeutic dose in humans was projected to be in the range of CSF exposure 
of 1xPDE9 IC50 corresponding to a dose in the range of 25 mg [c01694347-08]. Recent 
pharmacometric modelling indicates that a single dose of 25 mg once daily (q.d.) will result 
in therapeutic exposures in the CSF (1xIC50) in 49% of subjects over a 4 hour duration, 
while a 50 mg dose would result in 93% of subjects reaching such a CSF exposure for 5.9 
hours.  In line with the proposed mode of action, it is hypothesized that compounds which 
strengthen NMDA receptor signalling and LTP, exert long-lasting cognitive improvement in 
vivo outlasting drug exposure, therefore, a b.i.d. posology is 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 50 mg b.i.d. or 
placebo in a 1:1 ratio according to a randomisation plan. The assignment will occur in a 
blinded fashion via Interactive Response Technology (IRT).
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/assent 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 two 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.
To maintain the blind, all treatments will consist of one tablet of BI 409306 or placebo in the 
morning and one tablet of BI 409306 or placebo in the evening depending on the treatment 
group.


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Table 4.1.4: 1 Treatment administration per dose group and day
Treatment Group
Dose
Total tablets per daily dose
Placebo
n/a
2
(1 tablet in A.M., 1 tablet in P.M.)
BI 409306
50 mg
2
(1 tablet in A.M., 1 tablet in P.M.
Patients should be instructed to take their study medication with water at approximately the 
same time every day in the morning and in the evening (approximately 12 hours apart) with 
or without food.   BI 409306 tablets should not be chewed or crushed. If a dose is missed by 
more than 6 hours, that dose should be skipped and the next dose should be taken as 
scheduled.
A dose reduction of BI 409306 is not possible.
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.
4.1.5.2
Unblinding and breaking the code
Emergency unblinding will be available to the Investigator / Pharmacist / investigational drug 
storage manager via IRT. It must only be used in an emergency situation when the identity of 
the trial drug must be known to the Investigator in order to provide appropriate medical 
treatment or otherwise assure safety of trial participants. 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 (via 24-hour Emergency helpline). If the code 
break for a patient is accessed, the sponsor must be informed immediately. The reason for 
accessing the code break, together with the date, must be documented on the appropriate CRF 
page. In case a third party needs to break the code when the Investigator cannot be reached, 
the code can be opened by calling the emergency code manager.
Due to the requirements to report Suspected Unexpected Serious Adverse Reactions 
(SUSARs), it may be necessary for a representative from
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 will not be shared further. 


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4.1.6
Packaging, labelling, and re-supply
The investigational products will be provided by BI or a designated 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.
Training kits containing placebo will be provided to allow for practice with the child-proof 
packaging.
For details of packaging and the description of the label, refer to the ISF.
4.1.7
Storage conditions
Drug supplies will be kept in their original packaging and in a secure limited access storage 
area according to the recommended storage conditions on the medication label. A
temperature log must be maintained for documentation.
If the storage conditions are found to be outside the specified range, the local clinical monitor 
(as provided in the list of contacts) must be contacted immediately.
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 trial protocol by the IRB / ethics committee 

Availability of a signed and dated clinical trial contract between the sponsor and the head 
of the investigational site,

Approval/notification of the regulatory authority, e.g. competent authority,

Availability of the curriculum vitae of the principal Investigator,

Availability of a signed and dated clinical trial protocol

Availability of the proof of a medical license for the principal Investigator (if applicable)

Availability of Form FDA 1572 (if applicable)
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 center or alternative 
disposal of unused products. If applicable, the sponsor or warehouse / drug distribution centre
will maintain records of the disposal. 
These records will include dates, quantities, batch / serial numbers, expiry (‘use- by’) dates, 
and the unique code numbers assigned to the investigational product and trial patients. The 
Investigator / Pharmacist / investigational drug storage manager will maintain records that 
document adequately that the patients were provided the doses specified by the CTP and 
reconcile all investigational products received from the sponsor. At the time of return to the 


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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.
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
4.2
RESTRICTIONS
4.2.1
Other treatments and emergency procedures
If a patient is enrolled who is taking an antipsychotic medication that will continue during the 
treatment period, it is extremely important they continue to take the current antipsychotic 
medication at the same dose as when the patient was randomized. The dose of an 
antipsychotic medication can be decreased or discontinued entirely. A patient’s dose of 
antipsychotic medication should be increased only in circumstances of significant worsening 
of psychosis symptoms that the investigator feels qualifies for a first episode of psychosis.
Patients experiencing a first episode of psychosis should continue taking study drug at the 
discretion of the investigator.
When a patient begins a new prescription or increases their dose of an ongoing antipsychotic 
medication, this is an outcome event. The available information (e.g., SOPS interview video, 
medical records from prescribing physician) will be subsequently reviewed by the Central 
Rating Committee.
Antipsychotic 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. Prior and concomitant 
psychotherapy information should also be recorded in the eCRFs.
All patients (i.e., including those on BI 409306 and those on placebo) will receive Brief 
Supportive Psychoeducation at timepoints described in the Flow Chart. The supportive 
psychoeducation sessions will be administered by trained site staff and will educate patients 
and family members about the symptoms of attenuated psychosis syndrome as well as the 
clinical trial program, risk and protective factors, the impact of stress and the importance of 
medication adherence. Through these sessions, the patient’s and family’s needs are evaluated, 
a symptom reduction plan is developed and referrals for community services may be 
provided. Refer to Psychoeducation Manual and Materials in ISF.
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 medications known to be strong or moderate CYP1A2 inhibitors is not permitted
unless it is documented that the patient is NOT a CYP2C19 poor metabolizer. Patients taking 


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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 randomization, at the discretion of the 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.
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 and the 4-
week follow-up period, in the clinical judgment of the investigator, is not permitted.
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 in the opinion of the 
investigator. Urine drug screens for amphetamines, cannabis, cocaine, methadone, opiates, 
and phencyclidine (PCP) will be conducted during the trial for review by the Investigator.
Patients with positive drug screens may remain in the trial at the discretion of the 
investigator.
Patients will be instructed to refrain from caffeine, alcohol, dairy products, and 
nonprescription medications the evening before and the morning of salivary cortisol 
sampling. Other than the visits with saliva collection, 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 Section 
3.3.2.


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TREATMENT COMPLIANCE
4.3
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 in the investigator site file.
This trial will utilize a medication adherence monitoring platform (“Platform”). The Platform 
uses artificial intelligence on smartphones to confirm study medication ingestion. In addition, 
built-in reminders and a communication system allow 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 monitoring Platform requires that patients take each dose of the study medication while 
using a smartphone. The Platform will be provided to a patient preloaded on a smartphone or 
patients will download the Platform onto their own mobile device. 
Patients will receive reminders within predefined time windows to take their medication 
using the Platform. This notification reminds patients to take their medication dose while 
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 application 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. The amount 
of guidance that the device provides to the patient is automatically reduced as the patient 
becomes more proficient at using the application.
After the device confirms proper study medication ingestion, video recordings will be 
encrypted and transmitted to a secure centralized location for further analysis, including 
testing for duplicate enrolment and improving the predictive algorithms, accuracy or usability 
of the Platform. The captured data and video is reviewable through a roles and rules restricted 
system ensuring privacy of the information. The system is compliant with the Health 
Insurance Portability and Accountability Act (HIPAA) in the US, as well as UK and EU data 
protection regulations, which protect the privacy and security of healthcare 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 be provided with patient names, nor will they be 
given access to patient medical records.


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The Platform will allow for rapid and tailored intervention in case of non-adherence (drug 
interruptions) without having to visit the clinic for unscheduled visits. 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 patient’s 
source and on the appropriate eCRFs. 


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5.
VARIABLES AND THEIR ASSESSMENT
TRIAL ENDPOINTS
5.1
5.1.1
Primary Endpoint
The primary endpoint is time to remission from APS within a 52 week timeframe.
Per DSM-V, the proposed diagnostic criteria for APS are:
A. At least one of the following of symptoms is present in attenuated form, with relatively 
intact reality testing and is of sufficient severity or frequency to warrant clinical 
attention:

Delusions

Hallucinations

Disorganized speech.
B. Symptom(s) must have been present at least once per week in the last 1 month
C. Symptom(s) must have begun or worsened in the past year
D. Symptom(s) is sufficiently distressing and disabling to the individual to warrant 
clinical attention
E. Symptom(s) is not better explained by another mental disorder, including: Depressive 
or bipolar disorder with psychotic features and is not attributable to physiological 
effects of a substance or another medical condition
F. Criteria for any psychotic disorder have never been met.
A diagnosis of APS is defined by the presence of recent attenuated positive symptoms that 
meet ALL of 5 criteria: sufficient severity (criterion A), sufficient frequency (criterion B), 
recency of onset or worsening (criterion C), associated with sufficient distress or disability to 
warrant clinical attention (“warrant attention criterion,” criterion D), and not likely due to 
another disorder (“attribution criterion,” criterion E).
A patient in remission is defined as someone who no longer meets the severity criterion.
Remission from APS is defined as a score of <3 on all of the P1-P5 Positive Symptom items 
of the SOPS and maintained until the end of treatment. 
5.1.2
Secondary Endpoints

Time to first episode of psychosis within a 52 week timeframe as adjudicated by the 
Central Rating Committee.  First episode of psychosis defined as one or more SOPS 
P1-P5 rated a 6 AND either a symptom is seriously disorganizing or dangerous OR 
one of the symptoms above occurred at least one hour per day at an average frequency 
of four days/week over the past month. OR a new prescription or increase in dose of 
an ongoing antipsychotic medication. Time of onset of first episode psychosis is 
defined using the rater’s best estimate as determined in the SOPS interview or when 


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the patient began taking a new prescription or increased the dose of antipsychotic 
medication.

Change from baseline in everyday functional capacity as measured by Schizophrenia 
Cognition Rating Scale (SCoRS) total score after 24 and 52 weeks of treatment.

Change from baseline in the BAC App composite T score after 52 weeks of treatment.

Change from baseline in Positive and Negative Syndrome Scale (PANSS) positive 
items score, negative items score, and total score after 52 weeks of treatment.
ASSESSMENT OF EFFICACY
5.2
Remission of APS, conversion to psychosis, functional capacity, cognitive function, and 
disease state will be measured by the batteries and questionnaires listed below:
The Structured Interview of Psychosis-Risk Syndromes (SIPS) is a structured interview 
for diagnosing a clinical high risk (CHR) syndrome for psychosis and cases of first episode 
psychosis [R16-0681]. It contains a severity rating scale (Scale Of Prodromal Symptoms, or 
SOPS), a well-anchored Global Assessment of Functioning (GAF) [R16-0594], the DSM-5
schizotypal personality disorder checklist, a brief assessment of the family history of 
psychosis, the Criteria Of Psychosis-risk Syndromes (COPS) and Presence Of Psychosis 
Scale (POPS) and DSM-5 Attenuated Psychosis Syndrome criterion sets.


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The SOPS, contained within the SIPS, assesses Positive, Negative, Disorganization and
General symptoms.  It is administered as a semi-structured interview with 19 rating scales 
measuring severity and change of prodromal symptoms. Each item is scored from 0-6. The 
positive symptoms are scaled from 0 (absent) to 6 (severe and psychotic). The remaining 
items are scaled from 0 (absent) to 6 (extreme). The 19 rating scales are each independently 
anchored.
The Positive scale is used to make a diagnosis of attenuated psychosis syndrome (APS) and 
conversion to psychosis. To meet criteria for APS, a patient must at some point have rated 
level “3”, “4”, or “5” on at least one of the P1-P5 Positive Symptom items of the SOPS. The 
symptom(s) must have occurred at the then-current intensity level at an average frequency of 
at least once per week in the past month, and must not have been likely due to another 
disorder. The Negative, Disorganization and General domains are used to assess the severity 
of the diagnosis [R15-1441]. 
Conversion to psychosis and time to conversion will be adjudicated by the Central Rating 
Committee after review of video-taped SOPS interview. Adjudication will take into account 
information provided by patients, informants, and medical records when available.
Schizophrenia Cognition Rating Scale (SCoRS) will be used to evaluate everyday 
functional capacity.
The SCoRS is a 20-item interview-based assessment of cognitive deficits and the degree to 
which they affect day-to-day functions. It collects information from a patient interview, 
interview with an informant (if available), and the administering clinician.
The Schizophrenia Cognition Rating Scale (SCoRS) benefits from receiving information 
from an informant with frequent contact with the patient. However, it is not required and 
some patients may wish not to provide contact information for an informant. When 
conducting the SCoRS, in-person ratings are preferred whenever possible. The informant is 
any person who interacts with the patient at least 2 times per week.
Each of the 20 items of the SCoRS is rated on a 4-point scale. Higher ratings reflect a greater 
degree of impairment. The composite score will be the sum of the 20 items [R16-4322].
The Brief Assessment of Cognition in Schizophrenia (BACS) will be used to evaluate 
cognitive function. There are two versions of the BACS available: the traditional pen-and-
paper version and a tablet based Brief Assessment of Cognition (BAC App) [R17-0578].
The BACS consists of six tests assessing multiple domains of cognitive function: Verbal 
Memory, Digit Sequencing, Token Motor Task, Semantic and Letter Fluency, Symbol 
Coding, and Tower of London. 
The BAC App will be used for English speaking patients. The BAC App provides digital 
recording of data, audio recordings of verbally-delivered responses, and examiner-recorded 


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data for post-test verification of responses. Patients who do not speak English will take the 
pen-and-paper BACS available in their native language.
A composite T score that is calculated using the six standardized scaled sub-test scores will 
be generated. 
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 when possible. The total score is the summation of the 30 item scores [R13-5061].
The Brief Assessment of Cognition in Schizophrenia: Symbol Coding (BACS SC) and 
Hopkins Verbal Learning Test-Revised (HVLT-R) will be used to evaluate the effects of 
BI 409306 on cognitive function, and are variables required for the NAPLS Risk Calculator. 
The BACS SC measures speed of processing. This timed test involves using a key to write 
digits that correspond to nonsense symbols. The BACS SC score is the total number of 
correct responses in 90 seconds. 
The HVLT-R measures verbal learning.  The patient is asked to recall words from a list of 12 
words read orally by the Rater. There are three learning trials with each administration. 
Delayed recall and recognition will not be administered. The HVLT-R score is the total 
number of words correctly recalled across the three trials.
NAPLS Risk Calculator uses an algorithm designed to predict individualized risk of 
psychosis in clinical high-risk patients using demographic, clinical, neurocognitive, and 
psychosocial predictor variables.  The web-based risk calculator generates a score
representing the probability of transition to psychosis within the next 12 months. The 
predictor variables used in this study are: 

Age

Brief Assessment of Cognition in Schizophrenia: Symbol Coding (BACS SC)

Hopkins Verbal Learning Test-Revised (HVLT-R)

SIPS items P1 and P2 (unusual thought content and suspiciousness)


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
Global Functioning: Social (assessment of decline in social functioning in the past 
year)
ASSESSMENT OF SAFETY
5.3
Physical examination, vital signs, laboratory tests, ECG, suicidality, extrapyramidal 
symptoms, and occurrence of (S)AEs will be assessed.
5.3.1
Physical examination
A physical examination will be carried out as described in the Flow Chart.
A physical examination including, but not limited to, general appearance, skin, neck, eyes, 
ears, nose, throat, breast, lungs, heart, abdomen, back, lymph nodes, extremities, and nervous 
system will be performed. The physical examination will include examination of known and 
suspected sites of disease. 
Clinically relevant abnormal findings noticed after baseline assessment will be reported as 
(S)AEs.
5.3.2
Vital Signs
Vital signs (systolic/diastolic blood pressure and pulse rate), height and body weight will be 
recorded at the study visits as described in the Flow Chart. The same type of instrument/scale 
should be used for all measurements. Vital signs will be measured after the patient has been 
sitting for 5 minutes.
5.3.3
Safety laboratory parameters
All safety parameters that will be determined during the trial are listed in Table 5.3.3:1. 
Patients should be fasting for at least 8 hours prior to the blood samples taken at Visit 2 and 
Visit 23 or EOT. All analyses will be performed by a central laboratory. Instructions on 
collection, handling/ processing, and shipping of the samples will be provided in the lab 
manual by the central laboratory. For time points of laboratory sampling refer to the Flow 
Chart.


