Clinical trial NCT03669640
Conditions: Schizophrenia, Schizoaffective Disorder
Sponsor: Hoffmann-La Roche
Start date: 2018-12-04; Completion date: 2023-03-12
Enrollment: 131 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study investigates the effects of RO6889450 on the negative symptoms associated with schizophrenia and schizoaffective disorder.

Detailed description:

Arms: arm 1: Participants will receive RO6889450 or a dose-matched placebo. NOTE: Part A has completed enrollment. arm 2: Participants will receive a low or high dose of RO6889450 or a dose-matched placebo in addition to their usual anti-psychotic treatment(s).
Interventions: intervention 1: RO6889450 intervention 2: Placebo
Intervention descriptions: intervention 1: Participants will receive a once-daily, oral dose of RO6889450 for 12 weeks. intervention 2: Participants will receive a once-daily, oral dose of placebo matched to RO6889450 for 12 weeks.

Protocol documents:
Prot_000.pdf: 
Official Title: Phase 2, Randomized, Double-Blind, Placebo-Controlled Study to 
Assess the Effects of RO6889450 (Ralmitaront) in Patients With 
Schizophrenia or Schizoaffective Disorder and Negative Symptoms 
NCT Number: NCT03669640 
Document Dates: Protocol Version 6: 27-September-2021 


FINAL PROTOCOL APPROVAL
CONFIDENTIAL
The information contained in this document, especially any unpublished data, is the property of 
F. Hoffmann-La Roche Ltd (or under its control) and therefore, is provided to you in confidence as 
an investigator, potential investigator, or consultant, for review by you, your staff, and an 
applicable Ethics Committee or Institutional Review Board. It is understood that this information 
will not be disclosed to others without written authorization from Roche except to the extent 
necessary to obtain informed consent from persons to whom the drug may be administered.
RO6889450 (Ralmitaront) —F. Hoffmann-La Roche Ltd
Protocol BP40283, Version 6
PROTOCOL
TITLE:
PHASE 2, RANDOMIZED, DOUBLE-BLIND, 
PLACEBO-CONTROLLED STUDY TO ASSESS 
THE EFFECTS OF RO6889450 (RALMITARONT)
IN PATIENTS WITH SCHIZOPHRENIA OR 
SCHIZOAFFECTIVE DISORDER AND NEGATIVE 
SYMPTOMS
PROTOCOL NUMBER:
BP40283
VERSION:
6
IND NUMBER:
TEST PRODUCT:
RO6889450
SPONSOR:
F. Hoffmann-La Roche Ltd
DATE FINAL:
Version 1: 27 June 2018
DATE AMENDED:
Version 2: 23 May 2019
Version 3: 12 March 2020
Version 4: 10 July 2020
Version 5: 15 Sep 2020
Version 6: See electronic date stamp below
 
Company Signatory
Approver's Name
Title
Date and Time (UTC)
27-Sep-2021 07:04:49


RO6889450 (Ralmitaront) —F. Hoffmann-La Roche Ltd
2/Protocol BP40283, Version 6
PROTOCOL ACCEPTANCE FORM
TITLE:
PHASE 2, RANDOMIZED, DOUBLE-BLIND, 
PLACEBO-CONTROLLED STUDY TO ASSESS 
THE EFFECTS OF RO6889450 (RALMITARONT)
IN PATIENTS WITH SCHIZOPHRENIA OR 
SCHIZOAFFECTIVE DISORDER AND NEGATIVE 
SYMPTOMS
PROTOCOL NUMBER:
BP40283
VERSION NUMBER:
6
IND NUMBER:
TEST PRODUCT:
RO6889450
SPONSOR:
F. Hoffmann-La Roche Ltd
I agree to conduct the study in accordance with the current protocol.
Principal Investigator’s Name (print)
Principal Investigator’s Signature
Date
Please keep the signed original form in your study files, and return a copy to your local 
Study Monitor.


RO6889450 (Ralmitaront) —F. Hoffmann-La Roche Ltd
3/Protocol BP40283, Version 6
PROTOCOL AMENDMENT, VERSION 6:
RATIONALE
Version 6 was implemented to allow enrollment of participants without prior approval by 
the Medical Monitor. Additional changes have been made, as specified below.
•
Section 1.3, Table 2 Footnote 24 (new) and Appendix 4: The requirements 
for blood sampling to assess antipsychotic drug blood levels are clarified.
•
Section 2.3 Benefit/Risk Assessment: A statement has been added to clarify 
the impact of the Covid-19 pandemic on the benefit/risk assessment of this 
study protocol.
•
Section 4.1 Overall Study Design; Section 5.1 Inclusion Criteria (#4 and 
#5); Section 5.2 Exclusion Criteria (#13); Section 8.2.7 Medical History and 
Demographic Data; Section 8.11.1 Screening and Pretreatment 
Assessments; and Appendix 6: Medical Monitor language was updated to 
reflect new guidelines on medical monitoring in accordance with ICH E6(R2) 
4.3.1.
•
Section 5.1 Inclusion Criteria:
o
Inclusion Criterion #4: Version 6 clarifies the stability requirements of 
antipsychotics. 
o
Inclusion Criterion #5 Version 6 clarifies, that medication changes within 
the three months prior to screening are permitted, if not associated with 
medical stability.
o
Inclusion Criterion #10 Version 6 increases the upper limit of the body 
mass index from 35 to 40 kg/m2 (inclusive) to adequately reflect the 
patient population in this study.
•
Section 5.2 Exclusion Criteria: 
o
Exclusion Criterion #4 Version 6 further clarifies the scoring requirements. 
o
Exclusion Criterion #13 has been amended to clarify that laboratory tests 
of uncertain or questionable results may be accepted if they are, in the 
opinion of the Investigator, not clinically significant.
o
Exclusion Criterion #16. The history of clozapine treatment has been 
further clarified.

Section 6.5.2. Permitted Therapy: This section has been updated to allow 
changes in D2/5HT2A antagonists or D2 partial agonist medication if the change 
is not associated with the participant’s psychiatric stability. Treatment changes 
may be acceptable up to a minimum of three months prior to screening.
Confirmation that SARS-CoV-2 vaccines were permitted during the study was 
also added.


RO6889450 (Ralmitaront) —F. Hoffmann-La Roche Ltd
4/Protocol BP40283, Version 6

Section 6.5.3. Prohibited Therapy: Language has been updated to remove 
Sponsor acceptance for new concomitant medication.

Section 8.11.2. Assessments During Treatment: Guidelines for the order of 
assessments have been revised.

Section 9.2 Sample Size Determination: This section was updated to allow an 
increase in the sample size of Part B in case of an unexpectedly high number of 
participants not completing 12 weeks of treatment.
Minor corrections and clarifications have also been made. New text is shown in Book 
Antiqua italics.


RO6889450 (Ralmitaront) —F. Hoffmann-La Roche Ltd
5/Protocol BP40283, Version 6
TABLE OF CONTENTS
PROTOCOL ACCEPTANCE FORM .................................................................... 2
PROTOCOL AMENDMENT, VERSION 6: RATIONALE...................................... 3
1.
PROTOCOL SUMMARY............................................................................. 14
1.1
Synopsis................................................................................ 14
1.2
Schematic of Study Design.................................................... 21
1.3
Schedule of Activities ............................................................ 21
2.
INTRODUCTION ........................................................................................ 31
2.1
Study Rationale ..................................................................... 31
2.2
Background ........................................................................... 31
2.2.1
Background on Disease......................................................... 31
2.2.2
Background on RO6889450 .................................................. 32
2.3
Benefit/Risk Assessment....................................................... 34
3.
OBJECTIVES AND ENDPOINTS ............................................................... 36
4.
STUDY DESIGN......................................................................................... 38
4.1
Overall Design ....................................................................... 38
4.1.1
Length of the Study ............................................................... 40
4.1.2
Administrative Structure......................................................... 40
4.1.2.1
Independent Data Monitoring Committee .............................. 40
4.1.2.2
Patient Review Committee .................................................... 41
4.1.2.3
General Administrative Structure........................................... 41
4.2
Scientific Rationale for Study Design..................................... 41
4.2.1
Rationale for Study Population and Study 
Duration................................................................................. 42
4.2.2
Rationale for Withdrawal of Antipsychotics in Part 
A ............................................................................................ 42
4.2.3
Rationale for Inclusion of Antipsychotics in Part B................. 43
4.2.4
Rationale for Control Group................................................... 43
4.2.5
Rationale for Digital Biomarker Assessments........................ 43
4.2.6
Rationale for Clinical Genotyping .......................................... 43
4.3
Dose Justification .................................................................. 44
4.4
End of Study Definition .......................................................... 45


RO6889450 (Ralmitaront) —F. Hoffmann-La Roche Ltd
6/Protocol BP40283, Version 6
5.
STUDY POPULATION................................................................................ 45
5.1
Inclusion Criteria.................................................................... 45
5.2
Exclusion Criteria................................................................... 47
5.3
Confirmation of Eligibility at Baseline..................................... 49
5.4
Lifestyle Considerations......................................................... 49
5.4.1
Alcohol Consumption............................................................. 49
5.5
Screen Failures ..................................................................... 49
5.6
Recruitment Procedures........................................................ 50
6.
TREATMENTS
...................................................................................... 50
6.1
Treatments Administered....................................................... 50
6.2
Preparation/Handling/Storage/Accountability ........................ 53
6.3
Measures to Minimize Bias: Randomization and 
Blinding.................................................................................. 54
6.3.1
Method of Treatment Assignment.......................................... 54
6.3.2
Blinding.................................................................................. 54
6.4
Treatment Compliance .......................................................... 54
6.4.1
Medication Adherence Platform............................................. 55
6.5
Concomitant Therapy ............................................................ 55
6.5.1
Rescue Medicine During Part A............................................. 56
6.5.2
Permitted Therapy................................................................. 56
6.5.3
Prohibited Therapy ................................................................ 57
6.6
Dosage Modification .............................................................. 57
6.7
Treatment after the End of the Study..................................... 57
7.
DISCONTINUATION OF STUDY DRUG AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ......................................................... 58
7.1
Discontinuation of Study drug................................................ 58
7.1.1
Part A..................................................................................... 58
7.1.2
Part A and Part B................................................................... 59
7.2
Participant Discontinuation/Withdrawal from the 
Study ..................................................................................... 60
7.3
Lost to Follow-Up................................................................... 60
8.
STUDY ASSESSMENTS AND PROCEDURES ......................................... 61
8.1
Efficacy Assessments............................................................ 61


RO6889450 (Ralmitaront) —F. Hoffmann-La Roche Ltd
7/Protocol BP40283, Version 6
8.1.1
Efficacy Assessments to be Completed at Site 
Visits...................................................................................... 61
8.1.1.1
Brief Negative Symptom Scale.............................................. 61
8.1.1.2
Positive and Negative Syndrome Scale................................. 62
8.1.1.3
Clinical Global Impression Scales ......................................... 63
8.1.1.4
Fagerström Test for Nicotine Dependence............................ 63
8.1.1.5
Reinforcement Learning Working Memory Task.................... 63
8.1.1.6
Effort Cost/Benefit Tradeoff Task .......................................... 64
8.1.1.7
Brief Assessment of Cognition in Schizophrenia ................... 65
8.1.1.8
Virtual Reality Functional Capacity Assessment 
Tool ....................................................................................... 65
8.1.2
Digital Biomarkers ................................................................. 65
8.1.2.1
Study Phone Usage Tracker (Smartphone App) ................... 66
8.1.2.2
AiCure Digital Biomarkers...................................................... 66
8.1.3
Efficacy Assessments to be Completed by the 
Participant.............................................................................. 67
8.1.3.1
Defeatist Performance Attitude Scale.................................... 67
8.1.3.2
Assessment of Sleep, Mood, Well-being and 
Cognitive Functioning and Treatment Expectancy ................ 67
8.1.3.3
Ecological Momentary Assessment (EMA)............................ 67
8.2
Safety Assessments .............................................................. 68
8.2.1
Physical Examinations........................................................... 68
8.2.2
Vital Signs.............................................................................. 69
8.2.3
Electrocardiograms................................................................ 69
8.2.4
Clinical Safety Laboratory Assessments................................ 70
8.2.5
Suicidal Risk Monitoring ........................................................ 70
8.2.6
Extrapyramidal Symptom Rating Scale-
Abbreviated Version .............................................................. 71
8.2.7
Medical History and Demographic Data ................................ 71
8.3
Adverse Events and Serious Adverse Events ....................... 72
8.3.1
Time Period and Frequency for Collecting 
Adverse Event and Serious Adverse Event 
Information............................................................................. 73
8.3.2
Method of Detecting Adverse Events and Serious 
Adverse Events ..................................................................... 73


RO6889450 (Ralmitaront) —F. Hoffmann-La Roche Ltd
8/Protocol BP40283, Version 6
8.3.3
Follow-Up of Adverse Events and Serious 
Adverse Events ..................................................................... 73
8.3.3.1
Investigator Follow-Up........................................................... 73
8.3.3.2
Sponsor Follow-Up ................................................................ 74
8.3.4
Regulatory Reporting Requirements for Serious 
Adverse Events ..................................................................... 74
8.3.4.1
Emergency Medical Contacts................................................ 74
8.3.5
Pregnancy ............................................................................. 75
8.3.6
Non-Serious Adverse Events of Special Interest................... 75
8.4
Treatment of Overdose.......................................................... 75
8.5
Pharmacokinetics .................................................................. 76
8.6
Pharmacodynamics ............................................................... 76
8.7
Further Assessments............................................................. 76
8.7.1
Mini International Neuropsychiatric Interview ........................ 76
8.7.2
Wide Range Achievement Test 4 .......................................... 77
8.7.3
Wechsler Abbreviated Scale of Intelligence –
Second Edition ...................................................................... 77
8.8
Genetics ................................................................................ 77
8.8.1
Clinical Genotyping................................................................ 77
8.9
Biomarkers ............................................................................ 78
8.9.1
Samples for Research Biosample Repository ....................... 78
8.9.1.1
Overview of the Research Biosample Repository.................. 78
8.9.1.2
Sample Collection.................................................................. 78
8.10
Medical Resource Utilization and Health 
Economics............................................................................. 79
8.11
Timing of Study Assessments ............................................... 79
8.11.1
Screening and Pretreatment Assessments............................ 79
8.11.2
Assessments During Treatment ............................................ 80
8.11.3
Assessments at Study Completion/Early 
Termination Visit.................................................................... 80
8.11.4
Follow-Up Assessments ........................................................ 80


RO6889450 (Ralmitaront) —F. Hoffmann-La Roche Ltd
9/Protocol BP40283, Version 6
9.
STATISTICAL CONSIDERATIONS ............................................................ 81
9.1
Statistical Hypotheses ........................................................... 81
9.2
Sample Size Determination ................................................... 81
9.3
Populations for Analyses ....................................................... 82
9.4
Statistical Analyses................................................................ 82
9.4.1
Demographics and Baseline Characteristics ......................... 82
9.4.2
Efficacy Analyses .................................................................. 82
9.4.3
Safety Analyses..................................................................... 84
9.4.4
Pharmacokinetic Analyses..................................................... 85
9.5
Interim Analyses .................................................................... 85
9.6
Summaries of Conduct of Study............................................ 86
10. REFERENCES
...................................................................................... 87
11. SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS.................................................................................... 92
LIST OF TABLES
Table 1
Schedule of Activities for Part A of the Study.............................. 22
Table 2
Schedule of Activities for Part B of the Study.............................. 27
Table 3
Objectives and Endpoints ........................................................... 36
Table 4
Summary of Treatments Administered........................................ 51
Table 5
PANSS Positive and Negative Symptoms Factor Score............. 62
Table 6
Analysis Populations................................................................... 82
Table 7
Efficacy Statistical Analysis Methods.......................................... 84
Table 8
Safety Statistical Analysis Methods ............................................ 85
LIST OF FIGURES
Figure 1
Overview of Study Design........................................................... 21
LIST OF APPENDICES
Appendix 1
Regulatory, Ethical, and Study Oversight Considerations........... 93
Appendix 2
Adverse Events: Definitions and Procedures for Evaluating, 
Follow-up and Reporting........................................................... 102
Appendix 3
Procedures for Recording Adverse Events ............................... 111
Appendix 4
Clinical Laboratory Tests .......................................................... 116


RO6889450 (Ralmitaront) —F. Hoffmann-La Roche Ltd
10/Protocol BP40283, Version 6
Appendix 5
Contraceptive Guidance and Collection of Pregnancy 
Information................................................................................ 120
Appendix 6
Atypical Antipsychotic Pharmacokinetics .................................. 124
Appendix 7
Antipsychotic Equivalencies...................................................... 128
Appendix 8
Calculation of Body Mass Index................................................ 129
Appendix 9
Evaluation to Sign Consent (example form).............................. 130
Appendix 10
Assessment of Sleep, Mood, Well-being and Cognitive 
Functioning and Treatment Expectancy.................................... 131


RO6889450 (Ralmitaront) —F. Hoffmann-La Roche Ltd
11/Protocol BP40283, Version 6
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
5HT2A
Serotonin 2A receptor
AE
Adverse event
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
AUC
Area under the curve
BACS
Brief Assessment of Cognition in Schizophrenia
BMI
Body Mass Index
BNSS
Brief Negative Symptom Scale
CGI-I
Clinical Global Impression of Improvement
CGI-I NS
Clinical Global Impression of Improvement negative symptoms
CGI-S
Clinical Global Impression of Severity
CGI-S NS
Clinical Global Impression of Severity negative symptoms
Cmax
maximum concentration
CNS
Central nervous system
COA
Clinical outcome assessments
COVID-19
Corona virus pandemic: the name designation refers to COVI for 
the acronym of coronavirus, D for the word disease, and 19 for the 
year of the outbreak.
CRO
Clinical Research Organization 
CSR
Clinical study report
C-SSRS
Columbia-Suicide Severity Rating Scale
CTM
Site Clinical Team Manager
D2
dopamine 2 receptor
DLE
dose limiting events


RO6889450 (Ralmitaront) —F. Hoffmann-La Roche Ltd
12/Protocol BP40283, Version 6
Abbreviation
Definition
DNA
Deoxyribonucleic acid
DSM-5
Diagnostic and Statistical Manual of Mental Disorders , Fifth Edition
DPAS
Defeatist Performance Attitude Scale
EC
Ethics Committee
ECF
Eligibility Checklist Form
ECB
Effort-choice benefit
ECG
Electrocardiogram
eCRF
Electronic case report form
EDC
Electronic data capture
eCOA
Electronic clinical outcome assessment
EMA
Ecological Momentary Assessment 
EOT
End of treatment
EPS
Extrapyramidal symptoms
ESF
Eligibility screening form
ESRS-A
Extrapyramidal symptom rating scale, abbreviated
EU
European Union
FDA
Food and Drug Administration
FMO1
Flavin containing monooxygenase
FSH
Follicle-stimulating hormone
FSIQ
Full Scale Intelligence Quotient
FTND
Fagerström Test for Nicotine Dependence
HCV
Hepatitis C
HIPAA
Health Insurance Portability and Accountability Act
HIV
Human immunodeficiency virus
HLA
human leukocyte antigen
HR
heart rate
ICF
Informed Consent Form
ICH
International Council for Harmonisation
iDMC
Independent Data Monitoring Committee
IEC
Independent Ethics Committee
ITT
intent-to-treat
IMP
Investigational medicinal product
IND
Investigational New Drug (application)
IQ
Intelligence quotient


RO6889450 (Ralmitaront) —F. Hoffmann-La Roche Ltd
13/Protocol BP40283, Version 6
Abbreviation
Definition
IC-PANSS
Informant checklist Positive and Negative Syndrome Scale
IRB
Institutional Review Board
IxRS
Interactive (voice/web) response system
LDH
Lactate dehydrogenase
LPLO
Last participant, last observation
MAD
Multiple-ascending doses
MDR1
Multidrug resistance protein 1
MEDNO
Medication number
MINI
Mini International Neuropsychiatric Interview
MTD
Maximum tolerated dose
MTS
Most troubling symptom
NCI CTCAE
National Cancer Institute Common terminology criteria for adverse 
events
NMDA
N-methyl-D-aspartate
NSAESI
Non-serious adverse event of special interest
OTC
Over-the-counter


RO6889450 (Ralmitaront) —F. Hoffmann-La Roche Ltd
14/Protocol BP40283, Version 6
1.
PROTOCOL SUMMARY
1.1
SYNOPSIS
PROTOCOL TITLE:
PHASE 2, RANDOMIZED, DOUBLE-BLIND, PLACEBO-
CONTROLLED STUDY TO ASSESS THE EFFECTS OF 
RO6889450 (RALMITARONT) IN PATIENTS WITH 
SCHIZOPHRENIA OR SCHIZOAFFECTIVE DISORDER AND 
NEGATIVE SYMPTOMS
PROTOCOL NUMBER:
BP40283
VERSION:
6
TEST PRODUCT:
RO6889450
PHASE:
II
RATIONALE
The trace amine-associated receptor 1 (TAAR1) partial agonist RO6889450, a modulator of 
dopaminergic transmission, leads to a normalization of behaviors in rodent models of negative 
symptoms of schizophrenia. Results of a clinical study with RO6889450 in healthy volunteers 
suggest performance improvements in tasks that probe reward-based learning and motivated 
behavior, functions that are deficient in patients with negative symptoms (e.g., blunted affect, 
avolition/apathy). These results indicate a potential utility of RO6889450 in the treatment of 
negative symptoms associated with schizophrenia or schizoaffective disorder.
OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary
Part A: To compare the efficacy of 
 
once daily (QD) of RO6889450 as 
monotherapy with placebo on negative 
symptoms in patients with schizophrenia or 
schizoaffective disorder.
Part B: To compare the efficacy of 
 
 QD of RO6889450 as add-on therapy 
with placebo on negative symptoms in 
patients with schizophrenia or schizoaffective 
disorder.
Part A & B: Change from baseline at Week 12 
in the Brief Negative Symptoms Scale (BNSS) 
avolition/apathy subscore (sum of items 
“behavior” and “internal experience”).


RO6889450 (Ralmitaront) —F. Hoffmann-La Roche Ltd
15/Protocol BP40283, Version 6
Objectives
Endpoints

Secondary
To compare the effect of RO6889450 with 
placebo on:

Clinical Global Impression Severity 
(CGI-S) and change (CGI-I) (overall and 
negative symptoms)

Change from baseline in CGI-S and CGI-
S negative symptoms scores

CGI-I, and CGI-I negative symptoms 
scores
To compare the effect of RO6889450 with 
placebo on:

Symptoms of schizophrenia or 
schizoaffective as assessed with the 
Positive and Negative Syndrome Scale 
(PANSS), BNSS, and Defeatist 
Performance Attitude Scale (DPAS)

Change from baseline in PANSS total and 
symptom factor scores

Change from baseline in BNSS total and 
subscores

Change from baseline in DPAS scores

To compare the safety and tolerability of 
12 weeks of treatment with RO6889450 
as monotherapy (Part A) or add-on 
therapy with placebo (Part B) 

Incidence, nature, and severity of adverse 
events (AEs)

Incidence, nature, and severity of serious 
AEs (SAEs)

Incidence, nature, and severity of 
treatment discontinuations due to AEs

Change from baseline in vital signs 

Change from baseline in 
electrocardiogram (ECG) intervals: heart 
rate, PQ (PR), QRS, QT, RR and QTcF 
along with information on T- and U-waves 

Incidence of laboratory abnormalities, 
based on hematology, clinical chemistry, 
coagulation and urinalysis test results

Change from baseline in Columbia-
Suicide Severity Rating Scale (C-SSRS) 
and Extrapyramidal symptom rating scale, 
abbreviated (ESRS-A)

To evaluate the pharmacokinetics (PK) of 
RO6889450 and RO6889450-derived 
metabolite(s).

Concentration per time point

AUCss of RO6889450 and, if feasible, of
RO6889450-derived metabolite(s)

Cmax of RO6889450 and, if feasible, of
RO6889450-derived metabolite(s) 

Other PK parameters as appropriate
OVERALL DESIGN
This is a Phase 2, multicenter, randomized, double-blind, two-part, placebo-controlled, parallel-
group, study in patients with schizophrenia or schizoaffective disorder.
Study Design
Part A (monotherapy): 
Participants will be washed out (one week) from their antipsychotic therapy before being 
randomized to either
QD of RO6889450 or placebo for 12 weeks. Stratification will be 
based on baseline BNSS avolition/apathy subscore (BNSS ≤6 vs >6), age (18-35 years vs. 36-
55 years), and sex. The participants will have the option of an inpatient stay or partial 
hospitalization during the washout period as well as the first week of study drug.
Part B (add-on therapy): 
Participants will be randomized 1:1:1 to 
 QD of RO6889450, 
 QD of RO6889450, 
or placebo for 12 weeks. Stratification will be based on region (Ex-Japan; Japan). For non-


RO6889450 (Ralmitaront) —F. Hoffmann-La Roche Ltd
16/Protocol BP40283, Version 6
Japanese sites, stratification will additionally be based on baseline BNSS avolition/apathy 
subscore (sum of items “behavior” and “internal experience”; ≤6 vs. >6), age (18-35 years vs. 36-
55 years), sex, and antipsychotic treatment (1:1 stratification ratio between dopamine 2 receptor 
[D2]/serotonin 2A [5HT2A] receptor antagonists and D2 partial agonist). For Japanese sites, 
stratification will additionally be based on antipsychotic treatment (1:1 stratification ratio between 
dopamine 2 receptor [D2]/serotonin 2A receptor [5HT2A] antagonists and D2 partial agonist).
Approximately equal numbers of participants on D2/5HT2A antagonists or D2 partial agonists 
will be enrolled.
Participants who were screened for, but not enrolled in Part A can be screened for Part B if 
meeting criteria for re-screening and only after discussion with the Medical Monitor or delegate.
The reason(s) for the decision must be documented.
Part B is planned to start after Part A. If the result of Part A is negative, the Sponsor may choose 
not to conduct Part B. 
Interim analyses: 
The Sponsor may choose to conduct an interim efficacy analysis in Part A. The decision to 
conduct an optional interim analysis and the timing of the analysis will be documented in the 
Sponsor’s trial master file prior to the conduct of the interim analysis. The interim analysis will 
be performed and interpreted by members of the Sponsor study team and appropriate senior 
management personnel who will be unblinded at the treatment group level. Access to treatment 
assignment information will follow the Sponsor’s standard procedures.
The results of this analysis may support initiation of Part B enrollment during Part A if a positive 
results threshold is met as defined in the statistical analysis plan (SAP). In case of very slow 
recruitment, Part A may be stopped and/or Part B may be started without the interim analysis.
The Sponsor may choose to conduct up to two additional interim analyses of Part B to determine 
the chance of final success. The results of such an analysis may support an early termination of 
Part B. The decision to conduct an optional interim analysis and the timing of the analysis will be 
documented in the Sponsor’s trial master file prior to the conduct of the interim analysis. The 
interim analysis will be performed and interpreted by members of the Sponsor study team and 
appropriate senior management personnel, who will be unblinded at the treatment group level. 
Access to treatment assignment information will follow the Sponsor’s standard procedures.
Treatment Groups and Duration
The investigational medicinal product (IMP) is RO6889450 (and matching placebo) and will be 
given orally QD at a daily dose of 
in Part A and at a daily dose of either 
 
in Part B. 
Length of Study
Part A: The total duration will be approximately 147 days (from screening through study 
completion) for each enrolled participant as follows:

Screening: up to 35 days (including the placebo compliance and a 7-day washout 
period)

Treatment period: 84 days (12 weeks)

Follow up: 28 days
Part B: The total duration will be up to approximately 154 days (from screening through study 
completion) for each enrolled participant as follows: 

Screening: up to 42 days (including the placebo compliance period)

Treatment period: 84 days (12 weeks)

Follow up: 28 days
End of Study
The end of the study is defined as the date when the last participant last observation (LPLO) 
occurs. LPLO is expected to occur approximately 28 days after the last participant’s last dose.