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Laboratory results of the patients will be available to the respective investigator and to the BI 
Clinical Monitor of each country (via the central laboratory website), and selected abnormal 
laboratory alerts will be sent automatically to the sites and to the sponsor within 24 hours.
Table 5.3.3:1 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)
Chemistry
Chemistry (cont.)
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


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Category
Test name
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)
Endocrine
LH, FSH, testosterone, and estrogens (e.g. estradiol) 
(for randomised patients only)
5.3.4
Electrocardiogram
The 12-lead ECGs will be performed 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 significant, if abnormal. The electronic version of the 
ECG is regarded as source data. Dated and signed printouts will be stored in the patient’s 
medical file if there is no validated and certified e-medical record for ECG data.
ECGs may be repeated for quality reasons and the repeat used for analysis. Additional ECGs 
may be collected by the investigator for safety reasons. Clinically relevant abnormal findings 
noticed after baseline assessment will be reported as adverse events and followed up and/or 
treated locally until normal or stable condition.
5.3.5
Other safety parameters
5.3.5.1
Assessment of suicidality
Suicidality should be monitored closely during the study period. Suicidal thoughts and 
behavior will be assessed by Columbia-Suicide Severity Rating Scale (C-SSRS) (R08-1147).
An electronic version (eC-SSRS) utilizing a telephone solution will be used for this trial.  


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The C-SSRS is a semi-structured, investigator-rated interview, developed by clinical experts 
in cooperation with the FDA, assessing both suicidal behavior and suicidal ideation. It does 
not give a global score, but provides some categorical and some severity information 
specifically for behavior and ideation. 
The computer-automated eC-SSRS is a self-rated version of the C-SSRS using a phone, Web 
or tablet device.  Patients who do not have suicidal behavior or ideation will answer a limited 
number of questions and will usually complete the assessment in about 3 minutes. Patients 
with significant suicidal ideation or behavior may require up to 10 minutes answering all
relevant questions. This assessment should be conducted early in the visit to provide 
sufficient time for the report to be received at the trial site prior to patient departure. At the 
conclusion of each assessment, the site will receive an eC-SSRS Findings Report via email or 
fax. The report presents the findings for suicidal ideation, intensity of ideation, suicidal 
behavior, and lethality/medical damage (for actual suicide attempts only).
The C-SSRS/eC-SSRS has been widely used in large multinational clinical trials. The 
eC-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 
within a specified time prior to the screening or screening visit. The life time 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. The investigator/qualified rater must perform and 
document an additional interview if there is doubt about the validity of the report. 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 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. See Section 5.3.6.
The patient should be withdrawn from treatment if the patient exhibits suicidality and meets
the withdrawal criteria mentioned in Section 3.3.4.1.


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5.3.6
Assessment of adverse events
5.3.6.1
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.
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, this refers to an event in which the patient was at risk of death at 
the time of the event; it does not refer to an event that hypothetically might have 
caused death if more severe.

requires inpatient hospitalisation or prolongation of existing hospitalisation,

results in persistent or significant disability or incapacity, or

is a congenital anomaly / birth defect,

is deemed serious for any other reason if it is an important medical event when based 
on appropriate medical judgment 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. 


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All C-SSRS reports of suicidal ideation type 4 or 5 and all reports of suicidal behavior after 
the baseline visit 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 (see 
Section 5.3.5.1 for details). 
AEs considered “Always Serious”
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 given 
above.
The latest list of “Always Serious AEs” can be found in the Electronic Data Capture (EDC)
system. These events should always be reported as SAEs as described above.
Note: Cancers of new histology and exacerbations of existing cancer must be reported as a 
serious event regardless of the duration between discontinuation of the drug and the 
occurrence of the cancer.
Adverse events of special interest (AESIs)
The term AESI relates to any specific AE that has been identified at the project level as being 
of particular concern for prospective safety monitoring and safety assessment within this trial, 
e.g. the potential for AEs based on knowledge from other compounds in the same class. AESI 
need to be reported to the sponsor’s Pharmacovigilance Department within the same 
timeframe that applies to SAE, 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 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 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.
No other AESIs have been defined for this trial.
Intensity of AEs
The intensity of the AE should be judged based on the following:
Mild:
Awareness of sign(s) or symptom(s) that is/are easily tolerated


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Moderate:
Enough discomfort to cause interference with usual activity
Severe:
Incapacitating or causing inability to work or to perform usual activities
Causal relationship of AEs
Medical judgment should be used to determine whether there is a reasonable possibility of a 
causal relationship between the adverse event and the given study treatment, considering all 
relevant factors, including pattern of reaction, temporal relationship, de-challenge or re-
challenge, confounding factors such as concomitant medication, concomitant diseases and 
relevant history. 
Arguments that may suggest that there is a reasonable possibility of a causal relationship 
could be:
•
The event is consistent with the known pharmacology of the drug 
•
The event is known to be caused by or attributed to the drug class.
•
A plausible time to onset of the event relative to the time of drug exposure.
•
Evidence that the event is reproducible when the drug is re-introduced
•
No medically sound alternative aetiologies that could explain the event (e.g. pre-
existing or concomitant diseases, or co-medications).
•
The event is typically drug-related and infrequent in the general population not 
exposed to drugs (e.g. Stevens-Johnson syndrome).
•
An indication of dose-response (i.e. greater effect size if the dose is increased, smaller 
effect size if dose is diminished).
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 study drug treatment continues or remains 
unchanged.
5.3.6.2
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. 


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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 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 their patient files.
The following must be collected and documented on the appropriate CRF(s) by the 
Investigator:
•
From signing the informed consent/assent onwards through the Residual Effect Period 
(REP), until 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 relevant SAEs and relevant AESIs of which the Investigator may become aware of
by any means of communication, e.g. phone call. Those AEs should be reported on the BI 
SAE form, but not on the CRF.
The rules for Adverse Event Reporting exemptions still apply, please see Section 5.3.6.3.
Figure 5.3.6.2: 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


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After the individual patient’s end of the trial the Investigator does not need to actively 
monitor the patient for AEs but should only report relevant SAEs and relevant AESIs of 
which the Investigator may become aware of by any means of communication, e.g. phone 
call. Those AEs should be reported on the BI SAE form, but not on the CRF.
The rules for Adverse Event Reporting exemptions still apply, please see Section 5.3.6.3.
The REP is defined as 7 days after the last dose of trial medication is taken. All AEs which 
occurred through the treatment phase and throughout the REP will be considered as on 
treatment, please see Section 7.3.4. Events which occurred after the REP will be considered 
as post treatment events.
AE reporting to sponsor and timelines
The Investigator must report SAEs, AESIs, and non-serious AEs which are relevant for the 
reported SAE or AESI, on the BI SAE form via fax immediately (within 24 hours ) to the 
sponsor’s unique entry point (country specific contact details will be provided in the ISF). 
The same timeline applies if follow-up information becomes available. In specific occasions 
the Investigator could inform the sponsor upfront via telephone. This does not replace the 
requirement to complete and fax the BI SAE form.
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 
CRF pages and the BI SAE form. 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 SAE form (if applicable):
Worsening of the underlying disease or of other pre-existing conditions
Changes in vital signs, ECG, physical examination and laboratory test results, if they 
are judged clinically relevant by the Investigator.
If such abnormalities already pre-exist prior to trial inclusion they will be considered as 
baseline conditions.
All (S)AEs, including those persisting after an individual patient’s end of trial must be 
followed up until they have resolved, have been sufficiently characterised, or no further 
information can be obtained.
Pregnancy
In rare cases pregnancy may occur in a clinical trial. Once a patient has been enrolled into
this clinical trial and has taken trial medication, the Investigator must report immediately 
(within 24 hours) a potential drug exposure during pregnancy (DEDP) to the sponsor’s 
unique entry point (country-specific contact details will be provided in the ISF). The 
Pregnancy Monitoring Form for Clinical Trials (Part A) should be used.


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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.
5.3.6.3
Exemptions to SAE reporting
Psychosis is considered an Outcome Event and is exempted from reporting as an SAE. See 
Section 5.1.2 for the definition of psychosis. However, when there is evidence suggesting a 
causal relationship between study drug and an episode of psychosis, the event must 
immediately be reported as an SAE on the SAE form and on the appropriate eCRF. 
Psychosis events determined not related to study drug should be recorded on the appropriate 
pages of the eCRF as part of efficacy data collection. These outcome events will be collected, 
adjudicated by the Central Rating Committee, and monitored by the DMC.
DRUG CONCENTRATION MEASUREMENTS AND 
5.4
PHARMACOKINETICS
Not applicable.
ASSESSMENT OF BIOMARKERS 
5.5
This section refers to exploratory biomarkers. 
5.5.1
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.


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The BI-internal facilities storing biological samples from clinical trial participants as well 
as the external banking facility are qualified for the storage of biological samples collected 
in clinical trials. 
An appropriate sample and data management system, incl. audit trail for clinical data and 
samples to identify and destroy such samples according to ICF is in place 
A fit for the purpose documentation (biomarker proposal, analysis plan and report) ensures 
compliant usage 
A fit for purpose approach will be used for assay/equipment validation depending on the 
intended use of the biomarker data
Samples and/or data may be transferred to third parties and other countries as specified in 
the biobanking ICF
Methods and Timing of Pharmacogenomic Sample Collection
5.5.1.1
Sampling will be performed at the time points specified in the Flow Chart. Approximately 8.5 
mL 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.
5.5.2
Pre-specified Pharmacogenomic Analysis
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. Patients 
classified as poor metabolizers (poor metabolizers defined as presence of two non-functional 
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 
exploratory, prespecified 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. The sample will be used 
for DNA extraction and subsequent genotyping for variants in genes related to the disease 
and NMDA-R signaling, such as BDNF. Pre-specified analyses will be performed at the end 
of the trial and the data will be part of the clinical trial report.
All remaining samples will be destroyed no later than three months after the end of the trial.
Collection methods for the samples for pre-specified pharmacogenomic analyses at Visit 2 
are identical to that of the optional DNA banking sample. Please refer to Section 5.5.1.1.
Detailed instructions on sampling, preparation, processing, shipment and storage of the 
samples collected at screening for CYP2C19 genotyping are provided in the laboratory 
manual.


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5.5.3
Cortisol and Inflammatory Cytokines
Salivary cortisol and blood inflammatory cytokines such as Interleukin 6 (IL-6), Interleukin 1 
beta (IL 1β) and tumor necrosis factor alpha (TNFα) will be assessed as exploratory 
biomarkers at the visits indicated in the Flow Chart.
Cortisol levels vary across the day [R16-3638]. Multiple saliva samples for the cortisol assay 
will be obtained at three time points during each of the visits specified in the Flow Chart in 
order to derive an average and increase the reliability of the cortisol estimate. The first 
sample should be collected when the patient arrives at the site; the second and third saliva 
samples will be collected at approximately 1.5 hour intervals. If the patient has a meal or 
snack during the visit, samples should be collected an hour before or after eating. Care should 
be taken to collect samples at approximately the same times at each visit. 
The purpose of collecting these samples is to explore the association between stress or 
inflammatory biomarkers and clinical outcome in patients with attenuated psychosis 
syndrome.
Detailed instructions for sampling, handling and shipment of samples are provided in the 
Laboratory Manual, filed in the ISF.
5.5.4
BDNF Levels
BDNF levels will be assessed from peripheral blood as an exploratory biomarker to 
investigate its potential in disease modulation and as an outcome related pharmacodynamic 
biomarker. 
Blood samples will be collected at time points indicated in the Flow Chart.
Detailed instructions for sampling, handling and shipment of samples are provided in the 
Laboratory Manual, filed in the ISF.
5.5.5
Automated Speech Analysis
Automated speech analysis will be performed on audio-recorded patient interviews, 
comprising dream reports and short-term affective memories. Analysis will extract acoustic 
parameters from the speech data; generate speech graphs and semantic features from 
interview transcripts; apply classifiers to predict which patients will eventually develop 
psychosis by finding the optimal combination of acoustic, graph-theoretical and semantic 
features.
Patient interviews will be audio-recorded at the time points indicated in the Flow Chart. 
Instructions for recording patient interviews are provided in an automated speech analysis 
procedures manual, filed in the ISF.


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OTHER ASSESSMENTS
5.6
APPROPRIATENESS OF MEASUREMENTS
5.7
All measurements performed during this trial are acceptable measurements and commonly 
used in monitoring safety aspects or assessing treatment response in patients meeting 
diagnostic criteria for APS. 
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
VISIT SCHEDULE
6.1
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).
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
6.2
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. 
Each of the assessments (SIPS/SOPS, SCoRS, PANSS, BACS SC, HVLT-R and BAC App) 
should ideally be done by the same members of the site staff for a given patient throughout 
the study period. In addition, it is recommended that the BAC App and SCoRS not be 
administered to a patient by the same rater at the same visit to prevent bias on the SCoRS 
ratings. 
Patients should start the BACS SC and HVLT-R assessments at the same time of day (±60 
minutes) at each applicable visit. The start time of the BAC App assessment should also 
begin at the same time of day (±60 minutes) at each applicable visit. The BACS SC/HVLT-R
and BAC App start times do not have to be within the same +60 minute window. During the 
testing, patients are allowed to take short breaks as needed, in the judgment of the 
rater/investigator.
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/assent. 
After a patient has signed the informed consent/assent, 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/assent for the unspecified pharmacogenomics sample 
must be obtained if the patient is willing to provide the blood sample for DNA banking.
If the rater at the site concludes that the patient meets diagnostic criteria for APS, both the 
video-taped interview and the SIPS response forms must be reviewed and diagnosis 


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confirmed by 
prior to randomisation. Please refer to the Assessment 
Procedures Binder for further information.
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/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.
6.2.2
Treatment period
There is an optional, EEG sub-study that will enroll patients from a sub-group of study sites 
participating in the 1289-0032 study. Patients must provide a separate informed 
consent/assent prior to randomisation to participate in this study. See Section 10.
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 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. 
Phone Visits are to be conducted at the time points specified in the Flow Chart to assess the 
overall status of the patient, check compliance, and to collect new AE and concomitant 
medication information. Patients will be instructed to complete the eC-SSRS, and site staff 
will confirm completion. If symptom worsening is suspected, an unscheduled in-clinic visit 
should be scheduled to further assess the patient as outlined below.
During the treatment period, all SIPS/SOPS assessments will be video-taped for review by 
the 
.  Please refer to the Assessment Procedures Binder.


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Suspected First Episode of Psychosis: 
If any Positive Symptom Score of 6/Severe and Psychotic is assigned while administering the 
SOPS, the following should occur:

The PI should immediately contact 
to arrange for expedited video 
review.

PANSS should also be administered.

Treatment should begin immediately if the PI feels this is necessary for the patient’s 
safety. 
If worsening psychotic symptoms are suspected during a phone visit, or if the patient reports 
a new prescription or increase in dose of an ongoing antipsychotic medication, the following 
should occur:

Patient is to be scheduled for an unscheduled, in-clinic visit.

Administer SOPS. 

If any Positive Symptom Score of 6/Severe and Psychotic is assigned while 
administering the SOPS, the PI should immediately contact 
 to 
arrange for expedited video review.

PANSS should also be administered.

Treatment should begin immediately if the PI feels this is necessary for the patient’s 
safety.
If the patient is prescribed a new antipsychotic or has their ongoing antipsychotic dose 
increased by a physician other than the PI, medical records should be obtained for review by 
the Central Rating Committee.
Patients experiencing a first episode of psychosis should continue taking study drug at the 
discretion of the investigator.  
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 in-clinic and phone visits, the following should be 
performed:

EOT Visit should 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 for 
both in-clinic and phone visits through Visit 23.

A Follow-Up Visit will not be performed.
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: 


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
EOT Visit should be performed within 7 days of last intake of study drug, or as soon 
as possible.

A Follow-up Visit should be performed within 28 days of the EOT Visit.

Thereafter, patients should be followed up over the phone according to the regular 
visit schedule through Visit 23. 
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 should be performed within 7 days of last intake of study drug, or as soon 
as possible.