RO6889450 (Ralmitaront) —F. Hoffmann-La Roche Ltd
17/Protocol BP40283, Version 6
Data Monitoring Committee
An independent Data Monitoring Committee (iDMC) will regularly review unblinded safety and 
efficacy (as appropriate) data for Part A of the study. The iDMC will be composed of at least two 
psychiatrists external to the Sponsor and will be responsible for monitoring safety data to help 
assure that continuation of the study in its current design does not pose unacceptable safety 
risks to participants. Planned and ad hoc safety reviews will be performed as described within 
the iDMC charter.  
PARTICIPANT POPULATION
The participants of this study will be male and female outpatients between 18 to 55 years of age 
with a Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) diagnosis of 
schizophrenia or schizoaffective disorder with negative symptoms, who are stable. For Part B, 
participants also need to be stable on antipsychotic treatment. Participants who are in a 
residential inpatient setting are eligible for this study.
Inclusion/Exclusion Criteria
Unless otherwise stated, inclusion and exclusion criteria refer to evaluations or assessments at 
screening.
Inclusion Criteria:
Informed Consent
1.
Able and willing to provide written informed consent according to International Council for 
Harmonisation (ICH) and local regulations as assessed using the Evaluation to Sign 
Consent. If the participant has a legal representative, the informed consent must be signed 
by this person.
Patient and Disease Characteristics
2.
Male or female participants aged 18-55 years (inclusive).
3.
Patients with a DSM-5 diagnosis of schizophrenia or schizoaffective disorder as confirmed 
by the Mini International Neuropsychiatric Interview (MINI).
4.
Part B only: Stable treatment with a D2/5HT2A antagonists or pure D2 antagonist(s) or a 
D2 partial agonist for a minimum of six months and receiving no more than two 
antipsychotics (if no blood concentration of the prescribed antipsychotic medication [or 
active metabolites] is detected, the participant, should not be enrolled). Antipsychotic 
regimen: participants must be on a "primary" antipsychotic and may be on a secondary 
antipsychotic. Note: compliance of blonanserin and perospirone will be monitored via 
informant report. The secondary antipsychotic dose has to be equal to or less than the 
equivalent dose of the primary antipsychotic. The sum of the primary and secondary 
antipsychotics must be 6 mg of risperidone equivalents. Participants who have had a 
change of medication not associated with a change in the participant’s psychiatric stability 
in the Investigator’s opinion (e.g., insurance reasons, adjustment of dose) in the six months 
prior to screening may be considered for entry into the study; however no change of 
antipsychotic medication regimen will be allowed within 3 months prior to screening.
5.
Medically stable during the prior three months. Medication changes (other than 
antipsychotics) in the three months prior to screening may be acceptable, if, in the opinion 
of the Investigator, the change of medication does not affect the participant’s medical 
stability throughout the duration of the study
6.
Participant is outpatient with no psychiatric hospitalizations within the prior six (6) months 
(hospitalization for social management within this time is acceptable).
7.
PANSS-NSFS score of 18 or higher.
8.
The following rating on items of the PANSS: 
(a)
less than 5 on G8 (uncooperativeness), P1 (delusions), P3 (hallucinations), P4 
(excitement/hyperactivity), and P6 (suspiciousness/persecution)
(b)
less than 4 on P7 (hostility) and G14 (poor impulse control)
9.
Has an informant who is considered reliable by the Investigator to provide support to the 
participant and to help ensure compliance with study visits and protocol procedures; who 


RO6889450 (Ralmitaront) —F. Hoffmann-La Roche Ltd
18/Protocol BP40283, Version 6
preferably is also able to provide input helpful for completing study rating scales and is in 
regular contact with the participant in order to be able to alert the Investigator of worsening 
signs and symptoms for the participant.
10. Body mass index (BMI) between 18 and 40 kg/m2 inclusive.
Reproductive
11. A woman is eligible to participate if she is not pregnant, not breastfeeding, and at least one 
of the following conditions applies: 
(a) Not a woman of childbearing potential (WOCBP).
(b) WOCBP, who 
- agrees to remain abstinent (refrain from heterosexual intercourse) or use acceptable
contraceptive methods during the treatment period and for at least 28 days after the last 
dose of study drug.
- The following are acceptable contraceptive methods: bilateral tubal occlusion, male 
sterilization, established proper use of hormonal contraceptives that inhibit ovulation, 
hormone-releasing intrauterine devices and copper intrauterine devices, male or female 
condom with or without spermicide; and cap, diaphragm, or sponge with spermicide.
The contraception and abstinence requirements are intended to prevent exposure of an embryo 
to the study treatment. The reliability of sexual abstinence for female enrollment eligibility needs 
to be evaluated in relation to the duration of the clinical study and the preferred and usual 
lifestyle of the participant. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or 
post-ovulation methods) and withdrawal are not acceptable methods of contraception.
Exclusion Criteria:
Medical Conditions
1.
Part A only: Confirmed suicidal behavior based on Investigator judgment or violent behavior 
resulting in injury or property damage in the prior five years. A history prior to the last five 
years requires approval by the PRC on a case-by-case basis.
2.
Part A only: Lifetime history of homicidal behavior.
3.
Moderate to severe substance use disorder within six months (excluding nicotine) as defined 
by DSM-5.
4.
Any ESRS-A CGI subscore greater or equal to 3.
5.
Other current DSM-5 diagnosis (e.g., bipolar disorder, major depressive disorder).
6.
PANSS item G6 (depression) greater than or equal to 5.
7.
Significant risk of suicide or harming him- or herself or others according to the Investigator’s 
judgment.
8.
A prior or current general medical condition that might be impairing cognition or other 
psychiatric functioning (e.g., migraine headaches requiring prophylactic treatment, head 
trauma, dementia, seizure disorder, stroke; or neurodegenerative, inflammatory, infectious, 
neoplastic, toxic, metabolic, endocrine conditions).
9.
Positive result at screening for hepatitis B surface antigen (HBsAg), hepatitis C (hepatitis C 
antibody), or human immunodeficiency virus (HIV)-1 and -2. HCV antibody positive patients 
are eligible if HCV RNA is negative.
10.
Tardive dyskinesia that is moderate to severe or requires treatment. 
11.
History of neuroleptic malignant syndrome.
12.
Average triplicate QTcF interval greater than 450 msec for males and 470 msec for females 
or other clinically significant abnormality on screening ECG based on centralized reading.




RO6889450 (Ralmitaront) —F. Hoffmann-La Roche Ltd
20/Protocol BP40283, Version 6
CONCOMITANT MEDICATIONS
Rescue Medicine During Part A 
If early signs of relapse requiring treatment are noticed/recorded by the Investigator, an 
antipsychotic should be prescribed and the participant will be immediately withdrawn from the 
study drug.
Permitted Therapy
The use of stable, scheduled doses of benzodiazepines is permitted. The use of stable, 
scheduled doses of non-benzodiazepine hypnotics is permitted.
If deemed necessary by the Investigator to treat occasional anxiety, agitation or sleep problems, 
lorazepam, alprazolam, or oxazepam are allowed as needed ([PRN], up to a maximum daily 
dose of lorazepam 6 mg, alprazolam 3 mg, or oxazepam 90 mg). If PRN treatment of more than 
five consecutive days is necessary, this should be discussed with the Medical Monitor. PRN 
doses of benzodiazepines should not be administered within 12 hours of a clinic visit.
Non-prohibited medications used for the treatment of stable medical conditions other than 
schizophrenia (e.g., hypertension, diabetes, oral contraceptives, hormone-replacement therapy) 
are allowed during the study, provided that they have been stable for 28 days prior to screening 
and are intended to remain stable throughout the study up to the follow-up visits.
Patients in Part B of the study have to be on stable treatment (i.e., no medication changes or 
significant dose adjustments) with D2/5HT2A antagonists or D2 partial agonist for a minimum of 
six months prior to screening. In cases, where change in medication is not associated with the 
participant’s psychiatric stability, treatment changes can be accepted up to three months prior 
to screening. Co-administration of RO6889450 and weak P-gp substrates, such as risperidone, 
amisulpride, aripiprazole, and paliperidone, though permitted may result in slight elevations of 
the P-gp substrate so continued monitoring is suggested.
SARS-CoV-2 vaccines were permitted during the study.
Prohibited Therapy
Use of the following therapies (non-topical formulation where applicable) is prohibited during the 
study unless otherwise specified:

Clinically relevant substrates of P-gp, including quinidine and loperamide.

Cannabidiol (may affect schizophrenia symptoms [McGuire 2018])
In Part A, all antipsychotic treatment as well as medications used to treat extrapyramidal 
symptoms (EPS) (e.g., anticholinergics) will be discontinued before randomization. 
Antipsychotic medications that require longer washout periods (i.e., more than two weeks), such 
as cariprazine, brexpiprazole, and long-acting injectable antipsychotics (e.g., aripiprazole 
lauroxil, olanzapine pamoate, and haloperidol decanoate) are exclusionary.  
Patients receiving treatment for tardive dyskinesia (e.g., valbenazine or deutetrabenazine) are 
excluded. As a general rule, no new concomitant medications will be permitted, with the 
exception of medications to treat AEs, unless the rationale for exception is discussed with the 
Sponsor or designee and clearly documented between the Investigator and the Sponsor.






RO6889450 (Ralmitaront) —F. Hoffmann-La Roche Ltd
23/Protocol BP40283, Version 6
Period
Screening
Treatment Period
Follow-Up Visits
Placebo Compliance
Week
Week -4
Week -2
Week -1
1
2
3
4
5
6
7
8
9
10
11
12
13
14
16
Day
Day -35 to 
Day -19
Day -14
Day -7
Baseline1/
Day 1
Day 
7
Day 
14
Day 
21
Day 
28
Day 
35
Day 421
Day 
49
Day 
56
Day 
63
Day 
70
Day 
77
Day 84/ 
EOT1, 2
Day 
91
Day 
98
Day 
1121
Visit window (days)
±1
±1
-1
±1
±1
±1
±2
±2
±2
±2
±2
±2
±2
±2
±2
±2
±2
±4
Orthostatic vital signs
X
X
X
X
X
X
X
Viral serology
X
Prolactin sample
X
X
Alcohol levels
X
X
X
X
X
X
X
Drugs of abuse
X
X
X
X
X
X
X
Urinalysis
X
X
X
X
X
X
X
Pregnancy test 7
X
X
X
Blood chemistry and lipids
X
X
X
X
X
X
Hematology
X
X
X
X
X
X
Antipsychotic blood
levels 
X
X
X
X
PK sample
X9
X 9,10
X 9,10
X 9,10
Genotyping
X 11
RBR DNA (optional)
X 11
MINI
X
WASI-II 
X
WRAT-417
X






RO6889450 (Ralmitaront) —F. Hoffmann-La Roche Ltd
26/Protocol BP40283, Version 6
Table 1
Schedule of Activities for Part A of the Study (cont.)
1
To decrease patient burden, some assessments may be split within the visit window days. Baseline assessments should be done pre-dose on Day 1 or within 
24 hours prior to the first double-blind dose (i.e., on Day -1).
2
If treatment is discontinued early, the Week 12 visit assessments as well as the follow-up visit assessments (four weeks after last dose) should be performed.
3
Phone calls listed are for scheduled visits. Informal calls by a case manager up to three times per week to follow up with patients, especially during the 
washout period, are encouraged.
4
Eligibility will be confirmed at baseline (see Section 5.3).
5
Complete physical exam includes height and weight at screening. Limited physical exams (symptom driven) and weight will be done at subsequent visits 
including the follow-up visit (see Section 8.2.1).
6
Triplicate ECGs will be performed at screening and a single ECG at subsequent visits ECGs should be performed prior to meals or any scheduled vital sign 
measurements and blood draws.
7
Pregnancy testing will be using a blood sample at screening and urine sample at subsequent visits.  If urine test is positive, pregnancy must be confirmed by 
blood test. 
8
Washout may start earlier for antipsychotics with long half-life (2 week washout for aripiprazole, olanzapine, see Appendix 6).
9
Sample should be taken prior to the morning dose (pre-dose/trough).
10
One additional sample should be taken two hours (± 0.5) post-dose.
11
Samples can be taken at any time between baseline and follow-up.
12
The Study Phone Usage Tracker will be used only with screened patients who have suitable smartphones and agree to the 
assessment.
13
After informed consent, but prior to initiation of study drug, only SAEs caused by a protocol-mandated intervention will be collected. After initiation of study 
drug, all adverse events, regardless of relationship to study drug, will be reported until 28 days after the last dose of study drug. 
14
The placebo compliance period will start with a visit reviewing instructions with the patient.  
15
Study drug is three capsules administered once daily, preferably in the morning. The last dose is given at the Day 84/EOT visit.
16
Sleep, mood, cognition and treatment expectation questions will be presented on the AiCure app at select time points that will appear as random to the 
participant.
17
The exploratory endpoints Brief Assessment of Cognition in Schizophrenia (BACS) (digital version), Wechsler Abbreviated Scale of Intelligence – Second 
Edition (WASI-II), Wide Range Achievement Test (WRAT-4) and Virtual Reality Functional Capacity Assessment Tool (VRFCAT) are not available as 
validated Spanish translation. Therefore, sites will not be required to administer these tests to Spanish only speaking patients. If validated versions become 
available, they may be used.






RO6889450 (Ralmitaront) —F. Hoffmann-La Roche Ltd
29/Protocol BP40283, Version 6
Table 2
Schedule of Activities for Part B of the Study (cont.)
Abbreviations: BACS = Brief Assessment of Cognition in Schizophrenia, BNSS = Brief Negative Symptom Scale, CGI-I = Clinical Global Impression of 
Improvement,  CGI-S = Clinical Global Impression of Severity, C-SSRS = Columbia-Suicide Severity Rating Scale, DNA = deoxyribonucleic acid, DPAS = 
Defeatist Performance Attitude Scale, ECB = Effort-choice benefit, ECG = Electrocardiogram, EMA = Ecological Momentary Assessment, EOT = End of 
treatment, ESRS-A = Extrapyramidal symptom rating scale, abbreviated, FTND = Fagerström Test for Nicotine Dependence, IC- PANSS = informant checklist
Positive and Negative Syndrome Scale, MINI = Mini International Neuropsychiatric Interview, PANSS = Positive and Negative Syndrome Scale, PK = 
pharmacokinetic, RBR = Research Biosample Repository, RLWM = Reinforcement learning working memory, SAE = serious adverse event, VRFCAT = Virtual 
Reality Functional Capacity Assessment Tool, WASI-II = Wechsler Abbreviated Scale of Intelligence – Second Edition, WRAT-4 = Wide Range Achievement 
Test
1
To decrease patient burden, some assessments may be split within the visit window days. Baseline assessments should be done pre-dose on Day 1 or 
within 24 hours prior to the first double-blind dose (i.e. Day -1). 
2
If treatment is discontinued early, the week 12 visit assessments as well as the follow-up visit assessments (4 weeks after last dose) should be 
performed.
3
Eligibility will be confirmed at baseline (see Section 5.3)
4
Limited physical examination will be done for all visits except for those denoted with footnote 23 (see below), for which a complete physical 
examination is required.
5
Triplicate ECGs will be performed at screening and a single ECG at subsequent visits. To minimize variability, it is important that patients be in a 
resting position for at least 10 minutes prior to each ECG evaluation. ECGs should be performed 2 hours or longer after the last meal (with meal-time 
recorded) and before any scheduled vital sign measurements and blood draws.
6
Pregnancy testing will be using a blood sample at screening and urine sample at subsequent visits.  If urine test is positive, it must be confirmed by 
blood test. 
7
Sample should be taken prior to the morning dose (pre-dose/trough)
8
One sample should be taken three hours (+/- 0.5) post-dose
9
Samples can be taken at any time between BL and FU
10
The Study Phone Usage Tracker will be used only with screened patients who have suitable smartphones and agreed to the assessment. 
11
Study medication is 6 capsules administered once daily, preferably in the morning. The last dose is given at the Day 84/EOT visit.
12
After informed consent, but prior to initiation of study treatment, only SAEs caused by a protocol-mandated intervention will be collected. After initiation 
of study treatment, all adverse events, regardless of relationship to study treatment, will be reported until 28 days after the last dose of study treatment. 
13
Sleep, mood, cognition and treatment expectation questions will be presented on the AiCure app at select time points that will appear as random to the 
participant. 
14
The placebo compliance period for Part B will be at least 1 week and may be extended by one week (e.g. if the compliance is insufficient (<80% 
or >120%), participant requires further training).


RO6889450 (Ralmitaront) —F. Hoffmann-La Roche Ltd
30/Protocol BP40283, Version 6
Table 2
Schedule of Activities for Part B of the Study (cont.)
15
The exploratory endpoints Brief Assessment of Cognition in Schizophrenia (BACS) (digital version), ECB = Effort-choice benefit, RLWM = 
Reinforcement learning working memory, Ecological Momentary Assessment (EMA), AiCure Digital Biomarkers, Phone usage monitoring,  Wechsler 
Abbreviated Scale of Intelligence – Second Edition (WASI-II), Wide Range Achievement Test (WRAT-4) and Virtual Reality Functional Capacity 
Assessment Tool (VRFCAT) are not available as validated translations in several languages. These measures will not be performed for patients who 
are not proficient in the available language. If validated translations become available, they may be used. For the assessment of current and pre-
morbid IQ, equivalent scales may be used, if available.
16
If onsite visits are not permitted due to local restrictions, (e.g. due to travel restrictions for COVID-19) this assessment can be performed remotely if 
confirmed by the Sponsor, for visits subsequent to the Baseline visit. The scope of the assessment remains the same. Source documentation should 
detail if the assessment has been performed remotely.
17
If onsite visits are not permitted due to local restrictions, (e.g. due to travel restrictions for COVID-19) study drug can be shipped from 
sites directly to a patient, for visits subsequent to the Baseline visit if approved by sponsor and relevant health authorities, if applicable. This must be 
confirmed and documented in the patient's source file.
18
If an onsite visit is not possible these tests might not be performed, the protocol deviation should be documented in patient's source file and should be 
clearly designated as “COVID 19 RELATED.
19
Unless performed locally within 2 weeks and available documentation can be provided.
20
In exceptional situations (i.e. COVID-19 outbreak), the visit may be split between two days. 
21
Alcohol test will be performed using a urine dipstick test
22
For anthropometric measurements of weight and waist circumference the use of the same weighing scale and tape measure throughout the study is 
recommended.
23
Complete physical examination includes height at screening (see Section 8.2.1)
24
Testing of blonanserin and perospirone cannot be performed by the central laboratory. Therefore, no blood samples to assess antipsychotic drug 
levels will be drawn for participants being currently treated with blonanserin and/ or perospirone. Participants currently treated with other 
antipsychotics in addition to blonanserin or perospirone will have blood samples taken to assess antipsychotic blood levels. Antipsychotic 
medication compliance of participants taking blonanserin or perospirone will be monitored via informant report and recorded in the eCRF.


RO6889450 (Ralmitaront) —F. Hoffmann-La Roche Ltd
31/Protocol BP40283, Version 6
2.
INTRODUCTION
RO6889450 is a novel compound and a potent partial agonist of Trace Amine-
Associated Receptor 1 (TAAR1) for the treatment of schizophrenia. RO6889450 is 
currently in Phase 2 clinical development. 
2.1
STUDY RATIONALE
The TAAR1 partial agonist RO6889450, a modulator of dopaminergic transmission, 
leads to a normalization of behaviors in rodent models of negative symptoms. Results in 
healthy volunteers suggest performance improvements in tasks that probe reward-based 
learning and motivated behavior, functions that are deficient in patients with negative 
symptoms (e.g., blunted affect, amotivation/apathy). These results indicate a potential 
utility of RO6889450 in the treatment of negative symptoms associated with 
schizophrenia.
The rationale for the study design is provided in Section 4.2.
2.2
BACKGROUND
2.2.1
Background on Disease
Schizophrenia, a severe mental illness affecting approximately 1% of the adult 
population, is characteristically described by a heterogeneity of symptoms (Perälä et al 
2007; Tandon et al 2008). Based upon the Diagnostic and Statistical Manual of Mental 
Disorders, Fifth Edition (DSM-5), core symptoms in the diagnosis of schizophrenia 
include positive symptoms (e.g., delusions, hallucinations, or disorganized speech), 
negative symptoms (e.g., blunted affect, amotivation/apathy), grossly disorganized or 
catatonic behavior, and cognitive deficits. The onset is typically in late adolescence or 
early adulthood, then progresses with a course of exacerbations and remissions 
throughout the life of the patient (Rund et al 2016). Compared to the general population, 
there is a higher incidence of depression, suicide, homelessness, substance use 
disorders, medical comorbidities, and social isolation in patients with schizophrenia 
(Lehman et al 2010).  
Treatment with antipsychotics only partially addresses the key symptoms in 
schizophrenia, i.e., positive symptoms, with many patients experiencing a persistence of 
negative, cognitive, and non-acute positive symptoms (Stahl and Buckley 2007). Many 
patients continue experiencing primary and persistent negative symptoms after their 
positive symptoms have been controlled. To address the residual symptoms, clinicians 
often use multiple medications to treat patients with chronic schizophrenia, including 
combinations of antipsychotics and anticonvulsants (Correll et al 2009 Tseng et al 2016; 
Zheng et al 2017), despite little evidence supporting the benefit of this approach (Stahl 
and Grady 2004; Chakos et al 2006). Therefore, there is an urgent need for the 
development of more effective treatments for negative symptoms of schizophrenia for 
use in patients treated with antipsychotic drugs. 


RO6889450 (Ralmitaront) —F. Hoffmann-La Roche Ltd
32/Protocol BP40283, Version 6
Schizophrenia is believed to be caused by a combination of genetic and environmental 
factors that impact early neurodevelopmental processes, and include abnormalities of 
neuronal structure and function in targeted subcortical and cortical circuits. Underlying 
the symptomatic phenomena are disturbances in monoaminergic and glutamatergic 
neurotransmission (e.g., dopamine, serotonin, norepinephrine, and glutamate). These 
pathways are widely present in the central nervous system (CNS) and are involved in 
emotional processing, cognition, and behavior (Belmaker and Agam 2008; Racagni and 
Popoli 2008; Sen and Sanacora 2008). The original dopamine hypothesis attributed the 
pathophysiology of schizophrenia to excess levels of dopamine. This theory was later 
expanded to indicate a scarcity of dopamine in the prefrontal cortex and an excess 
dopamine in the subcortical region of the brain (Howes and Kapur 2009). 
2.2.2
Background on RO6889450
Trace amines (phenylethylamine, p- and m-tyramine, p- and m-octopamine, and 
tryptamine) are present throughout the CNS in close proximity to monoaminergic 
pathways, although they are expressed at much lower levels than monoaminergic 
neurotransmitters (Berry 2004; Burchett and Hicks 2006). Trace amines act as 
neuromodulators at physiological levels. In this capacity, their main role appears to be 
the modulation of serotonergic, noradrenergic, and dopaminergic neurotransmission. 
Recently, a family of G-protein coupled receptors has been identified and named Trace 
Amine-Associated Receptor, with TAAR1 being the best characterized of these 
receptors and the main target for endogenous trace amines (Burchett and Hicks 2006; 
Lindemann and Hoener, 2005; Zucchi et al 2006). Abnormalities in trace amine 
physiology have long been associated with schizophrenia. Furthermore, the TAAR 
genes map closely to one of the major genetic susceptibility loci for schizophrenia, 
SCZD5 (Burchett and Hicks 2006; Berry 2007). Therefore, specific drugs targeting this 
novel neuromodulatory system may have clinical applications in the treatment of 
schizophrenia (Berry 2007; Branchek et al 2003). 
RO6889450 is a selective partial agonist for TAAR1 being developed for the treatment of 
schizophrenia. RO6889450 has been extensively tested in nonclinical models, showing 
antipsychotic, stress-reducing, anti-addictive, and glucose-regulating activities. In 
mechanistic assays mimicking non-competitive N-methyl-D-aspartate (NMDA) 
hypofunction and dopamine hyperfunction as seen in schizophrenic patients, 
RO6889450 inhibited hyperactivity in mice. In rats, RO6889450 dose-dependently 
normalized the social impairment induced by isolation rearing, and modulation of ventral 
tegmental area (VTA) activity was observed. RO6889450 was well absorbed in rats and 
monkeys following oral administration and has low plasma protein binding across 
species, including humans. Brain/cerebrospinal fluid exposure has been demonstrated in 
rodents. 
RO6889450 is cleared in animals through a combination of mechanisms (metabolism 
and renal). RO6889450 is not an inhibitor or an inducer of the major human cytochrome 


RO6889450 (Ralmitaront) —F. Hoffmann-La Roche Ltd
33/Protocol BP40283, Version 6
P450 enzymes, but is a substrate for human CYP3A4, CYP2C19, and flavin-containing 
monooxygenase (FMO1). RO6889450 is directly sulfo-conjugated by sulfotransferases. 
The potential for interaction with other drugs that inhibit or induce these metabolizing 
enzymes is unlikely due to mixed elimination and metabolic pathways. The relative 
contribution of CYP3A4 and CYP2C19 is estimated to be 10% each based on recent in 
vitro work (RO6889450 Investigator’s Brochure). Results from an ongoing Phase I study 
(JP40960) showed
  
 
 
 
 
 
 
 
 
 
 
 
 
A Phase 1 single-ascending dose (SAD) and multiple-ascending dose (MAD) study 
(BP30134) was conducted in 82 healthy volunteers to evaluate the safety, tolerability, 
pharmacokinetics (PK), and pharmacodynamics of
 
Pharmacokinetics of RO6889450 were well characterized after single and multiple 
doses. Following multiple oral administration of RO6889450 Cmax,ss was reached at a 
median tmax of 1.07 to 2.50 hours across dose groups. Subsequently, RO6889450 
plasma concentration declined with an apparent terminal half-life ranging from 25.8 to 
34.5 hours across dose groups supporting a once daily (QD) dosing in the subsequent 
studies. Steady-state plasma concentration was achieved after five to six days of dosing.
No clinically significant or relevant abnormalities, including dose-related trends were 
observed in electrocardiograms (ECGs), ambulatory blood pressure measurements, and 
laboratory safety parameters (blood chemistry, hematology, urinalysis) for either single 
or multiple-dose administrations. Peripheral blood lymphocytes were collected during the 
MAD phase and examined by electron microscopy for signs of phospholipidosis 
(increased lamellar bodies); no signs of phospholipidosis were found in samples taken 
from any dose level. Two dose-limiting events (DLE) occurred 
: one event of generalized erythema resulting in treatment discontinuation, 


RO6889450 (Ralmitaront) —F. Hoffmann-La Roche Ltd
34/Protocol BP40283, Version 6
and one participant had several episodes of Postural Orthostatic Tachycardia (POT
pulse rate increased by 30 bpm without hypotension). Both participants had received 
active treatment. There were no serious adverse events (SAEs) or severe adverse 
events (AEs) reported. The most common AE observed was headache. A slight trend 
towards higher elevated pulse rates with the higher doses was observed. There were 
also multiple measures that showed evidence of POT however, the incidence was as 
common with the placebo group as with the treatment groups and some subjects 
appeared to have a decrease in POT after more than seven days of dosing. 
By targeting brain circuits implicated in psychotic and negative symptoms, as well as 
central and peripheral circuits that regulate energy homeostasis, RO6889450 represents 
a potential novel therapy for the treatment of schizophrenia. A detailed description of the 
chemistry, pharmacology, and safety of RO6889450 is provided in the RO6889450 
Investigator’s Brochure.
2.3
BENEFIT/RISK ASSESSMENT
RO6889450 has the potential to improve negative symptoms and ameliorate psychotic 
symptoms of schizophrenia. In healthy volunteers, RO6889450 was well tolerated when 
administered 
. No clinically significant or 
relevant abnormalities, including dose-related trends, were observed in ECGs, 
ambulatory blood pressure measurements, or laboratory safety parameters in either 
single- or multiple-dose administrations up to the maximum tolerated dose (MTD) 
 
 
 
 

During both Part A and Part B of this study, standard monitoring of blood 
chemistry, hematology, and urinalysis will be performed. In addition, some 
dedicated safety measures will be implemented to address mechanistic and pre-
clinical safety considerations as well as known co-morbidities of schizophrenia. 
Observations from the completed SAD and MAD study (BP30134) showed POT 
in the placebo and treatment groups, with a slight trend towards higher pulse 
rates only at the 
 of RO6889450. As such, detailed 
cardiovascular assessments will be performed at multiple pre-defined time 
points, including ECG monitoring and orthostatic heart rate.

Phospholipidosis was noted in rat and cynomolgus monkeys studies, though not 
in the healthy volunteer MAD part of the Phase 1 study. 


RO6889450 (Ralmitaront) —F. Hoffmann-La Roche Ltd
35/Protocol BP40283, Version 6

In an effort to consistently collect data in clinical trials, as well as to improve 
safety monitoring, certain regulatory agencies have requested inclusion of a 
prospective assessment for suicidality for CNS active compounds. Therefore, 
Columbia-Suicide Severity Rating Scale (C-SSRS) is part of the safety 
monitoring in this study. Additionally, in Part A, patients who had suicidal 
behavior in the prior five years as confirmed by chart data and/or caregiver will 
be excluded from study participation. For patients with a history of suicidal 
behavior that occurred prior to the last five years, additional review and approval 
will be sought through the Patient Review Committee (PRC) on a case by case 
basis. In Part B, patients with suicidal behavior or active suicidal ideation with 
specific plan and intent will be discontinued from study medication (see 
Section 7.1.2). Of note, no evidence of suicidality has emerged from the previous 
clinical trial with RO6889450.
In Part A of this study, participants who are on antipsychotics will be taken off their 
antipsychotic medication for a maximum of 13 weeks, inclusive of the washout and 
treatment periods. There is an increased risk of relapse during this period while 
participants are not receiving antipsychotic treatment. For this reason, only participants 
who have a reliable support system to alert the Investigator of any early signs of relapse 
will be enrolled. Participants have the option to be inpatient for two weeks (i.e. the 
washout period as well as the first week of treatment period) if deemed necessary by the 
Investigator or as requested by the patient/caregiver to ensure patient safety. 
Throughout Part A of the study, participants will be seen in clinic or called by site staff 
every week. Informal calls by a case manager up to three times per week to follow up 
with patients are encouraged, especially during the washout period. In addition, some 
dedicated safety measures will be implemented to address the ongoing relapse risk, 
including the use of clinical scales at each visit (see Section 8.1.1.3) and the review of 
unblinded safety and efficacy (as appropriate) data for Part A of the study by an iDMC at 
scheduled time points (see Section 4.1.2). In case early signs of relapse requiring 
treatment are noticed/recorded by the Investigator in Part A, an antipsychotic should be 
provided and the participant will be immediately withdrawn from the study drug.
In Part B, participants will be allowed to continue their usual antipsychotic treatment in 
addition to the randomized study drug, provided the antipsychotic treatment has been 
stable and is expected to stay stable during the study. 
The unmet medical need for effective treatment of negative symptoms in patients with 
schizophrenia is immense. Given the potential of RO6889450 to significantly improve 
negative symptoms in schizophrenia, the favorable safety profile 
 
 in healthy volunteers along with the measures implemented to ensure the patient’s 
safety, the overall benefit/risk assessment for clinical trial participation is deemed 
positive. It should also be noted that analyses of pharmacokinetic data from Part A of 
this study and from Study BP39833 demonstrated lower than expected exposures in 