A Follow-up visit should be conducted within 28 days of the EOT Visit.

Occurrence of psychiatric illness and vital status must be collected approximately one 
year after the patient was randomized.
6.2.3
Follow Up Period and Trial Completion
Patients who complete the treatment period should have a Follow-Up Visit 28 days after 
Visit 23.  
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 will not be 
conducted. 
A Follow-Up Visit should be conducted within 28 days of 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 5.3.6. 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
STATISTICAL DESIGN - MODEL
7.1
This is a randomised, double-blind, parallel group, multi-centre trial aiming to show 
superiority of BI 409306 to placebo as an early intervention in patients with attenuated 
psychosis syndrome.  All patients will be treated for 52 weeks.
The primary objective of the statistical analysis is to determine whether BI 409306
significantly increases the likelihood of remission from APS in comparison to placebo. The 
Cox proportional hazards model, stratified by the baseline use of antipsychotic medication,
will be used to estimate and test the hazard ratio of BI 409306 vs. placebo.
NULL AND ALTERNATIVE HYPOTHESES
7.2
The hypotheses for the superiority testing of the primary endpoint are (HR = hazard ratio):
Ho: HRBI 409306 / placebo = 1
vs. 
Ha: HRBI 409306 / placebo ≠1
Superiority will be declared if the hazard ratio between BI 409306 vs. placebo is significantly 
greater than 1 at the two-sided type I error level α = 0.10.
PLANNED ANALYSES
7.3
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 who have 
analysable data (observed or imputed) in at least one efficacy endpoint
Two follow-up periods are defined:

Full follow-up: 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 known vital status

On-treatment: until the date of discontinuation of trial medication + 7 days
Patients will be analysed using actual treatment taken.
7.3.1
Primary endpoint analyses
The primary endpoint is the time to remission from APS as defined in Section 5.1.1.  


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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 10% significance level. The model 
includes the treatment effect and NAPLS risk score as covariates and is stratified by baseline 
use of antipsychotic medication. 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 90% Wald confidence interval. A hazard ratio 
of more than one favors BI 409306.  The analysis will be implemented using 
® PROC 
PHREG. Cox proportional hazard model assumptions will be verified.
The primary analysis will be performed on the FAS for the on treatment period. The date of 
remission will be the visit date on which the patient taking the assessment meets the 
remission criteria. The time to remission is defined to be the start of treatment until remission 
is achieved. Although patients who discontinue study medication will be followed until the 
end of the trial for the primary endpoint, the data collected after treatment discontinuation 
will only be used for a sensitivity analysis.  Patients who are lost-to-follow up will be 
censored for the primary endpoint at the time of their last known SOPS assessment. Patients 
who begin taking a new prescription or increase in dose of ongoing antipsychotics will be 
considered as not eligible for remission. Such patients will be censored at the start of new 
prescription or increase of dose of ongoing antipsychotics. Further details regarding these 
analyses will be included in the TSAP.
The following sensitivity analyses will be performed: (1) on the primary endpoint that 
includes only patients from the TS during the time of the full follow-up period and (2) 
excluding patients who were recruited from the enriched population prior to amendment 3.
Subgroup analyses are planned and will be pre-specified in the TSAP.
7.3.2
Secondary endpoint analyses
Time to event endpoints will be analysed using Cox proportional hazard model as described 
for the primary endpoint analysis. All change from baseline endpoints specified in Section 
5.1.2 will be analysed using the restricted maximum likelihood (REML) based mixed effects 
model with repeated measurements (MMRM). The model will include the fixed, categorical 
effects of treatment, visit, treatment by visit interaction, and NAPLS risk score strata, and 
baseline use of antipsychotic medication, as well as the continuous fixed covariates of 
baseline score and baseline-by-visit interaction. The unstructured covariance structure will be 
used to model the within-patient errors. If this analysis fails to converge, compound 
symmetry covariance structure might be used. The Kenward-Roger approximation will be 
used to estimate the denominator degrees of freedom. Analyses will be implemented using 
® PROC MIXED. The primary treatment comparisons will be between the placebo and 
BI 409306 with respect to the mean change from baseline. Adjusted mean change from 
baseline as well as treatment contrasts will be presented together with the 95% confidence 
intervals. 


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7.3.4
Safety analyses
Adverse events will be coded using the Medical Dictionary for Drug Regulatory Activities
(MedDRA) coding dictionary. 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 
treatment period for evaluation.
All treated patients will be included in the safety analysis. In general, safety analyses will be 
descriptive in nature and will be based on BI standards. No hypothesis testing is planned.
Statistical analysis and reporting of adverse events will concentrate on treatment-emergent 
adverse events (i.e., by ‘treatment at onset’). To this end, all adverse events occurring 
between start of treatment and end of the residual effect period will be considered ‘treatment-
emergent’. Adverse events that start before first drug intake and deteriorate under treatment 
will also be considered as ‘treatment-emergent’.


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Frequency, severity, and causal relationship of adverse events will be tabulated by system 
organ class and preferred term after coding according to the current version of the Medical 
Dictionary for Drug Regulatory Activities (MedDRA).
Laboratory data will be analysed both quantitatively as well as qualitatively. The latter will 
be done via comparison of laboratory data to their reference ranges. Values outside the 
reference range as well as values defined as clinically relevant will be highlighted in the 
listings. Treatment groups will be compared descriptively with regard to distribution 
parameters as well as with regard to frequency and percentage of patients with abnormal 
values or clinically relevant abnormal values.
Vital signs, physical examinations, or other safety-relevant data observed at screening, 
baseline, during the course of the trial and at the end-of-trial evaluation will be assessed with 
regard to possible changes compared to findings before start of treatment.
Descriptive statistics are planned to quantify the frequency of patients with suicidal ideation 
and behaviour as recorded on the C-SSRS at any post-baseline visit.  
7.3.5
Pharmacokinetic and pharmacodynamic analyses
Pharmacogenetic analyses of gene variations within genes associated with the disease and 
NMDA-R signaling will be carried out using an explorative approach to test the potential 
influence on therapy response. Analyses may not be carried out if treatment response could 
not be shown.
INTERIM ANALYSES
7.4
Once there is a sufficient amount of data collected for review, the DMC will hold meetings 
three times per year.  Analyses will be conducted to ensure there is no imbalance in safety 
endpoints.  One formal unblinded interim analysis will be conducted by the DMC when 
approximately 67% of events have occurred to consider ending the trial early for 
overwhelming efficacy.  Further details on alpha spending will be detailed in the DMC 
Charter and TSAP.
A blinded sample size reassessment interim analysis with the option to adjust the sample size 
will be performed by the Sponsor’s Trial Statistician when 90% of patients have been 
randomised or at the same time as the formal interim analysis (whichever happens earlier).  
The number of observed remissions will be compared to the number predicted.  If the actual 
number is lower than predicted (given the actual already documented study time of 
randomised patients at the scheduled post-baseline SOPS visits; prediction: 40% for placebo 
& 57% for BI 409306 at 52 weeks), the sample size may be increased to allow the trial to 
achieve full power up to a maximum sample size of 400 patients.
HANDLING OF MISSING DATA
7.5
All patients who have not achieved remission will be censored in the analysis of the primary 
endpoint at the time of last known SOPS assessment.  No missing data will be imputed for 


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the primary and secondary analyses.  For secondary endpoints, the statistical model using 
MMRM will handle missing databased on a likelihood method under the “missing at random” 
assumption.  All FAS patients can be included in the model and therefore participate in 
variance estimation.
For the SCoRS, if an individual item is missing, it should be imputed with the average of the 
patient’s non-missing item scores.  If >5 responses of the 20 items are missing, the composite 
score of SCoRS will be missing.
Further details about handling missing data will be specified in the TSAP.
RANDOMISATION
7.6
Patients will be randomised in blocks to double-blind treatment. Approximately equal 
numbers of patients will be randomised to each treatment group. The randomisation will be 
stratified by baseline use of antipsychotic medication.  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 CTR. Access to the codes will be controlled and documented.
DETERMINATION OF SAMPLE SIZE
7.7
Remission rate of the population diagnosed with APS and without intervention was assumed 
to be 40% (R16-0991) by 52 weeks. The rate of remission for BI 409306 was assumed to be 
57% by 52 weeks. This will lead to a hazard ratio of 1.652.
Other study considerations are:

Two-sided alpha = 0.10

Dropout = 20% after one year

Interim analysis checking for early efficacy using user-defined alpha-spending 
boundary of 0.01 at the 67% information point
Table. 7.7: 1 Power calculations for sample size (for both arms combined) of 300 for various
remission rates for BI 409306 with fixed placebo group aggregate first remission rate 
prediction of 40% by 52 weeks
Remission 
Rate for 
Placebo
Remission 
Rate for BI 
409306
Hazard 
Ratio
Risk
Ratio
Power for 
N=300
# Events 
needed in 
total
40%
52%
1.437
1.300
64.9%
126
40%
55%
1.563
1.375
81.5%
130
40%
57%
1.652
1.425
89.3%
133
40%
59%
1.745
1.475
94.4%
136
40%
61%
1.843
1.525
97.4%
139
Table 7.7: 1 displays the power achieved for 300 total randomized patients given a group 
aggregate first remission rate of 40% for placebo with two-sided α= 0.10 and a user-defined 


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alpha spending boundary at interim analysis of α=0.01 (two-sided).  Group remission rates 
for BI 409306 treatment of 52%, 55%, 57%, 59% and 61% are considered.  Total number of 
events needed to achieve the power reported is also shown. 
Given remission rates of 40% for patients treated with placebo and 57% for patients treated 
with BI 409306, the risk ratio is 1.425 (implying that patients treated with BI 409306 will 
have 42.5% more chance of achieving remission of APS compared to placebo).A sample size 
of 300 (or 150 per group) was selected as the most logical for establishing proof of concept 
based on the risk / benefit considerations noted above.  In addition this was the sample size 
used in the previous protocol and is kept the same. This translates to 89% power. The type I 
error was selected to be 10% since this is a phase II study meant to provide an understanding 
of the effectiveness of the drug without being too strict as in a confirmatory setting.
One hundred and thirty three (133) events (remissions) are needed to be observed to meet the 
trial objectives.  This will not be an event driven trial, so the trial will end when all 
randomised patients have reached 12 months exposure, regardless of number of remissions 
observed.  However, a blinded sample size assessment will be performed (see Section 7.4) 
that may allow for an increase in sample size in an attempt to observe the number of 
remissions necessary for full power.
Calculations were performed using ADDPLAN® 6.1.1 statistical package by 
.


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8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY
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, 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, and also 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 (Investigator Site File).
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED 
8.1
CONSENT
This trial will be initiated only after all required legal documentation has been reviewed and 
approved by the respective Institutional Review Board (IRB) / Independent Ethics Committee 
(IEC) and competent authority (CA) according to national and international regulations. The 
same applies for the implementation of changes introduced by amendments.
Prior to patient participation in the trial, written informed consent/assent 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/assent and any additional 
patient-information form retained by the Investigator as part of the trial records. A signed 
copy of the informed consent/assent and any additional patient information must be given to 
each patient or the patient’s legally accepted representative.
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/assent form after confirming that the patient understands the contents. 
Re-consenting may become necessary when new relevant information becomes available and 
should be conducted according to the sponsor’s instructions.


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The consent and re-consenting process should be properly documented in the source 
documentation.
DATA QUALITY ASSURANCE
8.2
A quality assurance audit/inspection of this trial may be conducted by the sponsor, sponsor’s 
designees, 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/assent documentation of this clinical trial.
RECORDS
8.3
Case Report Forms (CRF) for individual patients will be provided by the sponsor. See 
Section 4.1.5.2 for rules about emergency code breaks. For drug accountability, refer to 
Section 4.1.8.
8.3.1
Source documents
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. In this case the Investigator must make three documented attempts to retrieve 
previous medical records prior to randomising a patient. If this fails a verbal history from the 
patient, documented in their medical records, would be acceptable.
Before providing any copy of patients’ source documents to the sponsor the investigator must 
ensure that all patient identifiers (e.g. patient’s name, initials, address, phone number, social 
security number) have properly been removed or redacted to ensure patient confidentiality.
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, date or year of birth (in accordance with local laws and 
regulations)

Patient participation in the trial (substance, trial number, patient number, date patient 
signed informed consent/assent)

Dates of patient’s visits, including dispensing of trial medication

Medical history (including trial indication and concomitant diseases, if applicable)

Medication history


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
Adverse events and outcome 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 on-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 on-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). The CRA and auditor may review all CRFs and informed consents/assents. The 
accuracy of the data will be verified by direct comparison with the source documents 
described in Section 8.3.1. The sponsor will also monitor compliance with the protocol and 
ICH GCP.
8.3.3
Storage period of records
Trial site:
The trial site must retain the source and essential documents (including ISF) according to the 
national or local requirements (whichever is longer) valid at the time of the end of the trial.
Sponsor:
The sponsor must retain the essential documents according to the sponsor’s SOPs.
EXPEDITED REPORTING OF ADVERSE EVENTS
8.4
BI is responsible to fulfil their legal regulatory reporting obligation and in accordance with 
regulatory requirements defined in this CTP. Psychosis events are considered outcome events 
and are not to be reported as SAEs, unless if considered related to trial medication. See 
Section 5.3.6.3.


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STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY
8.5
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 and in Section 5.5.1. 
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 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.
TRIAL MILESTONES
8.6
The start of the trial is defined as the date of the enrolment of the first patient in the whole 
trial.
The end of the trial is defined as the date of the last safety follow up visit of the last patient 
in the whole trial (“Last Patient Out”). The “Last Patient Drug Discontinuation” (LPDD) 
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 LPDD 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).


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9.
REFERENCES
PUBLISHED REFERENCES
9.1
P10-00647
Korostenskaja M, Kahkonen S. What do ERPs and ERFs reveal about the 
effect of antipsychotic treatment on cognition in schizophrenia? Curr Pharm 
Des 15 (22), 2573 - 2593 (2009).
P15-03385
Salisbury DF, Shenton ME, Griggs CB, Bonner-Jackson A, McCarley RW. 
Mismatch negativity in chronic schizophrenia and first-episode schizophrenia. 
Arch Gen Psychiatry. 2002;59(8):686-694.
R03-0520 
CGI clinical global impressions. GuyW. ECDEU Assessment Manual for 
Psychopharmacology. Rockville: U.S. Department of Health, Education, and 
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UNPUBLISHED REFERENCES
9.2
U12-1034 
 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.


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U12-2165 
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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
 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, 
placebocontrolled within dose groups Phase I study). 1289.2. 20 Feb 2013.
U13-1303
 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.
c01694347-08 Investigator’s Brochure: BI 409306 in Alzheimer’s Disease and Cognitive
Impairment associated with Schizophrenia.
c03808525-01
. A randomized, double-blind, double 
dummy, placebo controlled,three-way crossover study to assess cardiac effects 
after single oral doses of BI 409306 under resting and exercise conditions in 
healthy male volunteers. 1289.28. 17 Jun 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.
c09991178-01
 Other Clinical Report. 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. 1289.6. 27 Oct 2016.