RO6889450 (Ralmitaront) —F. Hoffmann-La Roche Ltd
39/Protocol BP40283, Version 6
Part A (monotherapy): 
Participants who meet eligibility criteria for Part A of the study will take open-label 
placebo for two weeks before randomization (Day -14 to baseline/Day 1). Intake will be 
recorded/tracked using a web-based platform/app provided on a smartphone (see 
Section 6.4.1). The purpose of this open-label placebo phase is to help familiarize the 
participant with use of this platform and identify potential issues with compliance. One 
week before randomization (Day -7 to baseline/Day 1), participants will be washed-out 
from their antipsychotic therapy. At baseline/Day 1, participants will be randomized 1:1 
to either 
 QD of RO6889450 or placebo for 12 weeks. Stratification will be based 
on baseline BNSS avolition/apathy subscore (sum of items “behavior” and “internal 
experience”; ≤6 vs. >6 [Marder and Galderisi, 2017]), age at screening (18-35 years vs. 
36-55 years), and sex. The participants will have the option of an inpatient stay or partial 
hospitalization during the wash out period as well as the first week of the treatment 
period.
Part B (add-on therapy): 
Participants who are enrolled in Part A cannot be screened for Part B. Participants who 
meet eligibility criteria for Part B of the study will take placebo for one or two weeks 
(depending on compliance) before randomization. Intake will be recorded/tracked using 
a web-based platform/app provided on a smartphone (see Section 6.4.1). The purpose 
of this open-label placebo phase is to help familiarize the participant with use of this 
platform and identify potential issues with compliance. At baseline/Day 1, participants 
will be randomized 1:1:1 to 
 QD of RO6889450, 
 QD of RO6889450, or 
placebo for 12 weeks. Stratification will be based on region (i.e., Ex-Japan; Japan). For 
non-Japanese sites, stratification will additionally be based on baseline BNSS 
avolition/apathy subscore (sum of items “behavior” and “internal experience”; ≤6 vs. >6), 
age at screening (18-35 years vs. 36-55 years), sex, and antipsychotic treatment (1:1 
stratification ratio between dopamine 2 receptor [D2]/serotonin 2A receptor [5HT2A] 
antagonists and D2 partial agonist). For Japanese sites, stratification will additionally be 
based on antipsychotic treatment (1:1 stratification ratio between dopamine 2 receptor 
[D2]/serotonin 2A receptor [5HT2A] antagonists and D2 partial agonist). Approximately
equal numbers of participants on D2/5HT2A antagonists or D2 partial agonists will be 
enrolled. 
Participants who were screened for, but not enrolled in Part A can be screened for 
Part B if meeting criteria as per Section 5.5 and only after discussion with the Medical 
Monitor or delegate. The reason(s) for the decision must be documented.
Interim analyses: 
The Sponsor may choose to conduct an interim efficacy analysis in Part A. The decision 
to conduct an optional interim analysis and the timing of the analysis will be documented 
in the Sponsor’s trial master file prior to the conduct of the interim analysis. The interim 


 
RO6889450 (Ralmitaront) —F. Hoffmann-La Roche Ltd 
40/Protocol BP40283, Version 6 
analysis will be performed and interpreted by members of the Sponsor study team and 
appropriate senior management personnel who will be unblinded at the treatment group 
level. Access to treatment assignment information will follow the Sponsor’s standard 
procedures. 
The results of this analysis may support initiation of Part B enrollment during Part A if a 
positive results threshold is met as defined in the statistical analysis plan (SAP). In case 
of very slow recruitment, Part A may be stopped and/or Part B may be started without 
the interim analysis. 
The Sponsor may choose to conduct up to two additional interim analyses of Part B to 
determine the chance of final success. The results of such an analysis may support an 
early termination of Part B (see Section 9.5).   
4.1.1 
Length of the Study 
Part A: The total duration will be approximately 147 days (from screening through study 
completion) for each enrolled participant as follows: 
• 
Screening: up to 35 days (including the placebo compliance and a 7-day washout 
periods) 
• 
Treatment period: 84 days (12 weeks) 
• 
Follow-up: 28 days 
Part B: The total duration will be up to approximately 154 days (from screening through 
study completion) for each enrolled participant as follows:  
• 
Screening: up to 42 days (including the placebo compliance period) 
• 
Treatment period: 84 days (12 weeks) 
• 
Follow-up: 28 days 
 
4.1.2 
Administrative Structure  
4.1.2.1 
Independent Data Monitoring Committee 
An iDMC will regularly review unblinded safety and efficacy (as appropriate) data for 
Part A of the study. The iDMC will be composed of at least two psychiatrists external to 
the Sponsor, as well as a statistician external to the Sponsor, and will be responsible for 
monitoring safety data to help ensure that continuation of the trial in its current design 
does not pose unacceptable safety risks to participants. A restricted number of people 
from the Sponsor (including a statistician, a statistical programmer, a clinical data 
manager, and a data acquisition specialist) will be unblinded in order to prepare the 
outputs required for iDMC reviews. Representatives from other functions may join the 
iDMC open session (blinded) meetings as required. A separate iDMC charter will 
document the roles, responsibilities, membership as well as scope of activities, time of 
meetings, and communication plan. 


RO6889450 (Ralmitaront) —F. Hoffmann-La Roche Ltd
41/Protocol BP40283, Version 6
The iDMC members will receive all Suspected Unexpected Serious Adverse Reactions 
(SUSARs) for RO6889450 within 72 hours of regulatory reporting and all other SAE 
reports on a scheduled basis. Planned and ad hoc safety reviews will be performed as 
described within the iDMC charter.
4.1.2.2
Patient Review Committee 
The PRC will consist of at least two independent psychiatrists external to the Sponsor. 
The PRC in Part A will act as final decision maker regarding exclusion or inclusion of 
participants who have a history of suicidal or violent behavior extending beyond the past 
five years (see exclusion criterion 1 Part A). 
The decisions of the PRC will be provided in writing to the medical monitor who will 
inform the study site and Sponsor. A separate PRC charter will document the roles, 
responsibilities, membership as well as scope of activities, time of meetings, and 
communication plan. No PRC will be implemented for Part B of the study.
4.1.2.3
General Administrative Structure
An interactive Voice/Web Response System (IxRS) will be used to register the 
screening/screening failures, enrollment, treatment allocation, withdrawal, 
discontinuation, and termination of participants.   
A central laboratory will be used to provide laboratory kits to all sites and collect samples
for the assessments listed in Appendix 4.
ECG recordings will be transferred to a central ECG analysis vendor. The following 
parameters will be obtained from the digital recordings: heart rate and rhythm, QRS 
duration, PQ (PR), RR and QT intervals (QTcF) as well as information on T-wave and U-
wave.
A smartphone-based medication adherence monitoring platform will be used for 
investigational medicinal product (IMP) compliance verification.
Central vendors specialized in symptom assessments (Section 8.1.1.7 and 
Section 8.1.1.8) will provide equipment for the assessments and will collect such data 
electronically.
An external company(ies) and external consultants will provide training to all site raters 
on the various scales and will provide all sites with the relevant record forms, instruction 
manuals, and kits as appropriate. This company will also conduct centralized ratings for 
the primary and selected secondary endpoints (Section 8.1.1.1 and Section 8.1.1.2).
4.2
SCIENTIFIC RATIONALE FOR STUDY DESIGN
The study rationale is provided in Section 2.1.


RO6889450 (Ralmitaront) —F. Hoffmann-La Roche Ltd
42/Protocol BP40283, Version 6
This study is a proof of concept study (Part A) followed by a dose-ranging study (Part B). 
A randomized, double-blind, 2-part, placebo-controlled, parallel-group, study design was 
chosen to first collect potential efficacy data, then collect safety and tolerability data in a 
patient population.
Due to concerns that background treatment with antipsychotics may curtail the ability of 
RO6889450 to ameliorate negative symptoms, the compound will also be evaluated in a 
monotherapy setting (Part A), i.e. the participants will withdraw from their antipsychotic 
treatment(s). Part B of the study is designed to evaluate potential efficacy of two dose 
levels of RO6889450 in combination with usual antipsychotic treatment(s).
4.2.1
Rationale for Study Population and Study Duration
Negative symptoms are a core feature of schizophrenia and schizoaffective disorder but 
the optimal patient population to evaluate in treatment trials remains a point of 
discussion among regulators as well as academia (Marder et al 2013). In order to 
demonstrate an improvement, a sufficiently high threshold of symptoms on the PANSS-
Negative Symptom Factor Score (PANSS-NSFS) is required and is comparable to study 
entry thresholds in prior studies (Krause et al 2018). As negative symptoms generally 
persist from the first episode throughout the course of illness (Rapado-Castro et al 
2010), it is essential that a clinical trial for establishing drug effectiveness be long-term 
rather than acute (Laughren and Levin 2006). Additionally, the study should be 
sufficiently long to assess the possibility of an increase or re-emergence of positive 
symptoms. The minimum duration considered likely to demonstrate efficacy with an 
effective treatment is three months, but may take as long as six months to demonstrate 
a functional improvement. For the purposes of this Phase 2 study, the duration of three 
months was the maximum covered by the current toxicology information. This is also in 
line with consensus recommendations and the possibility that, should efficacy be 
demonstrated earlier than three months, this longer duration will provide the opportunity 
to demonstrate sustained efficacy (Buchanan 2007; Marder et al 2013).
4.2.2
Rationale for Withdrawal of Antipsychotics in Part A 
Preclinical data suggests that the use of an antipsychotic may reverse the cAMP effects 
of a TAAR1 agonist (Harmeier et al 2015) – one of the mechanisms by which TAAR1 is 
assumed to exert its potential clinical effects. Negative symptoms are only minimally 
improved by standard of care antipsychotic drugs. Both first- and second-generation 
antipsychotics may impair normal hedonic drive in patients through dopamine D2 
receptor antagonism, contributing to poor adherence.  D2 antagonists have also been 
shown to induce core negative symptoms (i.e. apathy/avolition) in healthy volunteers
(Mas et al 2013; RO6889450 Investigator's Brochure). 
These results suggest that clinical effects of TAAR1 might be reduced or even abolished 
by the concomitant treatment with antipsychotics.


RO6889450 (Ralmitaront) —F. Hoffmann-La Roche Ltd
43/Protocol BP40283, Version 6
4.2.3
Rationale for Inclusion of Antipsychotics in Part B 
Currently antipsychotics are the mainstay of treatment in patients with schizophrenia, 
though data demonstrates efficacy only in the management of positive symptoms with 
no clinically relevant effects on negative symptoms. Therefore, in Part B of this study, 
antipsychotics are permitted in order to assess the impact of concomitant treatment with
RO6889450. To further assess the potential impact of different classes of antipsychotics 
on the study outcome, patients will be randomized using the type of antipsychotics 
(D2/5HT2A antagonists and D2 partial agonist) as a stratification factor.
4.2.4
Rationale for Control Group 
Using placebo as study comparator allows an unbiased evaluation of the magnitude of 
any treatment effects. Additionally, no active control is used, as there are no approved 
treatments for the negative symptoms of schizophrenia in the US, where most sites will 
be located.
In Part A, frequent and careful monitoring for early indicators of clinical worsening is in 
place with use of sensitive relapse criteria to declare an exacerbation of positive 
symptoms prior to the emergence of a full psychotic recurrence (Section 8.1.1.3). These 
dedicated safety measures will be implemented to address the ongoing relapse risk, 
including the use of clinical scales at each visit (see Section 8.1.1.3) and an iDMC (see 
Section 4.1.2). In case signs of relapse requiring treatment are noticed/recorded by the 
Investigator in Part A, the participant will be immediately withdrawn from the study drug 
(Section 6.5.1), and an antipsychotic should be prescribed. If possible, Investigators 
should perform the EOT assessment (including efficacy), before antipsychotic 
medication is started.
4.2.5
Rationale for Digital Biomarker Assessments
Studies have demonstrated the ability of phone usage behavior monitoring to capture 
information on symptoms and functioning in schizophrenia (Ben-Zeev et al 2017; Torous 
and Keshavan 2018). The assumed advantage of this method over traditional 
approaches to measure symptoms and functioning lies in its continuous real-time 
collection of information that is independent of the participant’s recall and potential 
expectation bias of both participant and examiner. This digital biomarker approach, 
i.e., “Study Phone Usage Tracker”, Ecological Momentary Assessment (EMA) and 
AiCure digital assessments will therefore be implemented in the study as an exploratory 
and optional tool to help understand a potential therapeutic effect of RO6889450, 
regarding participant’s functioning and behavior and to refine such outcome measures 
for future studies (see Section 8.1.2 for more details). 
4.2.6
Rationale for Clinical Genotyping
Dissection of the genetic architecture of a complex disorder such as schizophrenia is 
important to understand its biological basis, assess the individual predisposition of
disease, and evaluate the capacity of therapeutic interventions.


RO6889450 (Ralmitaront) —F. Hoffmann-La Roche Ltd
44/Protocol BP40283, Version 6
4.3
DOSE JUSTIFICATION
In Part A, only the dose of 
 QD will be evaluated. The reasons for this approach 
are as follows:

The goal is to keep the number of participants who will be recruited and hence 
are subject to the risk of a relapse as low as possible. Hence, only one dose will 
be explored.

Secondly, based on the preclinical data collected so far, a high dose should 
maximize the probability to detect a positive effect.

RO6889450 has been shown to be safe and well tolerated in the healthy 
volunteer study (see Section 2.2.2) up to the MTD dose of 
. In addition, 
improvements were observed in reward-related behavioral tasks in 
Study BP30134. In the RLWM task, the ability to learn appropriate 
stimulus-response mappings through trial-and-error feedback was assessed. 
Greater gains in reinforcement learning from baseline were observed under both 
 of RO6889450, as compared to placebo. The ECB task 
assesses the participant’s willingness to expend effort to obtain a reward of 
variable magnitude under low versus high probability of reward receipt. 
Treatment with 
 of RO6889450 increased the proportion of effortful 
choices under conditions of guaranteed reward (i.e., 100% reward probability) 
relative to placebo, after controlling for proportion effortful choices at baseline 
(RM-ANOVA t(44) 1.737, p 0.09). For these reasons, a dose of 
 QD 
of RO6889450 is considered adequate to demonstrate potential effects on key 
deficits driving negative symptoms.
In Part B, 
 QD will be tested. The dose of 
 was 
chosen for the following reasons:

A comparison between the exposure of healthy volunteers dosed with 
 
RO6889450 in fasted state in the Phase I Study BP30134 and the exposure of 
patients affected by schizophrenia dosed with 
 RO6889450 in the Phase
Ib Study BP39833 and the Phase II study BP40283, Part A has shown a 
reduced RO6889450 exposure of up to approximately 50% in patients. The 
difference in exposure between the healthy subjects and patients can be 
explained both by food (difficult to control in outpatient settings) and body weight 
effect.

It is critical at this stage of development to optimize the study to find an efficacy 
signal. As preclinical results demonstrated a linear increase of effects with 
higher exposure it is a reasonable hypothesis that higher exposures may be 
associated with stronger effects clinically. A daily dose of 
 was 


RO6889450 (Ralmitaront) —F. Hoffmann-La Roche Ltd
45/Protocol BP40283, Version 6
determined as Maximum Tolerated Dose (MTD) in the healthy volunteer MAD 
study and is expected to be well tolerated in patients.
Based on these data, the initially planned doses of 
 for Part B have 
been replaced with 
. Thus, both selected doses of 
 
are predicted to provide plasma concentrations of RO6889450 that will remain 
above EC50 over the dosing interval with good separation in exposure between the two 
doses in patients, whilst not exceeding concentrations that were associated with MTD in 
healthy subjects. 
4.4
END OF STUDY DEFINITION
The end of the study is defined as the date when the last participant last observation 
(LPLO) occurs. LPLO is expected to occur approximately 28 days after the last 
participant’s last dose.
5.
STUDY POPULATION
The study population rationale is provided in Section 4.2.1.
The participants of this study will be male and female outpatients between 18 to 
55 years of age with a DSM-5 diagnosis of schizophrenia or schizoaffective disorder with 
negative symptoms, who are stable. For Part B, participants also need to be stable on 
antipsychotic treatment. Participants who reside in a group home setting are eligible for 
participation in this study. 
Prospective approval of protocol deviations from recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted. 
Unless otherwise stated, inclusion and exclusion criteria refer to evaluations or 
assessments at screening.
5.1
INCLUSION CRITERIA
Participants are eligible to be included in the study only if all of the following criteria 
apply:
Informed Consent
1.
Able and willing to provide written informed consent according to International 
Council for Harmonisation (ICH) and local regulations as assessed using the 
Evaluation to Sign Consent (see Appendix 9). If the participant has a legal 
representative, the informed consent must be signed by this person.
Patient and Disease Characteristics
2.
Male or female participants aged 18-55 years (inclusive).