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10.
APPENDICES
BIOMARKER SUB-STUDY: EEG
10.1
10.1.1
Flowchart
MAIN
STUDY
Trial 
Periods
Screening 
Period
Randomised Treatment 
Period 
Follow-up 
Period
Visit
1
2
3-22
EOT
F/U
Study Week
-4 
0
1-48
52
56
Study Day
-28 to -7
1
8-337
365
393
SUB-
STUDY
Sub-study 
Visit
Screening
Pre*
Post
Sub-study 
Informed 
Consent/Assent
X
EEG 
(Resting, 
ERPs)
X
X
* EEG procedure to be completed before first dosing. Time point also referenced to as the baseline EEG 
assessment or baseline EEG measurement.
10.1.2
Background and Objectives
10.1.2.1 
Background of Biomarker sub-study: EEG
Prediction of psychosis is currently almost exclusively based on clinical criteria. A preventive 
intervention will benefit from a non-biased, reliable and valid biological biomarker of risk. 
Recent studies have demonstrated that electroencephalography (EEG)-based biomarkers, 
including clinical and quantitative EEG [R16-5225, R16-5226, R16-3193] event-related 
potentials (ERP) [R15-3300, R15-3327, R16-5260], are helpful for predicting later 
conversion to psychosis in CHR individuals. Thus, with further refinement, these EEG-based 
measures may eventually provide the clinician with a practical and useful tool for risk 
classification.
EEG is a non-invasive method to measure the electrical activity of large, synchronously 
firing, populations of neurons in the brain with electrodes placed on the scalp. Some EEG 
studies support the validity of quantitative EEG [R16-5226, R16-3193] for prediction of 
psychosis in the CHR syndrome, including frequency-specific measures of EEG power and 
cross-site neural synchrony. However, most EEG-based studies of CHR individuals to date 
have examined ERP components.  ERPs are assessed by measuring EEG responses to 
repetitive auditory, visual or tactile stimuli and are used to probe sensory, perceptual, and 
cognitive processing with millisecond precision. This high temporal resolution lends itself 
well to the study of the earliest stages of information processing and the subsequent 


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transitions from sensory-based perceptual processing to the higher cognitive functions [R15-
5841]. ERPs have been widely used to examine basic neuronal activity in both normal brain 
function and in schizophrenia, and several ERP components have shown promise as potential 
biomarkers of schizophrenia [R14-3417], including the auditory mismatch negativity and the 
auditory and visual P300.  Accordingly, these components have been most often investigated 
as predictors of psychosis onset in the CHR syndrome.
Mismatch Negativity
Mismatch negativity (MMN) is a negative voltage ERP component that is elicited following 
presentation of infrequent physically deviant sounds imbedded in a series of repeated 
standard sounds [R14-4683, R15-3300].  MMN is elicited automatically, with no overt 
behavioral response required and with minimal influence of attention. It reflects automatic 
feature analysis in the auditory cortex, referred to as auditory sensory “echoic” memory 
because of its dependence on representations of what is “standard” in order to detect deviance 
in the auditory stream.  Deviance in any number of physical sound properties (e.g., pitch, 
duration, intensity) can elicit variants of MMN, each produced at least partially by distinct 
neural generators located in primary and secondary auditory cortices as well as bilateral 
dorsolateral prefrontal cortices [R17-1764].  Deficits in MMN amplitude have been 
repeatedly demonstrated in patients with schizophrenia [R15-3299].  These deficits and have 
been linked to negative symptoms and poor functional outcomes.  While MMN deficits may 
improve (but do not normalize) as patients transition from acute to more stable clinical states, 
they are quite stable in chronic patients (ICCs ~0.90 over 1-2 year test-retest interval), and are 
not affected by antipsychotic medication [R14-4685; P10-00647].  Additional evidence 
suggests that MMN is dependent on neurotransmission at NMDA-receptors hypofunction of 
which has been implicated in schizophrenia [R15-3336; R14-4685].  Recent theoretical 
perspectives on MMN emphasize its reflection of short-term neural plasticity in the auditory 
cortex [R10-5103], with repetitions of the standard tone generating an increasingly strong 
memory trace in the service of auditory predictive coding.  In this view, the MMN is a 
prediction error signal that is elicited when a deviant sound violates the prediction generated 
by the repeated standard tone.  To date, several studies have shown reduced MMN amplitude 
to predict conversion to psychosis in CHR individuals [R15-3300, R15-3327].  
P300 (P3)
The P3 component of the ERP is a positive voltage deflection elicited about 300 ms 
following the presentation of an infrequent salient “oddball” stimulus randomly imbedded in 
a series of standard stimuli, usually in the context of an “oddball” target detection task.  P3 
can be elicited by stimuli presented in any sensory modality, but most commonly has been 
assessed in auditory or visual oddball tasks.  Prevailing views of the P3 consider its amplitude 
to be a neural reflection of attentional resource allocation [R16-3191].  Its latency is a 
reflection of processing speed or efficiency during stimulus evaluation [R17-1763].  Two 
variants of P3, “P3b” and “P3a”, have been distinguished based on the nature of the eliciting 
stimulus, scalp topography, peak latency, and underlying neural generators.  
P3b is elicited effort fully by “top down” allocation of attention to infrequent task relevant
target stimuli requiring a behavioral response (e.g., counting or button press).  It has a 
midline parietal scalp maximum and peaks about 300 ms following the target stimulus [R16-
3191]. P3a is elicited automatically by “bottom-up” orienting of attention to infrequent task 


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irrelevant novel or salient stimuli to which no response is required, such as novel sounds or 
visual images.  It has a midline frontocentral scalp maximum and peaks about 20 to 50 ms 
earlier than P3b.
P3b amplitude reduction and latency delay in auditory oddball tasks is one of the most 
consistently replicated functional brain abnormalities reported in schizophrenia [R17-1765].  
P3b abnormalities in schizophrenia are more robustly observed in auditory than visual 
paradigms. Importantly, auditory P3b deficits have been shown in first-episode schizophrenia 
patients  as well as in unaffected first-degree relatives of schizophrenic patients [P15-03385]. 
P3b has also been shown to have some sensitivity to clinical state fluctuations in patients, yet 
it does not normalize, consistent with its being a trait-like deficit in schizophrenia [R14-
3433]. Relatively few studies have examined automatic P3a responses to novel or salient task 
irrelevant stimuli in schizophrenia.  Most of these studies show auditory and/or visual P3a 
amplitude reductions in schizophrenia in response to novel stimuli [R17-1758].
Previous studies have reported lower auditory P3a [R16-5228, R16-5229, R16-5227, R16-
5260] and P3b [R15-3342, R16-1603, R15-3276] amplitudes in CHR patients compared to 
healthy volunteers and at least one published report [R16-5260] found reduced amplitude of 
the auditory target P3b to predict conversion to psychosis in CHR individuals.
Gamma Auditory Steady State Response (ASSR)
Synchronization of neural oscillations in the gamma range (30-80 Hz) is considered to be a 
mechanism for integrating sensory information across different modalities and cortical areas, thereby 
creating a coherent cortical representation of complex external sensory stimuli. Synchronous gamma 
oscillations have been shown to contribute to sensory registration and perceptual processes, as well 
as higher order cognitive operations such as attention and expectation [R17-1761]. The auditory 
gamma band response is a 40 Hz sinusoidal oscillation that occurs in the first 100 ms following a 
sound, as measured in vivo using EEG or magneto-encephalography (MEG) [R17-1760].  When an 
auditory stimulus is repeated at a fixed rate or frequency, it drives the auditory steady-state response 
(ASSR) in EEG/MEG at the same rate [R17-1756].  Although higher and lower frequencies have 
been tested, the ASSR reaches a maximum at a 40 Hz repetition rate.
The 40 Hz ASSR has been of particular interest in schizophrenia research because of the 
dependence of gamma band oscillations on neurotransmitter receptors implicated in the 
illness, particularly gamma-aminobutryic acid (GABAA) [R15-3342] and glutamatergic N-
methyl-D-aspartate (NMDA) receptors [R17-1759].  In particular, fast-spiking parvalbumin-
expressing inhibitory GABAergic interneurons have been implicated in the mediation of 
gamma oscillatory activity. The inhibition of pyramidal cell and interneuron networks by 
GABAergic interneurons produces gamma band oscillations through an inhibition and 
rebound excitation cycle that is modulated by GABAA receptors. Moreover, glutamatergic 
neurotransmission at NMDA receptors provides excitatory regulation of parvalbumin fast-
spiking interneurons, contributing to the generation of gamma oscillations in pyramidal cell 
networks. 
Selective deficits in 40 Hz ASSR in schizophrenia were first reported by Kwon et al [R15-
3332]. Subsequent ASSR studies have replicated this reduced 40 Hz ASSR deficit in 
schizophrenia [R17-1757].   Interestingly, recent studies have further shown that whereas the 


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power and phase synchrony of the 40 Hz ASSR response is reduced in schizophrenia, EEG 
gamma power is increased during the inter-trial intervals of this paradigm in schizophrenia 
patients, and this increase in baseline gamma power is inversely correlated with the power 
and phase synchrony of the 40 Hz ASSR [R17-1755].  Deficits in 40 Hz ASSR have also 
been reported in the first-degree relatives of schizophrenia patients [R17-1761], suggesting 
that abnormal gamma oscillations in response to auditory stimuli may be an endophenotypic 
marker of genetic risk for the illness. To date, no published reports have examined the 40 Hz 
ASSR in CHR individuals.  However, in unpublished preliminary analyses of data from the 
NAPLS2 study, CHR individuals showed an increase in baseline gamma EEG power similar 
and a trend toward reduced 40 Hz ASSR phase synchrony, similar to what has been reported 
in schizophrenia.  While no studies to date have shown the 40 Hz ASSR to predict conversion 
to psychosis in CHR individuals, it will be included in the current EEG sub-study because of 
its theoretical sensitivity to glutamatergic NMDA receptor neurotransmission and its 
translational utility for linking human and animal studies of gamma oscillations.
Given the established links between the amplitude of selected ERP components, the 
glutamatergic system, schizophrenia, and the transition to psychosis, we will assess 
quantitative EEG (qEEG) during rest, auditory MMN, auditory and visual P3, and gamma 
oscillations (baseline gamma power and 40 Hz ASSR power and phase synchrony) at 
baseline and after 52 weeks of PDE9 inhibition.  In order to compare data from the current 
EEG sub-study with the EEG/ERP data collected from large samples of CHR individuals 
(n=456) and healthy controls (n=236) in the NAPLS2 study, we use the NAPLS2 EEG 
paradigms in the current study.
10.1.2.2
Objectives of Biomarker Sub-study: EEG
The objective of this sub-study is to measure and analyze the change of neurophysiological 
functions of the brain from baseline to the end of treatment in a subset of patients from the 
main study, which is conducted in individuals with the psychosis-risk syndrome who are 
treated with BI 409306 50 mg b.i.d. or placebo over a treatment period of 52 weeks.
The study will investigate the clinical utility of resting qEEG, auditory MMN, auditory and 
visual P3, 40 Hz ASSR power and phase-synchrony, and baseline EEG gamma power (from 
inter-trial intervals of ASSR paradigm), as biomarkers for risk stratification and targeted 
intervention. The examination of EEG and ERP measures will be exploratory in nature, 
potentially providing further insights into the methodologies themselves, neurophysiological 
changes in patients with the psychosis-risk syndrome, and the effects of the treatment on 
these measures.
10.1.3
Selection of Study Population
This sub-study will enroll up to 80 patients from a subset of sites participating in the 1289-
0032 study, for exploratory purposes.  


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10.1.3.1
Inclusion Criteria
1. Patients who have provided informed consent/assent to participate in main 1289-0032 
study and a separate informed consent/assent for the sub-study before randomisation 
into the main study, i.e. Visit 2.
2. Patients willing and able to comply with the requirement for EEG procedures.
10.1.3.2
Exclusion Criteria
1. Patients in any clinical/non-clinical circumstance that would interfere with EEG 
procedures required for this sub-study, based on investigator’s discretion (e.g. 
clinically significant uncompensated hearing loss or severely impaired vision).
10.1.4
Sub-study Design
Resting state EEG, auditory and visual ERP measures, baseline EEG gamma power and 40 
Hz ASSR power and phase synchrony measures, will be explored and evaluated at the 
baseline Visit 2 (pre-dose) and EOT from a subset of the main study patient population.
10.1.5
Methods and Testing procedure
Total EEG testing procedure is expected to last for approximately 90 minutes, including 
preparing the patient (30 min) and EEG assessments (60 min), but the total duration of EEG 
set up might vary depending on each investigational site’s practice. 
Patients will be assessed on the following EEG paradigms: resting state EEG (6 minutes), 
MMN/Visual Oddball Task, Auditory Oddball Task, 40 Hz ASSR. EEG data will be 
continuously recorded at a digitization rate of 400 Hz) ) from a 32-channel electrode cap with 
electrodes positioned according to the International 10-20 system, as well as from electrodes 
placed at each mastoid and at the tip of the nose.  Recordings will be referenced to the left 
mastoid electrode during acquisition, with subsequent re-referencing to linked-mastoids or to 
the nose tip electrode offline.  Vertical and horizontal electro-oculograms, recorded from 
electrodes above and below the left eye and at the outer canthi of both eyes, respectively, will 
be used to correct EEG for eye movement and blink artifacts.
Resting State EEG (qEEG):
EEG will be recorded during the resting state for 3 minutes with eyes open and 3 minutes 
with eyes closed. Quantitative EEG (qEEG) is the mathematical processing of digitally 
recorded resting state EEG in order to transform the EEG into a format that elucidates 
relevant information [R15-5841] to allow the identification of CNS pharmacodynamic effects 
of compounds on spectral power frequency bands. Delta, Theta, Alpha, Beta and Gamma 
power will be measured at resting state according to the latest IPEG recommendations 
[International Pharmaco-EEG Society] [R15-5839].
An important application of qEEG is also its use in detecting drug-induced EEG changes 
occurring early in the course of a treatment, to identify early predictors of clinical response 


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[R16-5259]. qEEG in this project will be used to assess changes at baseline in patients with 
attenuated psychosis syndrome compared to end of treatment and to assess the 
pharmacodynamic response of the brain (i.e. change in power spectra) after multiple doses of 
BI 409306. 
Auditory MMN + Visual Oddball Task:
Auditory MMN is considered largely pre-attentive, and therefore, it is typical to ask patients
to ignore the auditory stimuli while engaging their attention towards a visual task.   One of 
the innovations of the NAPLS2 MMN paradigm is that runs concurrently with the Visual 
Oddball target detection task used to elicit the visual P3 ERP components.  Because the 
auditory tones presented in the MMN paradigm and the visual stimuli presented in the Visual 
Oddball task are not synchronized, it is possible to through signal averaging to derive from 
the continuous EEG both the auditory ERPs containing the MMN and the visual ERPs 
containing the visual P3.  Accordingly, the two paradigms are described separately here, but 
they are presented to the patient simultaneously.
MMN Paradigm: The multi-deviant MMN paradigm involves presentation, in a 
pseudorandom order, frequent (85% probability) standard tones (633 Hz, 50 ms duration), 
and three deviants: infrequent (5%) pitch deviant (1000 Hz, 50 ms duration), infrequent (5%) 
duration deviant tones (633 Hz, 100 ms duration), and infrequent (5%) pitch+duration double 
deviant tones (1000 Hz, 100 ms duration).  All tones have 5 millisecond rise/fall times and 
are presented via ear phones at 80 dB SPL, with a stimulus-onset asynchrony of 500 ms.  
Conventional ERP averaging of standards and each deviant type will be generated. ERP data 
will then be low-pass filtered at 20 Hz and baseline corrected prior to generating deviant-
standard difference waves, allowing identification and peak amplitude measurements of 
pitch-deviant, duration-deviant, and double-deviant MMN.
Visual Oddball Paradigm: The visual oddball task runs concurrently with the auditory 
MMN paradigm. In the visual oddball task, frequent (80% probability) standard stimuli 
(small blue circle on white screen), infrequent (10%) target stimuli (large blue circle on a 
white screen) and infrequent (10%) novel stimuli (fractal images) are presented on a 
computer screen in a pseudo-random sequence.  All images are presented for 500 ms with 
jittered (1550 ms - 2500 ms) with mean stimulus-onset asynchrony of 2 seconds.   Patients
are instructed to press a response button with their dominant hand index finger each time a 
target stimulus appears. A one-minute instructional cartoon is shown before the first run.  
Conventional ERP averaging of standards, targets, and novels, will be generated. ERP data 
will then be low-pass filtered at 20 Hz and baseline corrected prior to generating standard, 
target, and novel ERP waveforms.  P3 peak amplitudes are identified between 230 and 550 
ms in target (P3b) and novel (P3a) ERP waveforms, and have scalp maxima at midline 
parietal (Pz) and midline vertex (Cz) electrodes, respectively.  In addition, early visual 
sensory evoked potential components including the visual P1 (between 50-150 ms) will be 
identified and measured in response to the standard stimuli to assess early visual processing.
The MMN/Visual Oddball paradigm is presented in three runs of about 5 minutes each.  Each 
run comprises 120 standard, 15 target, and 15 novel stimuli.  Including instructions, 
clarification, and run time, the task takes about 20 minutes to complete.


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Auditory Oddball Task:
In the auditory oddball task, frequent (80% probability) standard tones (50 ms duration 500 
Hz pure tones, 5 ms rise/fall time), infrequent (10%) target tones (50 ms duration 1000 Hz 
pure tones, 5 ms rise/fall time) and infrequent (10%) novel sounds (durations varying 
between 250 and 500 ms, variable rise and fall times) are presented via ear phones at 80 dB 
SPL in a pseudorandom sequence with a fixed stimulus-onset asynchrony of 1250 ms. 
Patients are instructed to maintain fixation on visual fixation cross on the computer screen 
and to press a response button with the index finger of their dominant hand each time a target 
tone is presented.   Three runs of the task are presented, each comprising 120 standard tones, 
15 target tones and 15 novel sounds.  A one-minute instructional cartoon is shown before the 
first run. Conventional ERP averaging of standards, targets, and novels, will be generated. 
ERP data will then be low-pass filtered at 20 Hz and baseline corrected prior to generating 
standard, target, and novel ERP waveforms.  P3 peak amplitudes are identified between 230 
and 450 ms in target (P3b) and novel (P3a) ERP waveforms, and have scalp maxima at 
midline parietal (Pz) and midline vertex (Cz) electrodes, respectively.  In addition, early 
auditory sensory evoked potential components including the auditory N1 (between 75-150 
ms) will be identified and measured in response to the standard tones to assess early auditory 
processing.  Including instructions, clarification, and run time, the task takes about 15 
minutes to complete.
Auditory Steady State Response (ASSR) Paradigm: 
ASSR auditory stimuli consist of click trains that drive the auditory cortex at frequencies of 
20, 30, or 40 Hz, each presented in a separate block comprising 150 click trains.  Clicks are 
presented at 80 dB via ear phones.  Each click train is 500 ms in duration and comprises a 
series of repeated broadband clicks (1ms duration).  For the 20 Hz block, click trains 
comprise 10 clicks spaced 50 ms apart.  For the 30 Hz block, click trains comprise 15 clicks 
spaced 33.33 ms apart.  For the 40 Hz block, click trains comprise 20 clicks spaced 25 ms 
apart. The stimulus onset asynchrony is fixed at 1100 ms between each click train.  ASSR 20 
Hz, 30 Hz, and 40 Hz blocks are presented in a pseudo-random order across patients but the 
same order is maintained within patients across baseline and end of trial assessments.  
Patients are simply instructed to maintain fixation on visual fixation cross on the computer 
screen and to passively listen to the auditory stimuli presented.  Including instructions, 
clarification, and run time, the task takes about 10 minutes to complete.
10.1.6
Endpoint
Neurophysiological changes from baseline in qEEG, peak amplitudes (and latencies) of 
MMN, auditory and visual target P3b and novelty P3a, auditory N1 and visual P1, ASSR 
total power and ITC (inter-trial phase coherence) for 20, 30, and 40 Hz driving conditions, 
and baseline gamma power assessed during the ASSR paradigm, will be investigated and 
their differences between groups will also be investigated.


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10.1.8
Statistical Considerations 
10.1.8.1
Stastistical Design – Model
An exploratory analysis will be conducted on EEG signals across electrodes and temporal 
windows to examine drug effects on EEG variables.
10.1.8.2
Null and Alternative Hypotheses 
It is not planned to test any statistical hypotheses with regard to any of the endpoints of this 
EEG sub-study in a confirmatory sense. For the evaluation, a two-sided 95% confidence 
interval (CI) of adjusted treatment differences will be computed. However, the CI will have 
to be interpreted in the perspective of the exploratory character of the sub-study, i.e. as an 
interval estimate for effects under these conditions.


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10.1.8.3
Planned Analyses
The statistical model used for the analysis of the EEG endpoints will be an ANOVA (analysis 
of variance) model. This model will include effects for treatment, age and possibly other 
effects that will be specified in detail in the TSAP. Further descriptive statistics, including 
boxplots, will be provided. The variables may be transformed onto a logarithmic scale if 
severe skewedness is present. More details will be described in the TSAP.
Correlational analyses with clinical endpoints may be made and details therefore will be 
described in the TSAP.


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OCULAR SAFETY SUB-STUDY
10.2
10.2.1
Flowchart
MAIN
STUDY
Trial 
Periods
Screening 
Period
Randomised Treatment Period 
Follow-up 
Period
Visit
1
2
14
EOT
F/U
Study Week
-4 
0
24
52
56
Study Day
-28 to -7
1
169
365
393
SUB-
STUDY
Sub-study 
Visit
Screening
Pre*
6 months 
12 months
Best Corrected 
Visual Acuity 
(BCVA)
X
X
X
Color Vision 
Test (F-M 100)
X
X
X
* Ocular tests to be completed before first dose.
10.2.2
Background and Objective
In Phase I and II studies with BI 409306, the most frequently observed AEs were eye 
disorders. All of these AEs have been non-serious and mild to moderate in severity. These 
events have generally been reported as transient and resolve upon treatment discontinuation. 
While the frequency of these AEs generally increases with dose, at higher doses there is no 
obvious relationship between dose and maximum duration and intensity. Onset and duration 
of these events seem related to Cmax (i.e. in general, onset is approximately within the first 
1-2 hours of administration and duration is approximately 30 to 120 minutes). However, first 
onset after dosing appears variable, with some subjects experiencing these events after first 
dosing and others only after subsequent dosing. There are no obvious differences in 
frequency of these events for elderly or CYP2C19 poor metabolizer subjects, but relevant 
data is limited [c01694347-08].
The objective of this sub-study is to further characterize the ocular safety of BI 409306 in a 
subset of patients from the main study. 
10.2.3
Selection of Study Population
This sub-study will enroll approximately 50 patients from a subset of sites in the United 
States participating in the main study. Patients enrolled at the participating ocular sub-study 
sites will be required to complete all of the ocular safety assessments.
10.2.4
Sub-study Design
Best Corrected Visual Acuity and color vision will be evaluated at the baseline Visit 2 (pre-
dose), 24 weeks and 52 weeks or EOT from a subset of the main study patient population.


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10.2.5
Methods and Testing procedure
Testing conditions (i.e. exam room, chart distance, lighting conditions) should remain 
constant for each ocular testing visit. Patients who wear eye glasses or contact lenses should 
wear them for each of the visual acuity and color vision assessments.
Best Corrected Visual Acuity (BCVA)
BCVA will be determined using a Snellen chart at a 10 foot testing distance under standard 
lighting conditions.
Patients will be instructed to begin at the top of the Snellen chart and read down the chart 
until they reach a row where all letters on a line cannot be read correctly. The smallest line 
that a subject can read correctly at the 10 foot distance will be recorded.
BCVA will be determined and recorded at Visit 2 (pre-dose), 24 weeks and 52 weeks or 
EOT. 
Farnsworth-Munsell 100 hue test (F-M 100)
Color vision testing using the Farnsworth-Munsell 100 hue test will be used to evaluate color 
vision or color vision deficiency. It consists of 93 colors mounted in plastic caps of 
incremental hue variations, housed in four separate cases. Two caps are fixed as pilot colors 
at either end of the panel in each case. Patients will be asked to place the color caps in order 
of hue between each of the fixed anchors. The final arrangement of the hue caps represents 
the aptitude of the visual system in discerning differences in color hue. 
The standard software application included in the F-M 100 package will be used for scoring 
and analyzing the results. Total error score (TES) will be used as a measurement of color 
vision. Total error score and level of color vision deficiency classification (e.g. superior, 
average, low discrimination) will be recorded on the eCRF.
Examination of color vision will be performed at Visit 2 (pre-dose), 24 weeks and 52 weeks 
or EOT.
10.2.6
Endpoint
Ocular safety will be assessed in a descriptive way based on change from baseline for the 
following endpoints:

Best Corrected Visual Acuity test (BCVA) determined using a Snellen Chart  

Total error score from the Farnsworth-Munsel 100 hue testing (F-M 100)


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10.2.8
Statistical Considerations 
Descriptive statistics for change from baseline will be presented. The descriptive statistics 
will include paired t-tests and confidence intervals.


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11.
DESCRIPTION OF GLOBAL AMENDMENTS
Number of global amendment
1
Date of CTP revision
25 May 2017
EudraCT number
2016-004973-42
BI Trial number
1289-0032
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 52-week treatment period as an early 
intervention in patients with attenuated psychosis 
syndrome.
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
Title page
Description of change
Revised Lay Title
This study tests whether BI 409306 prevents 
patients with a specific type of mental illness 
(attenuated psychosis syndrome) from becoming 
worse. This study looks at how well patients 
tolerate the medicine and how safe and effective it 
is over 1 year.
Rationale for change
Removing “safe” from lay title as this could imply 
that it is not known whether BI 409306 is safe to 
use.
Sections to be changed
Synopsis
Section 4.2.1
Section 5.1.1
Section 7.3.1


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Description of change
Clarification of psychosis/outcome event 
Synopsis
First episode of psychosis defined as:
One or more of the following Positive Symptoms 
(Scale of Prodromal Symptoms (SOPS) criteria) in 
the psychotic range (rated at level 6):

Unusual Thought Content/Delusional 
Ideas 

Suspiciousness/Persecutory Ideas 

Grandiosity 

Perceptual Abnormalities/Hallucinations 

Disorganized Communication
AND either a symptom is seriously 
disorganizing or dangerous OR one of the 
symptoms above occurred at least one hour per 
day at an average frequency of four days/week 
over the past month. 
OR
A new prescription or increase in dose of an 
ongoing antipsychotic medication for worsening of 
psychosis symptoms.
Section 4.2.1
When a patient begins a new prescription or 
increases their dose of an ongoing antipsychotic 
medication due to worsening of psychosis 
symptoms, this is an outcome event. The available 
information (e.g., SOPS interview video, medical 
records from prescribing physician) will be 
subsequently adjudicated reviewed by the Central 
Rating Committee to determine whether the patient 
has converted to psychosis.
Section 7.3.1
The following sensitivity analyses will be 
performed: (1) on the primary endpoint that 
includes only patients from the TS during the time 
of the on-treatment follow-up period and (2) on the 
portion of the primary endpoint derived from the 
SOPS (that is, excluding patients with new 
prescriptions or increases in dose of ongoing 
antipsychotic medication for worsening of 
psychosis symptoms).  


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Rationale for change
Clarify that psychosis/outcome event criteria are 
met when a patient receives a new prescription or 
increase in dose of antipsychotic medication.
Section to be changed
Flow Chart
Description of change
Rationale for change
Sections to be changed
Flow Chart (footnote 9) 
Section 3.3.2
Section 6.2.1
Section 6.2.2
Description of change
Change “Central Rating Committee” to “
 
”
Flow Chart (footnote 9) 
9. The Structured Interview for Psychosis-Risk Syndromes (SIPS) 
and Scale of Prodromal Symptoms (SOPS) interviews will be video-
taped for review by the Central Rating Committee
 
.
Section 3.3.2
1.
Meet diagnostic criteria for attenuated 
psychosis syndrome as defined in DSM-5 and 
determined by SIPS administered at screening and 
diagnosis confirmed by Central Rating Committee
after review of video-taped SIPS 
interview.
Section 6.2.1
If the rater at the site concludes that the patient 
meets diagnostic criteria for APS and has a 
qualifying NAPLS risk calculator score, both the 
video-taped interview and the SIPS response forms 
must be reviewed and diagnosis confirmed by the 
Central Rating Committee
prior 
to randomisation.
Section 6.2.2
During the treatment period, all SIPS/SOPS 
assessments will be video-taped for review by the 
Central Rating Committee
  


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Section 6.2.2
If any Positive Symptom Score of 6/Severe and 
Psychotic is assigned while administering the 
SOPS, the following should occur:

The PI should immediately contact the 
Central Rating Committee chair/contact
to arrange for expedited 
video review.
Rationale for change
Clarification that 
 will perform the 
first review of SIPS/SOPS video recorded 
interviews.
Section to be changed
Abbreviations
Description of change
Abbreviations added and removed 
ASSR/auditory steady-state response 
GABAA/gamma-aminobutryic acid 
ICC/Intra-class correlation coefficient
ITC/Inter-trial phase coherence
MEG/magneto-encephalography
BVMT-R/Brief Visuospatial Memory Test—
Revised
CPT-IP/Continuous Performance Test—Identical 
Pairs
MSCEIT/Mayer-Salovey-Caruso Emotional 
Intelligence Test: Managing Emotions
NAB/Neuropsychological Assessment Battery: 
Mazes
WMS III/Wechsler Memory Scale-III
Rationale for change
Removing abbreviations not referenced in the 
protocol; new abbreviations added that apply to 
changes in Section 10.
Section to be changed
Section 3.3.1
Description of change
Patients with APS who have a NAPLS risk 
calculator score ≥ 0.20 at screening indicative of a 
group aggregate risk of greater than 35% of 
conversion to psychosis at 52 weeks will be 
included. Please refer to the ISF for the NAPLS 
risk calculator website. Patients may be enrolled 
if they are currently taking antipsychotic 
medication (See Section 4.2.1). If a patient 
discontinues an antipsychotic medication, they 
can be randomized two weeks after 
discontinuation.


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Rationale for change
Clarification for patients taking antipsychotic 
medication during the screening period.
Section to be changed
Section 3.3.3
Description of change
Exclusion Criteria added/clarified
1. Present or past diagnosis of schizophrenia, 
schizophreniform, schizoaffective disorder, bipolar 
disorder I or II, major depressive disorder with 
psychotic features, delusional disorder, brief 
psychotic disorder, other specified schizophrenia 
spectrum and other psychotic disorder (except 
attenuated psychosis syndrome), and unspecified 
schizophrenia spectrum and other psychotic 
disorder, according to DSM-5.
2. Patients taking antipsychotic medication for 
less than 8 weeks prior to informed consent. 
3. Patients who begin taking an antipsychotic 
between Visit 1 and Visit 2.
4. Patients who have discontinued an 
antipsychotic medication less than two weeks 
prior to randomization.
10. Diagnosis of a A serious developmental 
disorder that in the judgement of the investigator 
would inhibit the patient’s ability to comply 
with all study procedures, or mental retardation 
(documented IQ <70), cognitive disorder, or acute 
attenuated symptoms exclusively related to 
intoxication from a psychotropic substance. 
Rationale for change
Clarification of existing exclusion criteria and 
additional criteria to define stability of 
antipsychotic medication. 
Section to be changed
Section 4.2.1
Description of change
Antipsychotic medication clarification
If a patient is enrolled who is taking an 
antipsychotic medication that will continue 
during the treatment period, it is extremely 
important they continue to take the current 
antipsychotic medication at the same dose as when 
the patient was randomized. The dose of an 
antipsychotic medication can be decreased or 
discontinued entirely. A patient’s dose of 
antipsychotic medication should be increased only 


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in circumstances of significant worsening of 
psychosis symptoms that the investigator feels 
qualifies for a first episode of psychosis.
Increasing the dose of antipsychotic medication for 
other reasons will be a protocol violation.
Rationale for change
Clarification for patients taking antipsychotic 
medication during the treatment period. 
Section to be changed
Section 4.3
Description of change
Added instruction about monitoring for study drug 
abuse 
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 patient’s
source and on the appropriate eCRFs. 
Rationale for change
Text added regarding monitoring of potential study 
drug abuse and/or diversion.
Section to be changed
Section 5.3.2
Description of change
Clarification about vital signs collection
A similar type of The same calibrated
instrument/scale should be used for all 
measurements. Vital signs will be measured after 
the patient has been sitting for 5 minutes.
Rationale for change
Clarification about the type of instruments that 
should be used to measure vital signs, and when 
measurements should be collected.
Section to be changed
Section 5.3.4
Description of change
Clarification about ECG measurement
The 12-lead ECGs will be performed as scheduled 
in the Flow Chart after 5 minutes in the supine 
position.
Rationale for change
Clarify when ECG should be performed.
Section to be changed
Section 5.3.6.2
Description of change
Added explanation about monitoring for abuse 
related AEs
The potential for study drug abuse-related 
adverse events will be closely monitored and 
narratives provided in the CTR. Narratives will 
include standard AE data collection, including 
time of onset, duration, severity and outcome.
Rationale for change
Explanation regarding monitoring of potential 
abuse related adverse events.