RO6889450 (Ralmitaront) —F. Hoffmann-La Roche Ltd
46/Protocol BP40283, Version 6
3.
Patients with a DSM-5 diagnosis of schizophrenia or schizoaffective disorder as 
confirmed by the Mini International Neuropsychiatric Interview (MINI).
4.
Part B only: Stable treatment with a D2/5HT2A antagonists or pure D2 
antagonist(s) (for a complete list, see Appendix 6), or a D2 partial agonist for a 
minimum of six months and receiving no more than two antipsychotics (if no 
blood concentration of the prescribed antipsychotic medication [or active 
metabolites] is detected, the participant should not be enrolled). Note: 
compliance of blonanserin and perospirone will be monitored via informant 
report (see Appendix 4). Antipsychotic regimen: participants must be on a 
"primary" antipsychotic and may be on a secondary antipsychotic. The secondary 
antipsychotic dose has to be equal to or less than the equivalent dose of the 
primary antipsychotic. The sum of the primary and secondary antipsychotics 
must be ≤6 mg of risperidone equivalents (see Appendix 7). Participants who 
have had a change of medication not associated with a change in the 
participant’s psychiatric stability in the Investigator’s opinion (e.g., insurance 
reasons, adjustment of dose) in the six months prior to screening may be 
considered for entry into the study; however no change of antipsychotic 
medication regimen will be allowed within 3 months prior to screening. The 
reason for medication change must be documented. 
5.
Medically stable during the prior three months. Medication changes (other than 
antipsychotics) in the three months prior to screening may be acceptable, if, in 
the opinion of the Investigator, the change of medication does not affect the 
participant’s medical stability throughout the duration of the study.
6.
Participant is outpatient with no psychiatric hospitalizations within the prior six 
months (hospitalization for social management within this time is acceptable).
7.
PANSS-NSFS score of 18 or higher (see Section 8.1.1.2).
8.
The following rating on items of the PANSS: 
(a) less than 5 on G8 (uncooperativeness), P1 (delusions), P3 (hallucinations), 
P4 (excitement/hyperactivity), and P6 (suspiciousness/persecution)
(b) less than 4 on P7 (hostility)and G14 (poor impulse control) 


RO6889450 (Ralmitaront) —F. Hoffmann-La Roche Ltd
47/Protocol BP40283, Version 6
9.
Has an informant who is considered reliable by the Investigator to provide 
support to the participant and to help ensure compliance with study visits and 
protocol procedures; who preferably is also able to provide input helpful for 
completing study rating scales and is in regular contact with the participant in 
order to be able to alert the Investigator of worsening signs and symptoms for the 
participant.
10.
Body mass index (BMI) between 18 and 40 kg/m2 inclusive (Appendix 8)
Reproductive
11.
A woman is eligible to participate if she is not pregnant (negative serum 
pregnancy test at screening and negative urine pregnancy test at baseline, 
Appendix 5), not breastfeeding, and at least one of the following conditions 
applies: 
(a) Not a woman of childbearing potential (WOCBP, as defined in Section 1 of 
Appendix 5).
(b) WOCBP, who: 

agrees to remain abstinent (refrain from heterosexual intercourse) or use 
acceptable contraceptive methods during the treatment period and for at 
least 28 days after the last dose of study drug.
The following are acceptable contraceptive methods: bilateral tubal 
occlusion, male sterilization, established proper use of hormonal 
contraceptives that inhibit ovulation, hormone-releasing intrauterine 
devices and copper intrauterine devices, male or female condom with or 
without spermicide; and cap, diaphragm, or sponge with spermicide.  For 
further considerations regarding contraception guidance and abstinence 
see Appendix 5.
The contraception and abstinence requirements are intended to prevent exposure of an 
embryo to the study treatment. The reliability of sexual abstinence for female enrollment 
eligibility needs to be evaluated in relation to the duration of the clinical study and the 
preferred and usual lifestyle of the participant. Periodic abstinence (e.g., calendar, 
ovulation, symptothermal, or post-ovulation methods) and withdrawal are not acceptable 
methods of contraception.
5.2
EXCLUSION CRITERIA
Participants are excluded from the study if any of the following criteria apply:


RO6889450 (Ralmitaront) —F. Hoffmann-La Roche Ltd
48/Protocol BP40283, Version 6
Medical Conditions
1.
Part A only: Confirmed suicidal behavior based on Investigator judgment or violent 
behavior resulting in injury or property damage in the prior five years. A history 
prior to the last five years requires approval by the PRC (Section 4.1.2.2) on a 
case-by-case basis.
2.
Part A only: Lifetime history of homicidal behavior.
3.
Moderate to severe substance use disorder within six months (excluding nicotine) 
as defined by DSM-5.
4.
Any ESRS-A CGI subscore greater or equal to 3.
5.
Other current DSM-5 diagnosis (e.g., bipolar disorder, major depressive disorder).
6.
PANSS item G6 (depression) greater than or equal to 5.
7.
Significant risk of suicide or harming him- or herself or others according to the 
Investigator’s judgment.
8.
A prior or current general medical condition that might be impairing cognition or 
other psychiatric functioning (e.g., migraine headaches requiring prophylactic 
treatment, head trauma, dementia, seizure disorder, stroke; or neurodegenerative, 
inflammatory, infectious, neoplastic, toxic, metabolic, endocrine conditions).
9.
Positive result at screening for hepatitis B surface antigen (HBsAg), hepatitis C 
(hepatitis C antibody), or human immunodeficiency virus (HIV)-1 and -2. HCV 
antibody positive patients are eligible if HCV RNA is negative.
10. Tardive dyskinesia that is moderate to severe or requires treatment. 
11. History of neuroleptic malignant syndrome.
12. Average triplicate QTcF interval greater than 450 msec for males and 470 msec for 
females or other clinically significant abnormality on screening ECG based on 
centralized reading.
13. Clinically significant abnormalities in laboratory safety test results (including hepatic 
and renal panels, complete blood count, chemistry panel, coagulation, and 
urinalysis), including: 

Aspartate transaminase (AST), alanine transaminase (ALT) 2 upper limit 
of normal (ULN)

Total bilirubin >1.5 ULN with the exception of Gilbert syndrome

Serum creatinine 1.5 ULN
In case of uncertain or questionable results, tests performed during screening may 
be repeated before randomization to confirm eligibility or may be accepted if they 
are, in the opinion of the Investigator, not clinically significant.
14.
Significant or unstable physical condition that in the Investigator’s judgment might 
require a change in medication or hospitalization during the course of the study.


RO6889450 (Ralmitaront) —F. Hoffmann-La Roche Ltd
49/Protocol BP40283, Version 6
Prior/Concomitant Therapy
15.
On more than one antidepressant (Trazodone used at a dose up to and including 
50 mg at bedtime is considered a hypnotic agent), or if on one antidepressant, a 
change in dose within 28 days prior to screening.
16.
History of clozapine treatment: Clozapine treatment for schizophrenia within 
5 years prior to screening is prohibited. Low dose (< 200 mg/day) usage is 
permitted for insomnia or dyskinesia only, but not within 12 months prior to
screening.
17.
History of treatment with electroconvulsive therapy (ECT)
18.
Concomitant use of prohibited medications (see Section 6.5.3).
19.
Positive urine drug screen for amphetamines, methamphetamines, opiates, 
buprenorphine, methadone, cannabinoids, cocaine and barbiturates (see 
Section 8.2.4). In case of uncertain or questionable results, the urine drug screen 
may be repeated once during the screening period to confirm eligibility.
Other Exclusions
20.
Receipt of an investigational drug within 28 days or five times the half-life of the 
investigational drug (whichever is longer) before the first study drug 
administration.
21.
Donation of blood over 400 mL within three months prior to screening.
22.
Diagnosis of COVID-19 infection (confirmed or presumptive) 4 weeks prior to 
Screening or during Screening. Participants can be re-screened after 4 weeks of 
full recovery in addition to Investigator and/or institutional approval to enroll.
5.3
CONFIRMATION OF ELIGIBILITY AT BASELINE
1.
Part A only: Participant will be excluded if unable to taper off an antipsychotic in the 
one week prior to baseline (e.g., in the case of symptom exacerbation or 
antipsychotics with a longer half-life, see Appendix 6).
2.
Female participants who are of childbearing potential (see Appendix 5) must have a 
negative pregnancy test result at baseline.
5.4
LIFESTYLE CONSIDERATIONS
5.4.1
Alcohol Consumption
Consumption of alcohol is not recommended while taking RO6889450.
5.5
SCREEN FAILURES
Screen failures are defined as participants who consent to participate in the clinical study 
but are not subsequently randomized to study drug.
The Investigator will maintain a screening log to record details of all participants 
screened and to confirm eligibility or record reasons for screening failure. Screen failure 


RO6889450 (Ralmitaront) —F. Hoffmann-La Roche Ltd
50/Protocol BP40283, Version 6
data will not be entered in the electronic case report form (eCRF) but will be shared with 
the monitor on a regular basis.
Individuals who do not meet the criteria for participation in this study (screen failure) may 
be re-screened only once after discussion between the Investigator and the Medical 
Monitor or delegate if screen failure was not for safety reasons. Individuals who fail
screening due to clinical signs of COVID-19 or a positive COVID-19 PCR test, or other 
diagnostic tests when available, may be rescreened only once after discussion with the 
Medical Monitor or delegate. Re-screened participants should be assigned a new 
participant number. Participants who were not enrolled in Part A can be screened for 
Part B only after discussion with the Medical Monitor or delegate. The reason(s) for the 
decision must be documented.
Individuals for whom screening was stopped due to Sponsor’s decision to temporarily 
halt recruitment (e.g., due to an outbreak of COVID-19) can be re-screened after 
Sponsor approval. A new participant number should be assigned.
5.6
RECRUITMENT PROCEDURES 
Participants will be identified for potential recruitment per site-specific recruitment plans 
prior to consenting to participate in the study. Any patient-facing recruitment materials 
will receive Institutional Review Board (IRB) approval prior to use.
6.
TREATMENTS
Study drug is defined as any investigational treatment(s) or placebo intended to be 
administered to a study participant according to the study protocol.
All IMPs required for completion of this study (RO6889450 and matching placebo) will be 
provided by the Sponsor. The first dose of medication will be administered in the hospital 
or study center on Study Day 1, once all Baseline/Day 1 pre-dose assessments have 
been conducted, including the confirmation of eligibility at baseline. For all subsequent 
treatment period visit days, study drug administration will be at the study center under 
supervision of site staff. 
6.1
TREATMENTS ADMINISTERED
Table 5 summarizes the treatments administered. Of note, the daily dose of study drug 
has been increased in Part B of the study (from protocol Version 5: 
 RO6889450, 
 RO6889450, or placebo).


RO6889450 (Ralmitaront) —F. Hoffmann-La Roche Ltd
51/Protocol BP40283, Version 6
Table 5
Summary of Treatments Administered 
Study Part A
Study Drug Name:
RO6889450
(IMP)
RO6889450
(placebo; IMP)
Dosage Formulation:
Hard capsules
Hard capsules
Strength:
N/A
Route of 
Administration:
Oral
Oral
Dosing Instructions:
3 capsules QD
3 capsules QD
Daily Dose of 
RO6889450
NA
Packaging and 
Labelinga
HDPE bottle
HDPE bottle
Storage Conditions
Do not store above 
30°C, protect from 
light, keep container 
tightly closed.
Do not store above 
30°C, protect from 
light, keep container 
tightly closed.
Study Part B (prior to Protocol Version 5)
Study Drug Name:
RO6889450
(IMP)
RO6889450
(IMP)
RO6889450
(placebo; IMP)
Dosage 
Formulation:
Hard capsules
Hard capsules
Hard capsules
Strength:
N/A
Route of 
Administration:
Oral
Oral
Oral
Dosing 
Instructions:
3 capsules QD 
3 capsules QD
3 capsules QD
Daily Dose of 
RO6889450
NA
Packaging and 
Labelinga
HDPE bottle
HDPE bottle
HDPE bottle
Storage Conditions
Do not store above 
30°C, protect from 
light, keep container 
tightly closed.
Do not store above 
30°C, protect from 
light, keep container 
tightly closed.
Do not store above 
30°C, protect from 
light, keep container 
tightly closed.


RO6889450 (Ralmitaront) —F. Hoffmann-La Roche Ltd
52/Protocol BP40283, Version 6
Table 4
Summary of Treatments Administered (cont.)
Study Part B (from Protocol Version 5)
Study Drug Name:
RO6889450
(IMP)
RO6889450
(placebo; IMP)
Dosage 
Formulation:
Hard capsules
Hard capsules
Strength:
N/A
Route of 
Administration:
Oral
Oral
Dosing 
Instructions:
Patients will take 3 capsules from each of two bottles (total 6 
capsules) once daily, preferably in the morning, with or 
without food. 
 arm
3 capsules 
 
and
3 capsules placebo 
QD
 arm
6 capsules QD 
(three from each of 
two bottles)
N/A
Placebo arm
N/A
6 capsules QD 
(three from each of 
two bottles)
Daily Dose of 
RO6889450
NA
Packaging and 
Labelinga
 arm 
 arm
Placebo arm
1 HDPE bottle
2 HDPE bottles
N/A
1 HDPE bottle
N/A
2 HDPE bottles
Storage Conditions
Do not store above 
30°C, protect from 
light, keep 
container tightly 
closed.
Do not store above 
30°C, protect from 
light, keep 
container tightly 
closed.
Abbreviations: HDPE = high density polyethylene; IMP = investigational medicinal product; N/A = not 
applicable; QD = once a day
a Study drug will be provided in HDPE bottles. Each HDPE bottle will be labeled as required per country 
requirement.
Study drug should preferably be taken in the morning. Study drug can be taken with or 
without food, regardless of the timing of meals. A minimum of 8 hours between study 
drug intake on one day to the next daily dose is recommended.
Guidelines for dosage modification and treatment interruption or discontinuation are 
provided in Section 7.
Please see the RO6889450 Investigator’s Brochure for more details.


RO6889450 (Ralmitaront) —F. Hoffmann-La Roche Ltd
53/Protocol BP40283, Version 6
6.2
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY
Study drug packaging will be overseen by the Roche clinical trial supplies department.
The packaging and labeling of the IMPs will be in accordance with Sponsor standard 
and local regulations.
The investigational site will acknowledge receipt of IMPs and confirm the shipment 
condition and content. Any damaged shipments will be replaced.
Upon arrival of the IMPs at the site, site personnel will complete the following:

Check the IMPs for damage.