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Section to be changed
Section 5.5.2
Description of change
Collection methods for the samples for CYP2C19 
genotyping at screening and pre-specified 
pharmacogenomic analyses at Visit 2 are identical 
to that of the optional DNA banking sample. Please 
refer to Section 5.5.1.1. Detailed instructions on 
sampling, preparation, processing, shipment 
and storage of the samples collected at screening 
for CYP2C19 genotyping are provided in the 
laboratory manual.
Rationale for change
Clarification about collection of CYP2C19 
genotyping samples.
Section to be changed
Description of change
Rationale for change
Section to be changed
Section 7.4
Description of change
Clarification of interim analyses
One formal unblinded interim analysis will be 
conducted by the DMC when approximately 67% 
of events have occurred to consider ending the trial 
early for overwhelming efficacy.  
A blinded sample size reassessment interim 
analysis with the option to adjust the sample size 
will be performed by the Sponsor’s Trial 
Statistician when 90% of patients have been 
randomised or at the same time as the formal 
interim analysis (whichever happens earlier).  
Rationale for change
Clarification of interim analyses
Section to be changed
Section 9
Description of change
The following references were added: 
P10-00647
R10-5103
R14-4685
R15-3299
R15-3332
R15-3336
R15-3343 
R16-3191


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R17-1755
R17-1756
R17-1757
R17-1758
R17-1759
R17-1760
R17-1761
R17-1763
R17-1764
R17-1765
Rationale for change
References related to EEG added.
Section to be changed
Section 10
Description of change
EEG section revised to provide further background 
information and EEG paradigms adapted to be 
compatible with the NAPLS2 EEG paradigms.
Rationale for change
Adapting the NAPLS2 EEG paradigms in the 
current study in order to compare data from the 
current EEG sub-study with the EEG/ERP data 
collected from large samples of CHR individuals 
and healthy controls in the NAPLS2 study.


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Number of global amendment
2
Date of CTP revision
10 Jul 2017
EudraCT number
2016-004973-42
BI Trial number
1289-0032
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 52-week treatment period as an early 
intervention in patients with attenuated psychosis 
syndrome.
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
Flow Chart
Description of change
ECG and safety laboratory tests added at Visits 8,
12, 16, 20 and 22
Rationale for change
Increase frequency of safety monitoring
Section to be changed
Section 3.3.3
Description of change
Exclusion criteria added

Patients with a history of moderate to severe 
hepatic impairment (Child-Pugh B / C).

Patients with a history of moderate to severe 
renal impairment (Stage 3 – 5).
Rationale for change
Exclude patients with compromised organ function


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Number of global 
amendment
3
Date of CTP revision
04 Oct 2018
EudraCT number
2016-004973-42
BI Trial number
1289-0032
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 52-week treatment period as 
an early intervention in patients with attenuated psychosis 
syndrome.
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
Objective: To investigate the efficacy, safety and tolerability 
of BI 409306 compared to placebo given for 52 weeks to 
patients with attenuated psychosis syndrome. The study is 
designed to show superiority of BI 409306 over placebo in
achieving remission of APS preventing first episode of 
psychosis, as well as improvement in cognition and functional 
capacity.
Rationale for change
To reflect change in primary endpoint.
Section to be changed
Synopsis
Description of change
Main criteria for inclusion: 


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Risk calculator score ≥0.20 (using the North American 
Prodrome Longitudinal Study (NAPLS) risk calculator) at 
screening indicative of a group aggregate risk of greater than 
35% risk of conversion to psychosis within the next 52 weeks.  
No present or past diagnosis of schizophrenia, 
schizophreniform, schizoaffective disorder, bipolar disorder I, 
major depressive disorder with psychotic features, delusional 
disorder, brief psychotic disorder, other specified 
schizophrenia spectrum and other psychotic disorder (except 
attenuated psychosis syndrome), and unspecified 
schizophrenia spectrum and other psychotic disorder, 
according to DSM-5.
Rationale for change
To reflect change in primary endpoint.
Section to be changed
Synopsis
Description of change
Endpoints: 
Primary Endpoint: The primary endpoint is time to remission 
from APS time to first episode of psychosis within a 52 week 
timeframe.  Remission from APS is defined as a score of <3 
on all of the P1-P5 Positive Symptom items of the SOPS 
and maintained until the end of treatment.
First episode of psychosis defined as:
One or more of the following Positive Symptoms (Scale of 
Prodromal Symptoms (SOPS) criteria) in the psychotic range 
(rated at level 6):

Unusual Thought Content/Delusional Ideas 

Suspiciousness/Persecutory Ideas 

Grandiosity 

Perceptual Abnormalities/Hallucinations 

Disorganized Communication
AND either a symptom is seriously disorganizing or dangerous 
OR one of the symptoms above occurred at least one hour per 
day at an average frequency of four days/week over the past 
month. 
OR
A new prescription or increase in dose of an ongoing 
antipsychotic medication. 
Time of onset of first episode psychosis is defined using the 
rater’s best estimate as determined in the SOPS interview or 
when the patient began taking a new prescription or increased 
the dose of antipsychotic medication.


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Secondary Endpoints:

Time to first episode of psychosis within a 52 week 
timeframe as adjudicated by the Central Rating 
Committee. First episode of psychosis defined as one 
or more SOPS P1-P5 rated a 6 AND either a 
symptom is seriously disorganizing or dangerous OR 
one of the symptoms above occurred at least one 
hour per day at an average frequency of four 
days/week over the past month. OR a new 
prescription or increase in dose of an ongoing 
antipsychotic medication. Time of onset of first 
episode psychosis is defined using the rater’s best 
estimate as determined in the SOPS interview or 
when the patient began taking a new prescription or 
increased the dose of antipsychotic medication. 
Rationale for change
To reflect changes in primary and secondary endpoints.
Section to be changed
Synopsis
Description of change
Statistical Methods:
For the primary endpoint of time to first  episode of psychosis
remission from APS, 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 10% 
significance level. The model includes the treatment effect and 
categorized NAPLS risk score as the only covariates and is 
stratified by NAPLS risk calculator score and baseline use of 
antipsychotics. Time to event endpoints will be analysed 
using Cox proportional hazard model and change from 
baseline endpoints will be analysed using the restricted 
maximum likelihood (REML) based mixed effects model with 
repeated measurements (MMRM).
Rationale for change
To reflect changes in primary and secondary endpoints.
Section to be changed
Flow Chart
Description of change
Revisions to Rows:
Cannabis Substance Use Assessment
NAPLS Risk Calculator (row moved to lower section of flow 
chart)
Footnotes:
****
The End of Study CRFs will be completed at the time of the 
Follow-Up Visit for completed patients. Patients who prematurely 
discontinue study drug and remain in the study will have the End of 
Study CRFs completed one year after randomization.
5. Patients will be asked whether they have ever or are currently 
using/consuming tobacco, alcohol and cannabis.


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11. The BACS SC and HVLT-R are paper assessments. The paper 
BACS SC at Visit 23 is a different version than the BACS SC in the 
BAC App that is also completed at Visit 23.
11. The North American Prodromal Longitudinal study (NAPLS) risk 
calculator uses the following predictor variables: 1. Age, 2. Brief 
Assessment of Cognition in Schizophrenia: Symbol Coding (BACS SC), 3. 
Hopkins Verbal Learning Test (HVLT-R), 4. SIPS items P1 and P2 
(unusual thought content and suspiciousness), and 5. Global Functioning: 
Social (GF:Social). 
14. The Columbia Suicide Severity Rating Scale (C-SSRS) 
Baseline/Screening version will be used at Visit 1 (Screening Visit). At 
other scheduled visits, the C-SSRS Since Last Visit version will be used. 
The screening eC-SSRS report must be reviewed by the 
investigator/qualified rater for validity prior to randomization.
21. The NAPLS risk calculator score will be calculated and data 
entered by 
.
Rationale for change
Revision to Substance Use Assessment to align with CRFs; 
clarification of the timing End of Study data collection; 
additional instruction to align with revised suicidal behavior 
exclusion criterion; moved NAPLS Risk Calculator row lower 
in flow chart since sites no longer need to calculate the risk 
score.
Section to be changed
Abbreviations
Description of change
Abbreviations added:
BCVA/ Best Corrected Visual Acuity
F-M 100/Farnsworth-Munsell 100 hue test
TES/Total error score
Rationale for change
New abbreviations added that apply to changes in Section 10.2.
Section to be changed
1. Introduction
Description of change
BI 409306 is a Phosphodiesterase-9 (PDE9) inhibitor under 
development for the treatment of Alzheimer's disease (AD), 
prevention of relapse in persons with schizophrenia, and for 
the treatment of prevention of first episode of psychosis (FEP) 
in patients with attenuated psychosis syndrome (APS)
1.1 Medical Background
These at-risk individuals represent a population who stand to 
benefit from early detection and treatment of the 
aforementioned symptoms as well as possible prevention of 
subsequent psychotic conversion.  Such symptoms as well as 
the occurrence of first psychotic episodes are the focus of the 
investigation plan for BI 409306.


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Data from a recent analysis of a large US insurance claims 
database (R18-0654) demonstrated that as far back as five 
years before an incident diagnosis of schizophrenia subjects 
presented for care and utilized healthcare resources at a 
rate twice that of age and region matched controls.  The 
data demonstrated that these individuals are prescribed a 
number of medications including antipsychotics and 
antidepressants, suggesting that their level of 
symptomatology has already become problematic in their 
lives.
Rationale for change
To reflect change in primary endpoint
Section to be changed
2.1 Rationale for Performing the Trial
Description of change
In conclusion, these preclinical and clinical findings suggest 
that inhibition of PDE9 by 
BI 409306 represents a rational approach for improvement and 
potentially normalization of those processes dysfunctional in 
individuals with attenuated psychosis syndrome, leading to 
reduction or remission of the symptoms, and the delay or 
even prevention of FEP in individuals with attenuated 
psychosis syndrome via decreasing synaptic over-pruning and 
strengthening the NMDA-receptor signaling and synaptic 
plasticity
Rationale for change
To reflect change in primary endpoint
Section to be changed
2.2 Trial Objectives
Description of change
The objective of this study is to investigate the efficacy, safety 
and tolerability of BI 409306 compared to placebo given for 52 
weeks to patients with attenuated psychosis syndrome. The 
study is designed to show superiority of BI 409306 over 
placebo in preventing first episode psychosis achieving 
remission of APS as well as improvement in cognition and 
functional capacity.
A subset of patients will complete ocular safety tests to 
further characterize the ocular safety of BI 409306. See 
Section 10.2.
Rationale for change
To reflect change in primary endpoint and addition of ocular 
safety sub-study
Section to be changed
2.3 Benefit Risk Assessment
Description of change
NAPLS has constructed an algorithm to estimate the risk of 
conversion to psychosis depending on several risk 
factors. When applied, this algorithm predicts the conversion 


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rates for patients without treatment [R16-3564].  In order to 
minimize exposure to individuals at the lower strata of risk for 
conversion to psychosis, This algorithm will be utilized to 
enrich assess the sample of eligible patients with those more 
likely to convert to psychosis within the treatment period than
would occur in a naturalistic setting to better quantify risk for 
conversion.   Patients who convert to psychosis will continue 
to be followed in the trial. 
A potential effect of BI 409306, a centrally acting compound, 
on suicidality cannot be ruled out. This must be balanced 
with an effort to ensure that the population under study is 
representative to the extent possible, of the population 
intended to be prescribed the compound, should it ever 
receive regulatory approval.  Since suicidality is known to 
be common in the CHR population, the exclusion criteria 
for this study allow for an assessment of past suicidal 
behaviour by the investigator while excluding recent 
significant suicidal ideation. Therefore, sSuicidality 
monitoring will be performed pre-dose and throughout the 
study to ensure that potential suicidality will be recognized in 
order to apply appropriate action.
Rationale for change
To reflect change in primary endpoint and revised exclusion 
#6.
Section to be changed
3.1 Overall Trial Design and Plan
Description of change
Randomisation will be stratified by the NAPLS risk score and
baseline use of antipsychotics
Rationale for change
To reflect change to inclusion criteria
Section to be changed
3.2 Discussion of Trial Design, Including the Choice of Control 
Group
Description of change
A randomised, double-blind, parallel group design was chosen 
for this study to observe the effects of BI 409306 compared to 
placebo on the remission of APS symptoms in the prevention 
of first episode psychosis as well as improvement in cognition 
and functional capacity.  
There is currently no approved medication indicated for the 
treatment of symptoms of APS early intervention or for the 
prevention of first episode of psychosis
Rationale for change
To reflect change to primary endpoint
Section to be changed
3.3 Selection of Trial Population
Description of change
It is planned that approximately 50 trial centres in three up to 
four countries will be participating in this trial to randomise 


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300 patients
Rationale for change
To allow for the possibility of another participating country
Section to be changed
3.3.1 Main Diagnosis for trial entry
Description of change
Patients meeting the following diagnostic criteria for 
attenuated psychosis syndrome (APS) as defined in DSM-5 
will be included: with APS who have a NAPLS risk calculator 
score ≥ 0.20 at screening indicative of a group aggregate risk of 
greater than 35% of conversion to psychosis at 52 weeks will 
be included. Please refer to the ISF for the NAPLS risk 
calculator website.
Per DSM-V, the proposed diagnostic criteria for APS are:
A. At least one of the following of symptoms is present 
in attenuated form, with relatively intact reality 
testing and is of sufficient severity or frequency to 
warrant clinical attention:

Delusions

Hallucinations

Disorganized speech.
B. Symptom(s) must have been present at least once per 
week in the last 1 month
C. Symptom(s) must have begun or worsened in the past 
year
D. Symptom(s) is sufficiently distressing and disabling 
to the individual to warrant clinical attention
E. Symptom(s) is not better explained by another 
mental disorder, including: Depressive or bipolar 
disorder with psychotic features and is not 
attributable to physiological effects of a substance or 
another medical condition
F. Criteria for any psychotic disorder have never been 
met.
A diagnosis of Attenuated Positive Symptom Syndrome is 
defined by the presence of recent attenuated positive 
symptoms that meet ALL of 5 criteria: sufficient severity 
(criterion A), sufficient  frequency (criterion B), recency of
onset or worsening (criterion C), associated with sufficient 
distress or disability to warrant clinical attention (“warrant 
attention criterion,” criterion D), and not have been likely 
due to another disorder (“attribution criterion,” criterion 
E).
Rationale for change
To reflect change to inclusion criteria.
Section to be changed
3.3.2 Inclusion Criteria


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Description of change
2. NAPLS risk calculator score ≥ 0.20 at screening. Inclusion 
criterion 2 removed in global amendment 3. Numbering of 
subsequent criteria not changed.
Rationale for change
To reflect change in primary endpoint
Section to be changed
3.3.3 Exclusion Criteria
Description of change
Exclusion criterion revised: 
2. Patients taking antipsychotic medication for less than 8 
weeks prior to informed consent or patients taking 
antipsychotic medication for a longer duration but who 
have not been on a stable dose for 8 weeks prior to 
informed consent prior to informed consent.
6. Any Suicidal behavior in the past 2 years (i.e. actual attempt, 
interrupted attempt, aborted attempt, or preparatory acts or 
behavior) reported in the Columbia Suicide Severity Rating 
Scale (C-SSRS) with a lethality of attempt ≥1, or with a 
lethality of 0 but a potential lethality of 2, 
or that in the judgement of the investigator would 
jeopardize the patient’s safety while participating in the 
trial. The investigator/qualified rater must review all 
screening C-SSRS reports prior to randomization,
documenting an additional interview assessing lethality of 
the behavior history when appropriate.
14. Significant history of drug or alcohol dependence or abuse
Meets criteria for Substance Use Disorder as defined in(DSM-
5) within the last six months prior to informed consent/assent. 
Exclusion criterion added: 
24. Known hypersensitivity to the drug product excipients 
(lactose monohydrate, pregelatinized starch, 
hydroxypropylcellulose, croscarmellose sodium, 
magnesium stearate, hypromellose, propylene glycol, 
titanium dioxide, talc and iron oxide yellow).
Rationale for change
Clarification of exclusion #2, #6, and 14, and addition of 
criterion #24 to exclude patients with hypersensitivity to the 
excipients in the IMP.
Section to be changed
3.3.4.1 Removal of individual patients
Description of change
Premature study drug discontinuation
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 


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complete the End of Treatment (EOT) procedures as described 
in the Flow Chart and Section 6.2.2. Patients who discontinue 
study drug prematurely should ideally be observed until the end 
of the trial study (week 52) as if they were still receiving 
blinded study treatment.
Rationale for change
Clarification to emphasize that patients who prematurely 
discontinue study drug should be followed for one year after 
randomization. 
Section to be changed
4.2.1
Other treatments and emergency procedures
Description of change
Patients experiencing a first episode of psychosis should 
continue taking study drug at the discretion of the 
investigator.
Rationale for change
Clarification that patients should remain in the study after 
experiencing psychosis.
Section to be changed
5.1.1 Primary Endpoint
Description of change
The primary endpoint is time to remission from APS time to 
first episode of psychosis within a 52 week timeframe as 
adjudicated by the Central Rating Committee.  
Per DSM-V, the proposed diagnostic criteria for APS are:
A. At least one of the following of symptoms is present 
in attenuated form, with relatively intact reality 
testing and is of sufficient severity or frequency to 
warrant clinical attention:

Delusions

Hallucinations

Disorganized speech.
B. Symptom(s) must have been present at least once per 
week in the last 1 month
C. Symptom(s) must have begun or worsened in the past 
year
D. Symptom(s) is sufficiently distressing and disabling 
to the individual to warrant clinical attention
E. Symptom(s) is not better explained by another 
mental disorder, including: Depressive or bipolar 
disorder with psychotic features and is not 
attributable to physiological effects of a substance or 
another medical condition
F. Criteria for any psychotic disorder have never been 
met.
A diagnosis of Attenuated Positive Symptom Syndrome is 
defined by the presence of recent attenuated positive 
symptoms that meet ALL of 5 criteria: sufficient severity
(criterion A), sufficient frequency (criterion B), recency of 


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onset or worsening (criterion C), associated with sufficient 
distress or disability to warrant clinical attention (“warrant 
attention criterion,” criterion D), and not likely due to 
another disorder (“attribution criterion,” criterion E). 
A patient in remission is defined as someone who no longer 
meets the severity criterion.
Remission from APS is defined as a score of <3 on all of the 
P1-P5 Positive Symptom items of the SOPS and maintained 
until the end of treatment. 
One or more of the following Positive Symptoms (Scale of 
Prodromal Symptoms (SOPS) criteria) in the psychotic range 
(rated at level 6):

Unusual Thought Content/Delusional Ideas 

Suspiciousness/Persecutory Ideas 

Grandiosity 

Perceptual Abnormalities/Hallucinations 

Disorganized Communication
AND either a symptom is seriously disorganizing or 
dangerous OR one of the symptoms above occurred at least 
one hour per day at an average frequency of four days/week 
over the past month. 
OR
A new prescription or increase in dose of an ongoing 
antipsychotic medication. 
Time of onset of first episode psychosis is defined using the 
rater’s best estimate as determined in the SOPS interview or 
when the patient began taking a new prescription or increased 
the dose of antipsychotic medication.
Rationale for change
Change in primary endpoint.
Section to be changed
5.1.2 Secondary Endpoints
Description of change

Time to first episode of psychosis within a 52 week 
timeframe as adjudicated by the Central Rating 
Committee.  First episode of psychosis defined as 
one or more SOPS P1-P5 rated a 6 AND either a 
symptom is seriously disorganizing or dangerous OR 
one of the symptoms above occurred at least one 
hour per day at an average frequency of four 
days/week over the past month. OR a new 
prescription or increase in dose of an ongoing 
antipsychotic medication. 
Time of onset of first episode psychosis is defined 


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using the rater’s best estimate as determined in the 
SOPS interview or when the patient began taking a 
new prescription or increased the dose of 
antipsychotic medication.
Rationale for change
To reflect change in primary endpoint. Formal primary 
endpoint now a secondary endpoint.
Section to be changed
Description of change
Rationale for change
Section to be changed
5.2 Assessment of Efficacy
Description of change
Remission of APS, conversion to psychosis, functional 
capacity, cognitive function, and disease state will be measured 
by the batteries and questionnaires listed below:
The Positive scale is used to make a diagnosis of attenuated 
psychosis syndrome (APS) and conversion to psychosis. To 
meet criteria for APS, a patient must at some point have 
rated level “3”, “4”, or “5” on at least one of the P1-P5 
Positive Symptom items of the SOPS. The symptom(s) must 
have occurred at the then-current intensity level at an 
average frequency of at least once per week in the past 
month, and must not have been likely due to another 
disorder. The Negative, Disorganization and General other
domains are used to assess the severity of the diagnosis [R15-
1441]. 
A composite T score that averages five is calculated using the 
six of the standardized scaled sub-test scores will be generated. 
The token motor test score will not be included because at the 
time of protocol writing there were no norms available on this 
sub-test.
Rationale for change
To reflect change in primary endpoint; to clarify APS 
diagnosis; update to the calculation of BAC App T score.
Section to be changed
5.3.5.1 Assessment of suicidality
Description of change
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. The investigator/qualified 
rater must perform and document an additional interview 
if there is doubt about the validity of the report. Doubtful 
reports may be repeated or reports may be validated by a 
consulting psychiatrist.


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Rationale for change
To clarify C-SSRS procedures.
Section to be changed
5.3.6.1 Definitions of AEs
Description of change
Adverse reaction
An adverse reaction is defined as a response to a medicinal 
product which is noxious and unintended. Response in this 
context means that a causal relationship between a medicinal 
product and an adverse event is at least a reasonable possibility. 
Adverse reactions may arise from use of the product within or 
outside the terms of the marketing authorisation or from 
occupational exposure. Conditions of use outside the marketing 
authorization include off-label use, overdose, misuse, abuse 
and medication errors.
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, this refers to an event in which the 
patient was at risk of death at the time of the event; it 
does not refer to an event that hypothetically might have 
caused death if more severe.

requires inpatient hospitalisation or prolongation of 
existing hospitalisation,

results in persistent or significant disability or 
incapacity, or

is a congenital anomaly / birth defect, or
is to be deemed serious for any other reason if it is an important 
medical event when based upon appropriate medical judgment 
which may jeopardise the patient and may require medical or 
surgical intervention to prevent one of the other outcomes listed 
in the above definitions. Medical and scientific judgement 
should be exercised in deciding whether other situations should 
be considered serious reactions, such as important medical 
events that might not be immediately life threatening or result 
in death or hospitalisation but might jeopardise the patient or 
might require intervention to prevent one of the other outcomes 
listed above. 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. 
Any suspected transmission via a medicinal product of an 
infectious agent is also considered a serious adverse reaction.
Causal relationship of AEs
The definition of an adverse reaction implies at least a 


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reasonable possibility of a causal relationship between a 
suspected medicinal product and an adverse event. An adverse 
reaction, in contrast to an adverse event, is characterised by the 
fact that a causal relationship between a medicinal product and 
an occurrence is suspected. 
Medical judgment should be used to determine the relationship
whether there is a reasonable possibility of a causal 
relationship between the adverse event and the given study 
treatment, considering all relevant factors, including pattern of 
reaction, temporal relationship, de-challenge or re-challenge, 
confounding factors such as concomitant medication, 
concomitant diseases and relevant history. 
Rationale for change
To align this section with updated standard protocol text.
Section to be changed
5.3.6.2 Adverse event collection and reporting
Description of change
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).
•
From signing the informed consent/assent onwards through 
the Residual Effect Period (REP), until individual patient’s 
end of trial: 
-all AEs (serious and non-serious) and all AESIs.
However, if an individual patient discontinues trial 
medication prematurely but stays in the trial (i.e. if further 
visits include telephone visits, or vital status assessments 
are planned) from then on and until the individual patient’s 
end of the trial the Investigator must report related SAEs 
and related 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 relevant SAEs and relevant 
AESIs of which the Investigator may become aware of by any 
means of communication, e.g. phone call. Those AEs should 
be reported on the BI SAE form, but not on the CRF.
The rules for Adverse Event Reporting exemptions still 
apply, please see section 5.3.6.3.
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 


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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 only report relevant SAEs and relevant 
AESIs of which the Investigator may become aware of by 
any means of communication, e.g. phone call. Those AEs 
should be reported on the BI SAE form, but not on the 
CRF.
The rules for Adverse Event Reporting exemptions still 
apply, please see section 5.3.6.3.
Rationale for change
To align this section with updated standard protocol text.
Section to be changed
6.2.1 Screening Period
Description of change
If the rater at the site concludes that the patient meets 
diagnostic criteria for APS and has a qualifying NAPLS risk 
calculator score, both the video-taped interview and the SIPS 
response forms must be reviewed and diagnosis confirmed by 
prior to randomisation.  Please refer to the 
Assessment Procedures Binder SIPS Process Document in 
the ISF for further information.
Rationale for change
To reflect change to inclusion criteria; clarification on the name 
of the procedural reference.
Section to be changed
6.2.2 Treatment Period
Description of change
Please refer to the Assessment Procedures Binder SIPS 
Process Document in the ISF.
Patients experiencing a first episode of psychosis should 
continue taking study drug at the discretion of the 
investigator.  
Rationale for change
Clarification on the name of the procedural reference; 
clarification that patients should remain in the study after 
experiencing psychosis.
Section to be changed
7.1 Statistical Design - Model
Description of change
The primary objective of the statistical analysis is to determine 
whether BI 409306 significantly reduces the risk of first 
episode of psychosis increases the likelihood of remission 
from APS in comparison to placebo. The Cox proportional 
hazards model, stratified by the NAPLS risk score strata and
baseline use of antipsychotic medication, will be used to 


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estimate and test the hazard ratio of BI 409306 vs. placebo.
The NAPLS risk score is dichotomized into two strata:

0.20 ≤ NAPLS risk score < 0.40

NAPLS risk score ≥ 0.40.
Rationale for change
To reflect change in primary endpoint.
Section to be changed
7.2 Null and Alternative Hypotheses
Description of change
Superiority will be declared if the hazard ratio between 
BI 409306 vs. placebo is significantly less greater than 1 at the 
two-sided type I error level α = 0.10.
Rationale for change
To reflect change in primary endpoint.
Section to be changed
7.3.1 Primary Endpoint analyses
Description of change
The primary endpoint is the time to first episode psychosis
remission of from APS as defined in Section 5.1.2.  
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 10% significance level. The model 
includes the treatment effect and NAPLS risk score as the 
only covariates and is stratified by NAPLS risk score and
baseline use of antipsychotic medication. 
A hazard ratio of more less than one favors BI 409306.  
The primary analysis will be performed on the FAS for the full 
follow-up on treatment period.  The date of remission will be 
the visit date on which the patient taking the assessment 
meets the remission criteria. The time to remission is 
defined to be the start of treatment until remission is 
achieved. Although Ppatients who discontinue study 
medication will be followed until the end of the trial for the 
primary endpoint, the data collected after treatment 
discontinuation will be only used for sensitivity analysis.  
Patients who are lost-to-follow up will be censored for the 
primary endpoint at the time of their last known SOPS 
assessment. Patients who begin taking a new prescription or 
increase in dose of ongoing antipsychotics will be considered 
as not eligible for remission. Such patients will be censored 
at the start of new prescription or increase of dose of 
ongoing antipsychotics. Further details regarding these 
analyses will be included in the TSAP.
The following sensitivity analyses will be performed: (1) on the 
primary endpoint that includes only patients from the TS during
the time of the on-treatment full follow-up period and (2) 
excluding patients who were recruited from the enriched 


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population prior to amendment 3 on the portion of the 
primary endpoint derived from the SOPS (that is, excluding 
patients with new prescriptions or increases in dose of ongoing 
antipsychotic medication).  
Rationale for change
To reflect change in primary endpoint.
Section to be changed
7.3.2 Secondary endpoint analyses
Description of change
Time to event endpoints will be analysed using Cox 
proportional hazard model as described for the primary 
endpoint analysis. All change from baseline endpoints 
specified in Section 5.1.2 will be analysed using the 
restricted maximum likelihood (REML) based mixed 
effects model with repeated measurements (MMRM). All 
secondary endpoints specified in Section 5.1.2 will be analyzed 
using a restricted maximum likelihood estimation based on 
MMRM for the change from baseline.
Rationale for change
To reflect change in secondary endpoint.
Section to be changed
7.4 Interim Analyses
Description of change
Once there is a sufficient amount of data collected for 
review, tThe DMC will hold meetings three times per year.
The number of observed remissions primary endpoints will be 
compared to the number predicted.  If the actual number is 
lower than predicted (given the actual already documented 
study time of randomised patients at the scheduled post-
baseline SOPS visits; prediction: 35 40% for placebo & 20
57% for BI 409306 at 52 weeks), the sample size may be 
increased to allow the trial to achieve full power up to a 
maximum sample size of 400 patients.
Rationale for change
To reflect change in primary endpoint.
Section to be changed
7.5 Handling of Missing Data
Description of change
All patients who have not converted to psychosis achieved 
remission will be censored in the analysis of the primary 
endpoint at the time of last known SOPS assessment.  
Rationale for change
To reflect change in primary endpoint.
Section to be changed
7.6 Randomization
Description of change
The randomisation will be stratified by risk score on the 
NAPLS risk calculator (0.20 ≤ score < 0.40 vs. score ≥ 0.40), 
and baseline use of antipsychotic medication.  
Rationale for change
To reflect removal of stratification factor.
Section to be changed
7.7 Determination of Sample Size
Description of change
Remission rate of the population diagnosed with APS and 


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without intervention was assumed to be 40% (Addington, 
2011) by 52 weeks. The rate of remission for BI 409306 was 
assumed to be 57% by 52 weeks. This will lead to a hazard 
ratio of 1.652 NAPLS has constructed an algorithm to estimate 
the risk of conversion to first episode psychosis depending on 
several risk factors.  This algorithm, when applied, predicts the 
conversion rates for patients without treatment, i.e., patients 
taking placebo.  For example, for the group of patients with a 
risk score ≥ 0.20, approximately 35% of patients are predicted 
to convert to psychosis within one year.  For the group of 
patients with risk score ≥ 0.15, approximately 27% of patients 
are predicted to convert to psychosis within one year [R16-
3564]. Selection of the targeted conversion rate in the APS 
population is somewhat arbitrary, but the risk score ≥ 0.20 was 
selected to maximize the risk of conversion to enable the trial 
to be able to differentiate between treatment and placebo within 
an acceptable risk/benefit profile.
Table 7.7: 1
Power calculations for sample size (for both 
arms combined) of 300 for various conversion remission rates 
for BI 409306 with fixed placebo group aggregate conversion
first remission rate prediction of 35%40% by 52 weeks
BI 409306 group aggregate conversion rate
15%
20%
25%
80% power
Total N=115 
patients
230
560
90% power
160
319
775
Remission 
Rate for 
Placebo
Remission 
Rate for 
BI 409306
Hazard 
Ratio
Risk
Ratio
Power 
for 
N=300
# 
Events 
needed 
in 
total
40%
52%
1.437
1.300
64.9%
126
40%
55%
1.563
1.375
81.5%
130
40%
57%
1.652
1.425
89.3%
133
40%
59%
1.745
1.475
94.4%
136
40%
61%
1.843
1.525
97.4%
139
Table 7.7: 1 displays the power achieved for 300 number of
total randomized patients needed to randomise given a group 
aggregate conversion first remission rate of 35 40% for 
placebo with two-sided α= 0.10 and a user-defined alpha 
spending boundary at interim analysis of α=0.01 (two-sided).  
Group conversion remission rates for BI 409306 treatment of 


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15%, 20%, and 25%52%, 55%, 57%, 59% and 61% are 
considered.  Sample size considerations for 80% and 90% 
power are displayed. Total number of events needed to 
achieve the power reported is also shown.
Given conversion remission rates of 35 40%  for patients 
treated with placebo and 2057% for patients treated with BI 
409306, the risk ratio is 0.57 1.425 (equating to a 43% risk 
reductionimplying that patients treated with BI 409306 will 
have 42.5% more chance of achieving remission of APS 
compared to placebo). and a total sample size of 319 patients 
is required for 90% power.  A sample size of 300 (or 150 per 
group) was selected as the most logical for establishing proof 
of concept based on the risk / benefit considerations noted 
above.  In addition this was the sample size used in the 
previous protocol and is kept the same. This translates to 
8889% power. The type I error was selected to be 10% since 
this is a phase II study meant to provide an understanding 
of the effectiveness of the drug without being too strict as in 
a confirmatory setting.
Seventy-five One hundred and thirty three (75133) events 
(conversions remissions) are needed to be observed to meet the 
trial objectives.  This will not be an event driven trial, so the 
trial will end when all randomised patients have reached 12 
months exposure, regardless of number of conversions
remissions observed.  However, a blinded sample size 
assessment will be performed (see Section 7.4) that may allow 
for an increase in sample size in an attempt to observe the 
number of conversions remissions necessary for full power.
Rationale for change
To reflect change in primary endpoint.
Section to be changed
9 References
Description of change
The following references were added:
R16-0991
R18-0654
Rationale for change
References added in section 1and 7.
Section to be changed
10.2 Ocular Safety Sub-Study
Description of change
Addition of Ocular safety sub-study
Rationale for change
Section added to provide information on the background, 
patient selection, design, procedures, endpoints, analytical 
determination and statistical considerations for the ocular safety 
sub-study. 