Verify proper identity, quantity, and integrity of seals.

Report any deviations or product complaints to the study monitor upon discovery.
For the placebo compliance period, the bottles are open-label and the batch number is 
the identifier. The qualified individual responsible for dispensing will dispense the batch 
number assigned to a participant by the IxRS.
Each double-blind bottle of capsules will be labeled with a unique medication number 
(MEDNO). The qualified individual responsible for dispensing the study drug will 
dispense the correct bottles of IMP to the participant at each dispensing visit by 
matching the MEDNOs allocated by the IxRS for that visit with the number printed on the 
IMP label.
Only participants enrolled in the study may receive study drug and only authorized site 
staff may supply or administer IMP. If the IMP dispensing visit cannot take place in the 
clinic (e.g., due to travel restriction due to an outbreak of COVID-19) and alternatives 
methods of delivery are not feasible, the IMP dispensing may be done with direct site to 
patient shipment (with a prior approval from relevant health authority if applicable). All 
IMPs must be stored in a secure, environmentally controlled, and monitored (manual or 
automated) area in accordance with the labeled storage conditions with access limited to 
the Investigator and authorized site staff. Any deviations or product complaints should be 
reported to the study monitor upon discovery.
The Investigator, Institution, or the Head of the Medical Institution (where applicable) is 
responsible for IMP accountability, reconciliation, and record maintenance (i.e., receipt, 
reconciliation and final disposition records).
IMPs will either be disposed of at the study site according to the study site’s institutional 
standard operating procedure or returned to the Sponsor with the appropriate 
documentation. The site's method of IMP destruction must be agreed upon by the 
Sponsor. Local or institutional regulations may require immediate destruction of used 
IMP for safety reasons. The site must obtain written authorization from the Sponsor 


RO6889450 (Ralmitaront) —F. Hoffmann-La Roche Ltd
54/Protocol BP40283, Version 6
before any IMP is destroyed, and IMP destruction must be documented on the 
appropriate form.
6.3
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND 
BLINDING
6.3.1
Method of Treatment Assignment 
An IxRS will be used to randomize the participants in equal proportion to the treatment 
arms.
The randomization numbers will be generated by the Sponsor or its designee. Details on 
randomization and stratification factors are described in Section 4.1.
6.3.2
Blinding
This is a double-blind study, i.e., the study participants, the Investigators, and all 
individuals in direct contact with the study participants at the investigative site and the 
Sponsor Study Management Team (SMT) will be blinded.
If unblinding is necessary for participant management (e.g., in case the knowledge is 
needed for treatment of a SAE), the Investigator will be able to break the treatment code 
using IxRS. Treatment codes should not be broken except in emergency situations. If 
the Investigator wishes to know the identity of the study drug for any other reason, he or 
she should contact the Medical Monitor directly. The Investigator should document and 
provide an explanation for any premature unblinding (e.g., accidental unblinding, 
unblinding due to a SAE).
The randomization list will be made available to the individual responsible for PK sample 
bioanalysis and to statisticians or statistical programmers at Roche. Also, members of 
the iDMC will be unblinded. The Sponsor’s study statistician as well as a statistical 
programmer will be unblinded to provide unblinded safety information to the iDMC.  
PK data can be received and cleaned on an ongoing basis. The data will be handled and 
cleaned in a secure area that is not accessible by any blinded SMT member.
As per Health Authority reporting requirements, the Sponsor will break the treatment 
code for all unexpected SAE (see Section 8.3.4 and Appendix 2) that are considered by 
the Investigator to be related to study drug.
Whenever disclosure of the identity of the test medication is necessary, adequate 
procedures will be in place to ensure integrity of the data.
6.4
TREATMENT COMPLIANCE
The qualified site personnel will dispense the correct bottles of IMP according to the 
visits outlined in the Schedule of Activities (SoA; see Section 1.3) and according to the 
IxRS instructions (see Section 6.2). This individual will write the date dispensed and 


RO6889450 (Ralmitaront) —F. Hoffmann-La Roche Ltd
55/Protocol BP40283, Version 6
participant number on the IMP label. To improve compliance bottles will be marked as 
Bottle A and Bottle B. This individual will also record the unique batch numbers for the 
placebo compliance period or MEDNOs for the double-blind period received by each 
participant in the participant’s records. Treatment compliance verification will be done 
using the medication adherence platform via a smartphone app (see Section 6.4.1) and 
will also be checked by the site.
6.4.1
Medication Adherence Platform
This trial will employ a medication adherence monitoring platform (“Platform”). The 
Platform will either be provided to a participant preloaded on a smartphone, or the 
participant may download the Platform onto their own smartphone. Participants will 
receive a medication reminder at a time within a pre-defined window to take their 
medication. Participants will follow a series of prescribed steps in front of the front-facing 
webcam of the smartphone to confirm participant identity and medication to be taken. In 
addition, built-in reminders and a communication system allows real-time intervention in 
case of non-compliance. Use of this Platform will in no way supersede or replace the 
physician and/or prescribed medication protocol. Because the Platform does not change 
the medication protocol, but rather encourages adherence, use of this Platform presents 
minimal risk to the participants.
After local determination by the Platform of proper medication administration, video 
recordings and data indicating whether or not the participant has properly taken the 
medication will be encrypted and transmitted to a secure centralized location for further 
analysis, including testing for duplicate enrollment. The captured video and data is 
reviewable through a roles- and rules-restricted Health Insurance Portability and 
Accountability Act (HIPAA)-compliant system ensuring privacy of the information and 
only accessible to authorized personnel through two-way authentication.
Phone numbers of the participants will be collected and stored in an encrypted manner, 
allowing for direct communication to each participant from the system in an automated 
manner, or by study staff or other study monitoring personnel. Individuals not part of the 
study staff will not know the identity of study participants and will have no access to any 
medical or health records of the participants.
Participants who are found to regularly not take their medication will be contacted by 
study staff for retraining and motivational interventions.
6.5
CONCOMITANT THERAPY
All medications (prescription and over-the-counter [OTC]) taken within 28 days of study 
screening will be recorded on the appropriate eCRF page as well as any non-
pharmacological interventions (e.g., individual psychotherapy, cognitive behavioral 
therapy, smoking cessation therapy, and rehabilitative therapy [excluding supportive 
psychotherapy]).


RO6889450 (Ralmitaront) —F. Hoffmann-La Roche Ltd
56/Protocol BP40283, Version 6
The Medical Monitor or delegate should be contacted if there are any questions 
regarding concomitant or prior therapy.
6.5.1
Rescue Medicine During Part A
If early signs of relapse requiring treatment are noticed/recorded by the Investigator, an 
antipsychotic should be prescribed and the participant will be immediately withdrawn 
from the study drug. Investigators should make reasonable effort to complete a final 
assessment including efficacy endpoints before starting antipsychotic medication.
6.5.2
Permitted Therapy
Concomitant therapy includes any medication, e.g., prescription drugs, OTC drugs, 
approved dietary and herbal supplements, nutritional supplements and any non-
medication interventions (e.g., individual psychotherapy, cognitive behavioral therapy, 
smoking cessation therapy, and rehabilitative therapy) used by a participant from 
28 days prior to screening until the follow-up visits. All concomitant medications should 
be reported to the Investigator and recorded in the eCRF.
All therapy and/or medication administered to manage adverse events should be 
recorded on the AE eCRF. For further information regarding the management of specific 
AE, please see Appendix 2.
The use of stable, scheduled doses of benzodiazepines is permitted.  The use of stable, 
scheduled doses of non-benzodiazepine hypnotics is permitted. 
If deemed necessary by the Investigator to treat occasional anxiety, agitation, or sleep 
problems, lorazepam, alprazolam, or oxazepam are allowed as needed ([PRN], up to a 
maximum daily dose of lorazepam 6 mg, alprazolam 3 mg, or oxazepam 90 mg). If PRN 
treatment of more than five consecutive days is necessary, this should be discussed 
with the Medical Monitor. PRN doses of benzodiazepines should not be administered 
within 12 hours of a clinic visit.
Non-prohibited medications used for the treatment of stable medical conditions other 
than schizophrenia (e.g., hypertension, diabetes, oral contraceptives, hormone-
replacement therapy) are allowed during the study, provided that they have been stable 
for 28 days prior to screening and are intended to remain stable throughout the study up 
to the follow-up visits.
Participants in Part B of the study have to be on stable treatment (i.e., no medication 
changes or significant dose adjustments) with D2/5HT2A antagonists or D2 partial 
agonist for a minimum of six months prior to screening. In cases where change in 
medication is not associated with the participant’s psychiatric stability, treatment 
changes can be accepted up to three months prior to screening. 


RO6889450 (Ralmitaront) —F. Hoffmann-La Roche Ltd
57/Protocol BP40283, Version 6
Co-administration of RO6889450 and weak P-gp substrates, such as risperidone, 
amisulpride, aripiprazole, and paliperidone, though permitted may result in slight 
elevations of the P-gp substrate, so continued monitoring is suggested.
SARS-CoV-2 vaccines were permitted during the study (see Section 2.3).
6.5.3
Prohibited Therapy
Use of the following therapies (non-topical formulation where applicable) is prohibited 
during the study unless otherwise specified:

Clinically relevant substrates of P-gp, including quinidine and loperamide.

Cannabidiol (may affect schizophrenia symptoms [McGuire 2018]).
In Part A, all antipsychotic treatment as well as medications used to treat EPS (e.g., 
anticholinergics) will be discontinued before randomization. Antipsychotic medications 
that require longer washout periods (i.e., more than two weeks), such as cariprazine, 
brexpiprazole, and long-acting injectable antipsychotics (e.g., aripiprazole lauroxil, 
olanzapine pamoate, and haloperidol decanoate) are exclusionary at screening (see 
Section 5.3, and Appendix 6).  
Patients receiving treatment for tardive dyskinesia (e.g., valbenazine or 
deutetrabenazine) are excluded (see Section 5.2). As a general rule, no new 
concomitant medications will be permitted, with the exception of medications to treat 
AEs, unless the rationale for exception is discussed with the Sponsor or designee and 
clearly documented between the Investigator and the Sponsor.
6.6
DOSAGE MODIFICATION
No dosage modifications are allowed in this study.
6.7
TREATMENT AFTER THE END OF THE STUDY
The Sponsor does not intend to provide RO6889450 or other study interventions to 
participants after conclusion of the study or any earlier participant withdrawal. 
Participants should consult with their physician on available treatment options, such as 
antipsychotics, to begin after the last dose of study drug.


RO6889450 (Ralmitaront) —F. Hoffmann-La Roche Ltd
58/Protocol BP40283, Version 6
7.
DISCONTINUATION OF STUDY DRUG AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL
An excessive rate of withdrawals (either participants discontinuing study drug or 
withdrawing from the study) can render the study non-interpretable. Therefore, 
unnecessary withdrawal of participants should be avoided and efforts should be taken to 
motivate participants to comply with all the study specific procedures as outlined in this 
protocol.
Details on study and site closures are provided in Appendix 1 Study Governance 
Considerations Study.
7.1
DISCONTINUATION OF STUDY DRUG
Any participants must discontinue study drug if they have withdrawn consent or 
experience any of the following:

Pregnancy

Participant unable to continue to comply with study requirements

Any medical condition that the Investigator or Sponsor determines may 
jeopardize the participant’s safety if he or she continues in the study. The
Sponsor should be informed by the Investigator, preferably prior to, or 
immediately after withdrawal of the participant, as feasible, considering the safety 
of the participant is first priority.

Investigator or Sponsor determines it is in the best interest of the participant.
7.1.1
Part A
During Part A, participants will be monitored for signs of relapse by evaluating their 
typical prodromal symptoms, referred to as MTS (see Section 8.1.1.3) at scheduled site 
visits and during phone calls. If an increase in MTS is noted during a phone call as 
described below for either the CGI-S or CGI-I MTS, the participant will be asked to come 
in for an unscheduled visit for a full evaluation by the clinician. 
CGI-S-MTS

at least an increase of 1 point on two CGI-S-MTS as compared to baseline 
scores
OR

an increase of 2 points on one CGI-S-MTS as compared to the baseline score 
CGI-I-MTS

at least a CGI-I-MTS score of 5 on two CGI-I-MTS
OR

at least a CGI-I-MTS score of 6 on one CGI-I-MTS


RO6889450 (Ralmitaront) —F. Hoffmann-La Roche Ltd
59/Protocol BP40283, Version 6
Participants exhibiting signs or symptoms of a psychotic relapse or considered at 
imminent risk of relapse by the investigator at a scheduled or unscheduled visit should 
be withdrawn from the study.
The following guidance is provided for the use of investigators in Part A:

Participants that have a CGI-I 5 (minimally worse) and an increase on any of 
the following PANSS items: conceptual disorganization, suspiciousness, 
hallucinatory behavior, and unusual thought content to a score of > 4 with an 
absolute increase of 2 on that specific item since randomization should be 
considered for treatment discontinuation. If a patient meets these criteria and is 
not withdrawn from the study, the investigator needs to discuss this with the 
Medical Monitor.
7.1.2
Part A and Part B
In Part A and Part B, patients that meet the following criteria will be discontinued from 
study medication:
1. hospitalization due to worsening of psychotic symptoms.
2. suicidal behavior or active suicidal ideation with specific plan and intent.
3.
violent or aggressive behavior resulting in injury or property damage.
4. symptomatic with moderate or severe COVID-19 infection (as per WHO 
guidelines) with signs of pneumonia or hypoxia.
If, in the judgement of the Investigator, the participant is at an imminent risk of relapse, 
even if none of the above criteria are met, the participant should be withdrawn from the 
study as well. 
Discontinuation of study intervention for abnormal liver function should be considered by 
the Investigator when a participant meets one of the conditions outlined (Section 6 of 
Appendix 3) or if the Investigator determines that it is in best interest of the participant.
If a clinically significant finding is identified (including, but not limited to QT interval 
corrected using QTcF exceeding 500 msec [if confirmed in control ECG to be recorded 
within 60 minutes] or a change from baseline QTcF by more than 60 msec [if confirmed 
in control ECG to be recorded within 60 minutes]) after enrollment, the Investigator or 
qualified designee will determine if the participant can continue in the study and if any 
change in participant management is needed. This review of the ECG printed at the time 
of collection must be documented. Any new clinically relevant finding should be reported 
as an AE.
Participants who discontinue study drug prematurely will be asked to return to the clinic 
for a study completion/early termination visit (see Section 8.11.3) and may undergo 


RO6889450 (Ralmitaront) —F. Hoffmann-La Roche Ltd
60/Protocol BP40283, Version 6
follow-up assessments (see Section 8.11.4). The primary reason for premature study 
drug discontinuation should be documented on the appropriate eCRF. 
See the SoA (Section 1.3) for data to be collected at the time of treatment 
discontinuation and follow-up and for any further evaluations that need to be completed.
7.2
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE 
STUDY
Participants have the right to voluntarily withdraw from the study at any time for any 
reason.
In addition, the Investigator has the right to withdraw a participant from the study for 
medical and psychiatric conditions that the Investigator or Sponsor determines may 
jeopardize the participant’s safety if he/she continues in the study.
If possible, information on reason for withdrawal from the study should be obtained. The 
primary reason for withdrawal from the study should be documented on the appropriate 
eCRF. Participants will not be followed for any reason after consent has been withdrawn.
When a participant voluntarily withdraws from the study, or is withdrawn by the 
Investigator, samples collected until the date of withdrawal will be analyzed, unless the 
participant specifically requests for these to be discarded or local laws require their 
immediate destruction. However, if samples have been tested prior to withdrawal, results 
from those tests will remain as part of the overall research data.
Participants who withdraw from the study will not be replaced. 
See the SoA (Section 1.3) for data to be collected at the time of study discontinuation 
and at safety and follow-up visits, and for any further evaluations that need to be 
completed.
7.3
LOST TO FOLLOW-UP
A participant will be considered lost to follow-up if the participant repeatedly fails to 
return for scheduled visits and is unable to be contacted by the study site.