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c08964447
5.0
clinical-trial-protocol-version-03
A phase II randomised, double-blind, placebo-controlled study to evaluate the
efficacy, safety, and tolerability of orally administered BI 409306 during a 52-week
treatment period as an early intervention in patients with attenuated psychosis
syndrome.
Author-Trial Statistician
05 Oct 2018 12:44 CEST
Approval-Clinical Trial Leader
05 Oct 2018 12:45 CEST
Approval-Team Member Medicine
05 Oct 2018 20:24 CEST
Approval-Therapeutic Area 
08 Oct 2018 10:24 CEST
Verification-Paper Signature
Completion
08 Oct 2018 12:09 CEST


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c08964447
5.0

SAP_001.pdf: 
TITLE PAGE
TRIAL STATISTICAL ANALYSIS PLAN
c17518576-03
BI Trial No.:
1289.32
Title:
A phase II randomised, double-blind, placebo-controlled study to 
evaluate the efficacy, safety, and tolerability of orally administered 
BI 409306 during a 52-week treatment period as an early 
intervention in patients with attenuated psychosis syndrome.
Investigational
Product(s):
BI 409306
Responsible trial 
statistician(s):
Telephone: 
Date of statistical 
analysis plan:
21 MAY 2021 SIGNED 
Version:
“Final” 
Page 1 of 23
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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(S) ....................................................................................................9
5.1
PRIMARY ENDPOINT(S) ..................................................................................9
5.2
SECONDARY ENDPOINT(S) ............................................................................9
5.2.1
Key secondary endpoint(s)...................................................................................9
5.2.2
Secondary endpoint(s) ..........................................................................................9
6.
GENERAL ANALYSIS DEFINITIONS ..........................................................13
6.1
TREATMENT(S)................................................................................................13
6.2
IMPORTANT PROTOCOL VIOLATIONS ...................................................13
6.3
SUBJECT SETS ANALYSED...........................................................................13
6.5
POOLING OF CENTRES .................................................................................14
6.6
HANDLING OF MISSING DATA AND OUTLIERS....................................15
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS ...................16
7.
PLANNED ANALYSIS......................................................................................17
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS.........17
7.2
CONCOMITANT DISEASES AND MEDICATION .....................................17
7.3
TREATMENT COMPLIANCE........................................................................17
7.4
PRIMARY ENDPOINT(S) ................................................................................17
7.4.1
Sensitivity Analyses.............................................................................................18
7.5
SECONDARY ENDPOINT(S) ..........................................................................18
7.5.1
Key secondary endpoint(s).................................................................................18
7.5.2
(Other) Secondary endpoint(s) ..........................................................................18
7.7
EXTENT OF EXPOSURE.................................................................................19
7.8
SAFETY ANALYSIS..........................................................................................19
7.8.1
Adverse events.....................................................................................................19
7.8.2
Laboratory data ..................................................................................................20
7.8.3
Vital signs.............................................................................................................20


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7.8.4
ECG......................................................................................................................20
8.
REFERENCES....................................................................................................21
10.
HISTORY TABLE..............................................................................................23


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LIST OF TABLES
Table 6.1: 1
Treatments and their labels per randomization list...........................................13
Table 6.3: 1
Subject sets analyzed........................................................................................14
Table 6.7: 1
Visit calculation relative to study start .............................................................16
Table 10: 1
History table .....................................................................................................23


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2.
LIST OF ABBREVIATIONS
Include a list of all abbreviations used in the TSAP 
Term
Definition / description
AE
Adverse Event
APS 
Attenuated Psychosis Syndrome
AR(1)
Autoregressive covariance matrix of order 1
BAC App
Tablet based Brief Assessment of Cognition
BACS
Brief Assessment of Cognition in Schizophrenia
BACS SC 
Brief Assessment of Cognition in Schizophrenia: Symbol Coding
BCVA
Best Corrected Visual Acuity
BDNF
Brain-derived neurotrophic factor
BI
Boehringer Ingelheim
C-SSRS
Columbia- Suicide Severity Rating Scale
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
CYP
Cytochrome P450
DRA
Drug Regulatory Affairs
DSM
Diagnostic and Statistical Manual of Mental Disorders
EC
Exclusion Criteria
ECG
Electrocardiogram
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


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Term
Definition / description
IC
Inclusion Criteria
ICH
International Conference On Harmonisation
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
Max
Maximum
Min
Minimum
MMRM
Mixed Model with Repeated Measurements
MedDRA
Medical Dictionary For Regulatory Activities
N
Sample Size
NAPLS
North American Prodromal Longitudinal Study
PANSS
Positive and Negative Syndrome Scale
PK
Pharmacokinetic
PSP
Personal and Social Performance
PT
Preferred Term
RS
Randomized Set
SAE
Serious Adverse Event
SCoRS
Schizophrenia Cognition Rating Scale
SD
Standard Deviation
SOC
System Organ Class
SOPS
Scale of Prodromal Symptoms
TS
Treated Set
TSAP
Trial Statistical Analysis Plan
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
Due to recruitment challenges, the trial has a much smaller sample size than originally 
intended. The following are the changes in the analyses due to the limited sample size:

No subgroup analyses.

No evaluation of psychometric properties of SIPS/SOPS.  

No additional sensitivity analyses excluding patients who were recruited from the 
enriched population prior to amendment 3.


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5.
ENDPOINTS(S)
5.1
PRIMARY ENDPOINT(S)
The primary endpoint is time to remission from APS within a 52 week timeframe (please see 
section 5.1.1 of the CTP).
Per DSM-V, the proposed diagnostic criteria for APS are:
A. At least one of the following of symptoms is present in attenuated form, with 
relatively intact reality testing and is of sufficient severity or frequency to warrant clinical 
attention:

Delusions

Hallucinations

Disorganized speech.
B. Symptom(s) must have been present at least once per week in the last 1 month
C. Symptom(s) must have begun or worsened in the past year
D. Symptom(s) is sufficiently distressing and disabling to the individual to warrant 
clinical attention
E. Symptom(s) is not better explained by another mental disorder, including: Depressive 
or bipolar disorder with psychotic features and is not attributable to physiological effects 
of a substance or another medical condition
F. Criteria for any psychotic disorder have never been met.
A diagnosis of APS is defined by the presence of recent attenuated positive symptoms that 
meet ALL of 5 criteria: sufficient severity (criterion A), sufficient frequency (criterion B), 
recency of onset or worsening (criterion C), associated with sufficient distress or disability to 
warrant clinical attention (“warrant attention criterion,” criterion D), and not likely due to 
another disorder (“attribution criterion,” criterion E).
A patient in remission is defined as someone who no longer meets the severity criterion.
Remission from APS is defined as a score of <3 on all of the P1-P5 Positive Symptom items 
of the SOPS and maintained until the end of treatment.
5.2
SECONDARY ENDPOINT(S)
5.2.1
Key secondary endpoint(s)
This section is not applicable.
5.2.2
Secondary endpoint(s)
The following are the secondary endpoints as defined in section 5.1.2 of the CTP.


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
Time to first episode of psychosis within a 52 week timeframe as adjudicated by the 
Central Rating Committee. 
First episode of psychosis defined as:
•
One or more SOPS P1- P5 rated a 6 
•
AND either a symptom is seriously disorganizing or dangerous 
•
OR one of the symptoms above occurred at least one hour per day at an 
average frequency of four days/week over the past month
•
OR a new prescription or increase in dose of an ongoing antipsychotic 
medication. 
Time of onset of first episode psychosis is defined using the rater’s best estimate as 
determined in the SOPS interview or when the patient began taking a new prescription 
or increased the dose of antipsychotic medication.

Change from baseline in everyday functional capacity as measured by Schizophrenia 
Cognition Rating Scale (SCoRS) total score after 24 and 52 weeks of treatment.

Change from baseline in the BAC App composite T score after 52 weeks of treatment.

Change from baseline in Positive and Negative Syndrome Scale (PANSS) positive 
items score, negative items score, and total score after 52 weeks of treatment.


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENT(S)
As described in Section 3 of the CTP, patients will be randomized in equal allocation to one 
of two treatment dosage groups (50 mg and placebo) for analysis purposes.
For randomization purposes 2 arms have been defined: 

BI 409306 50 mg q.d. for 52 weeks.

Placebo for 52 weeks.
Table 6.1: 1
Treatments and their labels per randomization list
Treatment 
Short label 
BI 409306 50 mg q.d. 
BI 409306 50 mg 
Placebo 
Placebo 
The trial consists of a 28 day screening period, followed by a 52 week treatment period (after 
randomization), and a 28 day residual effect period for follow-up. 
For analysis purposes two periods have been defined in section 7.3.1 of the CTP:

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 residual effect period. 

On-treatment
This includes the time period from treatment start date until drug discontinuation + 7 
days.
Patients who discontinue early will be followed up according to the section 3.3.4.1 of the 
CTP.
6.2
IMPORTANT PROTOCOL VIOLATIONS
According to latest iPD HTG, important protocol deviations are recorded in the DV template. 
6.3
SUBJECT SETS ANALYSED
Screened/Enrolled 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.


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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, RS and TS 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, vital signs and ECG). 
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
Analysis periods are defined in the revised CTP and in section 6.1.
6.5
POOLING OF CENTRES
This section is not applicable because country is not included in the statistical model.


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6.6
HANDLING OF MISSING DATA AND OUTLIERS
Assessment of remission data (primary endpoint):
All patients will be followed up for remission from APS. As specified in section 5.1, 
remission from APS has to be maintained until the end of treatment to satisfy the primary 
endpoint. 
Any patient who has not remitted will be censored in the analysis of the primary endpoint at 
the time of their planned completion of 52-week treatment period or at the time of 
discontinuation. 
Any patient who has remitted but relapsed to APS will be also censored in the analysis of 
primary endpoint at the time of their planned completion of 52-week treatment period or at 
the time of discontinuation. 
Any patient who has an episode of psychosis will be censored at the time point of psychosis.
Patients who begin taking a new prescription or increase in dose of ongoing antipsychotics 
will not be considered eligible for remission. Such patients will be censored at the start of new
prescription or increase of dose of ongoing antipsychotics.
No missing data will be imputed for primary and secondary analyses. 
SCoRS:
For the SCoRS, if an individual item is missing, it should be imputed with the average of the
patient’s non-missing item scores.
PANSS positive symptoms (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 is missing.
AE dates
Missing or incomplete AE dates are imputed according to BI standards (see “Handling of 
missing and incomplete AE dates”) (3).


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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 before the 
first time drug administration (at screening (Visit 1), or an unscheduled visit) will be used. 
For demographics, medical history, ECG, concomitant antipsychotic medication, AEs, 
concomitant therapies and vital signs, Visit 1 (screening) will be considered as “baseline”.
Visit will be labelled according to the flow chart in the protocol: Visit 1 (for screening), Visit
2 (randomization and start of treatment), Visits 3-23, End of Treatment (EOT), Follow Up 
(FU) (28 days after Visit 23 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
3
8
Visit 3 date – first dose date +1
4
15
Visit 4 date – first dose date +1
5
22
Visit 5 date – first dose date +1
Etc...
...
...
23
365
Visit 23 date – first dose date +1
EOT
Visit 23 + (7 days)
EOT– first dose date + 1
FU
Visit 23 + 28 days
FU date – first dose date + 1


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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. Both baseline and on-treatment mediations will be summarized.
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 <50%, 50% - <80%, >80% (cf. section 5.4.2 for calculation of treatment
compliance). Similar table with the same categories will be prepared for patient adherence 
obtained via 
. A patient level listing comparing traditional treatment compliance with 
patient adherence from 
 will also be included to facilitate patient level insights.  
7.4
PRIMARY ENDPOINT(S)
The hypothesis testing strategy for primary endpoint is described in Section 7.2 of the CTP:
The hypothesis for the superiority testing of the primary endpoint time to remission from APS 
is (HR = hazard ratio):


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Ho: HRBI 409306 / placebo = 1
vs. 
Ha: HRBI 409306 / placebo ≠ 1, where HRBI 409306 is the 
hazard ratio for the active treatment arms (i.e. BI 409306 50 mg q.d.), over 52 weeks.
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 = 0.1.
7.4.1
Sensitivity Analyses 
The following sensitivity analyses will be conducted: (1) on the primary endpoint that 
includes only patients from the TS during the time of the full follow-up period and (2) 
Patients who have 
 adjusted adherence over 80%. 
7.5
SECONDARY ENDPOINT(S)
7.5.1
Key secondary endpoint(s)
This section is not applicable, as no key secondary endpoint has been specified in the 
protocol.
7.5.2
(Other) Secondary endpoint(s)
Secondary endpoints will be analyzed as described in section 7.3.2 in the revised CTP:
Time to First Episode of Psychosis: 
Time to event endpoint will be analyzed using Cox proportional hazard model as described 
for the primary endpoint analysis. 
Change from baseline SCoRS (at time points 24 weeks, 52 weeks respectively), BAC App
(composite T score), PANSS (positive items score, negative items score and total score 
respectively):
All change from baseline endpoints specified in Section 5.2.2 will be analyzed using the 
restricted maximum likelihood (REML) based mixed effects model with repeated 
measurements (MMRM). The model will include the fixed, categorical effects of treatment, 
visit, treatment by visit interaction, and baseline NAPLS risk score, and baseline use of 
antipsychotic medication, as well as the continuous fixed covariates of baseline score and 
baseline-by-visit interaction. The unstructured covariance structure will be used to model the 
within-patient errors. If this analysis fails to converge, compound symmetry covariance 
structure might be used. The Kenward-Roger approximation will be used to estimate the 
denominator degrees of freedom. Analyses will be implemented using 
® PROC MIXED. 
The primary treatment comparisons will be between the placebo and BI 409306 with respect 
to the mean change from baseline. Adjusted mean change from baseline as well as treatment 
contrasts will be presented together with the 95% confidence intervals.


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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.
The analysis of adverse events will be based on the concept of treatment emergent adverse 
events. That means all adverse events with an onset between start of treatment and end of the 
on-treatment period, which is 7 days after the last dose of trial medication, will be assigned to 
the treatment period for evaluation. 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). 
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
(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, and will be summarized by treatment, primary system organ class and 


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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 (only if 
defined) and for subjects with serious adverse events.
The system organ classes and preferred terms (within system organ class) will be sorted by 
frequency.
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 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. See section 7.3.4 of the 
CTP.
7.8.4
ECG
12-lead ECG measurements will be assessed as described in the CTP Flow Chart. ECG 
findings before first intake of study drug will be considered as baseline condition. 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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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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10.
HISTORY TABLE
Table 10: 1
History table
Version
Date
(DD-MMM-YY)
Author
Sections 
changed
Brief description of change
Initial
13-DEC-17
None
This is the initial TSAP with necessary 
information for trial conduct
Final
21-MAY-21
All were 
updated.
This is the final TSAP