RO6889450 (Ralmitaront) —F. Hoffmann-La Roche Ltd
61/Protocol BP40283, Version 6
The following actions must be taken if a participant fails to return to the clinic for a 
required study visit:

The site must attempt to contact the participant and reschedule the missed visit 
as soon as possible, counsel the participant on the importance of maintaining the 
assigned visit schedule, and ascertain whether or not the participant wishes to 
and/or should continue in the study.

Before a participant is deemed lost to follow-up, the Investigator or designee 
must make every effort to regain contact with the participant. These contact 
attempts should be documented in the participant’s medical record.

Should the participant continue to be unreachable, he/she will be considered to 
have withdrawn from the study.
Discontinuation of sites or of study as a whole are handled as part of Appendix 1.
8.
STUDY ASSESSMENTS AND PROCEDURES
Study procedures and their time points are summarized in the SoA (Section 1.3). 
Protocol waivers or exemptions are not allowed.
Immediate safety concerns should be discussed with the Sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
study drug.
8.1
EFFICACY ASSESSMENTS
8.1.1
Efficacy Assessments to be Completed at Site Visits
Training, guidance on rater qualifications and procedures are described separately in the 
Ratings Manual. The following assessments will be performed by an approved remote 
centralized rater:

BNSS

PANSS 
Remote centralized raters will administer assessments live via secure videoconference. 
The centralized rater may be observed by another clinician for quality control purposes. 
If a remote administration session cannot occur for an unforeseen reason, it will be 
rescheduled.
8.1.1.1
Brief Negative Symptom Scale
The BNSS (Strauss et al 2012) is a 13-item instrument designed for clinical trials that 
measures the severity of negative symptoms in five domains (subscales): blunted affect, 
alogia, asociality, anhedonia, and avolition/apathy. All ratings are based on a semi-
structured interview with prompts and queries. Items are rated on a 7-point scale, 




RO6889450 (Ralmitaront) —F. Hoffmann-La Roche Ltd
63/Protocol BP40283, Version 6
8.1.1.3
Clinical Global Impression Scales
The CGI rating scales are tools used to evaluate both the severity of illness and change 
from baseline (Guy 1976). The CGI-S reflects the severity of illness on a 7-point scale 
ranging from no symptoms (1) to very severe (7). The CGI-I is used to assess the clinical 
change as compared to symptoms at baseline using a 7-point scale, ranging from very 
much improved (1) to very much worse (7). In this study, overall clinical status will be 
evaluated with the CGI-S and CGI-I. Overall global impression of negative symptoms will 
be assessed using the CGI-S and CGI-I for negative symptoms (Haro et al 2003). 
Only in part A: At screening, clinicians will gather information from the patient’s past 
psychiatric history, caregiver feedback, and clinical judgement to determine two to three 
prodromal or MTS historically associated with a signal of the patient’s relapse. The 
patient’s MTS (including frequency, intensity, interference with daily function or family 
life, and other salient consequences) will be recorded and these symptoms evaluated 
using the CGI-S MTS. At post-baseline visits, the clinician will use the MTS description 
and re-evaluate the MTS using the CGI-S and CGI-I. This re-assessment of the patient’s 
prodromal symptoms will support with the ongoing clinical evaluation of relapse risk. 
It takes approximately 15 to 20 minutes to complete all CGI-I and CGI-S scales.
8.1.1.4
Fagerström Test for Nicotine Dependence
The Fagerström Tolerance Scale (Heatherton et al. 1991) will be used to assess nicotine 
consumption during the course of the study. The Fagerström test is a standard 
instrument for assessing the intensity of physical addiction to nicotine. The test was 
designed to provide an ordinal measure of nicotine dependence related to cigarette 
smoking. The test will only be administered to participants that are cigarette smokers 
and is not applicable for other forms of nicotine consumption or non-smokers.
It contains six items that evaluate the quantity of cigarette consumption, the compulsion 
to use, and dependence. Yes/No items are scored from 0 to 1 and multiple-choice items 
are scored from 0 to 3. The items are summed to yield a total score of 0-10. The higher 
the total Fagerström score, the more intense is the participant’s physical dependence on 
nicotine. The scale takes approximately five minutes to complete.
8.1.1.5
Reinforcement Learning Working Memory Task 
This task assesses the ability to learn from positive reward and establish corresponding 
mental value representations, functions that are deficient in patients with negative 
symptoms (Gold et al 2008, Gold et al 2012)
In completing the RLWM task, participants have to learn to select one out of three button 
presses for each stimulus (one stimulus present at a time) (Gold et al 2012). The 
number of stimuli in the set to be learned at any one time ranges from 2, 3, 4, 5, 6. 
Reinforcement probabilities are deterministic, so the correct action is always correct and 
the incorrect one is always incorrect. The reward magnitudes associated with a correct 


RO6889450 (Ralmitaront) —F. Hoffmann-La Roche Ltd
64/Protocol BP40283, Version 6
action will be probabilistically assigned, with reward values 1 or 2, with probability 0.25, 
0.5, or 0.75 depending on the stimulus (incorrect actions will always lead to no reward). 
Note that encoding this reward value is not necessary for learning the task, since the 
best one can hope to do for any stimulus is just select the correct action; they have no 
control as to whether they obtain one or two points. However, the striatal reinforcement 
learning system is expected to nevertheless learn to represent higher expected reward 
values for those stimuli associated with higher probability of two points, which we can 
assess in the test phase below.
In addition, with lower set sizes, participants can rely on working memory, but this is 
subject to decay in time and capacity limitations. As set size exceeds their working 
memory capacity, they have to rely on incremental reinforcement learning. The paradigm 
can thus isolate working memory from reinforcement learning processes that are striatal 
dependent.
In a subsequent test/transfer phase after initial learning, learned stimulus values will be 
probed by having participants choose between pairs of previously observed stimuli. 
Instead of selecting the response that had been ‘correct’ for each of the individual stimuli 
during the learning phase, now participants will be asked to select among pairs of stimuli 
and to indicate their preferences (which ones they thought had led to more points). 
Typically, participants are more likely to select the more rewarding stimuli, and they do 
so more reliably as the difference between their reward values grows. This test also 
allows us to assess whether participants perform better at choosing the most rewarding
stimuli or in avoiding the least rewarding stimuli, when each of these are paired with 
neutral stimuli; this difference in performance in these conditions is related to striatal 
dopaminergic measures in various studies.
The RLWM task takes approximately 30 minutes to complete. This assessment will not 
be performed in countries without validated translation. If validated translations become 
available, they may be used.
8.1.1.6
Effort Cost/Benefit Tradeoff Task 
This task will assess the degree to which participants are willing to engage in effortful 
responding as a function of the probability and magnitude of potential rewards (monetary 
compensation). Patients with negative symptoms show reduced willingness to engage in 
effortful behavior probably reflecting deficits in mental value representations and/or 
motivation (Gold et al 2013). 
There will be a low effort/low reward and a high effort/high reward condition. In the low-
effort condition, participants will respond a fixed number of times (e.g., 20) to obtain a 
certain reward (e.g., $3). In the high-effort condition, rather than having a fixed payoff, 
the reward will be proportional to the number of key presses made in that same 20 
second interval. The payoff will be manipulated across trials such that in some trials, 
they can obtain 10¢/press (in which case 30 presses would be needed to get the same 


RO6889450 (Ralmitaront) —F. Hoffmann-La Roche Ltd
65/Protocol BP40283, Version 6
$3 as the low-effort condition, but more than 30 presses could allow them to win that 
much more: 100 presses would be $10). In other trials the payoff/press would be more 
(e.g., 20¢/press) or less (5¢/press). 
This task takes approximately 30 minutes to complete. This assessment will not be 
performed in countries without validated translation. If validated translations become 
available, they may be used.
8.1.1.7
Brief Assessment of Cognition in Schizophrenia
The BACS was designed to measure cognition in schizophrenia. The domains of 
cognitive function measured by the BACS including verbal memory, working memory, 
motor speed, attention, executive functions, and verbal fluency found to be impaired in 
schizophrenia (Addington et al 2003; Bilder et al 2002; Censits et al 1997; Hobart et al 
1999; Keefe et al 2004; Mohamed et al 1999; Nuechterlein et al 2004; Saykin et al 
1991). The BACS is found to be a valid outcome measure for the effects of rehabilitation, 
medication, and therapy on cognitive function, and is an indicator of functional relevance 
with respect to independent living skills, performance-based assessments of everyday 
living skills, and interview-based assessments of cognition in patients with schizophrenia 
(Keefe et al 2004; Keefe et al 2006). The BACS will be administered by qualified site 
raters using the tablet-based BACS App and should take approximately 30 minutes to 
complete. This assessment will not be performed in countries without validated 
translation. If validated translations become available, they may be used.
8.1.1.8
Virtual Reality Functional Capacity Assessment Tool 
The VRFCAT is a computerized measure that was developed to be a reliable, valid, and 
sensitive measure of functional capacity, with the potential to demonstrate real-world 
functional improvements associated with cognitive change. The VRFCAT presents 
participants with a realistic simulated environment to recreate routine activities of daily 
living (Ruse et al 2014). The VRFCAT uses a game engine (the “Unreal Engine”) to 
create a realistic, interactive, and immersive environment consisting of four mini-
scenarios that follow a story, including: (1) exploring a kitchen, (2) catching a bus to a 
grocery store, (3) finding/purchasing food in a grocery store, and (4) returning home on a 
bus. To permit repeated testing while avoiding learning effects, six alternate forms were 
created that vary the ingredients stored in the cabinets, items on the recipe and grocery 
list, cost of the bus rides, cost of groceries, and money available in a wallet. Participants 
complete each scenario through a progressive storyboard design. The VRFCAT should 
take approximately 30 minutes to complete. This assessment will not be performed in 
countries without validated translation. If validated translations become available, they 
may be used.
8.1.2
Digital Biomarkers
See Section 4.2.5 for the rationale for digital biomarker assessments.


RO6889450 (Ralmitaront) —F. Hoffmann-La Roche Ltd
66/Protocol BP40283, Version 6
8.1.2.1
Study Phone Usage Tracker (Smartphone App)
Participants who have a suitable personal smartphone will be asked to download the 
Study Phone Usage Tracker App (Torous et al 2016; Wang et al 2016; Wang et al 
2017). This app will record: 

Time spent on the phone and on different apps

Ambient noise 

Location
To fully protect study participant’s privacy, the data will be collected in an anonymized 
manner. No participant-identifying information is collected. For example, the Study 
Phone Usage Tracker monitors the apps the participants use and how long they use 
them, but never what is done in the apps. Similarly, the ambient noise recording stores 
the level and quality of background noise rather than a sound clip of the background 
noise. Patients have the option to pause location, phone usage, and ambient noise 
recording.
Data are encrypted and uploaded to secure servers whenever the phone is connected to 
WiFi. If participants have a WiFi network at home, they are encouraged to connect their 
smartphone to enable data transfer. If no WiFi network is available, the sensor data will 
be transferred during site visits.
The decision to install the app is strongly encouraged. The decision not to install the app
will not affect the participant’s eligibility for the study. Participants can at any time point 
decide to remove the app from their smartphone.
Additional information will be provided in the Digital Biomarker Manual. This assessment 
will not be performed in countries without validated translation. If validated translations 
become available, they may be used.
8.1.2.2
AiCure Digital Biomarkers
AiCure provides a brief smartphone-based automated assessment of negative 
symptoms of schizophrenia. The assessment includes components to produce both 
spontaneous and evoked responses following validated methodologies in the scientific
literature consisting of the following components:
Spontaneous Response Evocation: Facial Expressivity and Free Speech 
This first component asks participants brief open-ended questions along with positively 
and negatively valenced images and asks the participant to speak about them. This 
component is designed to collect spontaneous facial expressivity and free speech 
behavior when responding to the open-ended questions and in response to positive and 
negative stimuli.


RO6889450 (Ralmitaront) —F. Hoffmann-La Roche Ltd
67/Protocol BP40283, Version 6
Elicited Verbal and Emotionally Expressive Behaviors
This second component evokes elicited behaviors. The first elicited behavior is a 
sustained vowel sound (e.g., saying ‘aaaah’). This component is used to calculate 
acoustic characteristics indicative of symptom severity in schizophrenia. The second 
elicited behavior is creating evoked emotional expressions (e.g. happy face, sad face). 
This allows for quantification of evoked emotional expressivity.
Tasks are designed to be low burden, taking approximately 2-3 minutes to complete. A 
pop-up visualization will signal participants once throughout the day, 3 days a week 
during the week prior to the visits when the BNSS is administered.
The decision to install the AiCure Digital Biomarker app is strongly encouraged. The 
decision not to install the AiCure Digital Biomarker app will not affect the participant’s 
eligibility for the study. Participants can at any time point decide to remove the AiCure 
Digital Biomarker app from their smartphone.
Additional information will be provided in the training session while using the app.
This assessment will not be performed in countries without validated translation. If 
validated translations become available, they may be used. 
8.1.3
Efficacy Assessments to be Completed by the Participant 
8.1.3.1
Defeatist Performance Attitude Scale 
The DPAS is a 15-item, patient-rated assessment that evaluates expectations of failures 
or self-defeating beliefs related to prior failed experiences as well as illness on a 7-point 
Likert scale ranging from totally agree (1) to totally disagree (7). Previous research 
suggests a correlation in defeatist beliefs (e.g., “People will probably think less of me if I 
make a mistake” or “People who have good ideas are more worthy than those who do 
not”) and negative symptoms in schizophrenia (Grant and Beck 2009). This scale takes 
approximately 10 minutes to complete. It will be completed by the participant during site 
visits.
8.1.3.2
Assessment of Sleep, Mood, Well-being and Cognitive 
Functioning and Treatment Expectancy
Three Likert scales assessing sleep quality, mood / well-being, and cognitive functioning 
will be administered via the smartphone (Appendix 10). Participant will be instructed to 
fill in the Likert scales (made of six smiley icons) at defined time points during the trial. In 
addition, participants will be asked to answer the following question at the end of the 
study: “Do you think you were taking placebo or drug?” The scales will be completed by 
the participant at pre-specified time points that will appear random to the participant.
8.1.3.3
Ecological Momentary Assessment (EMA)  
EMA is an ambulatory data collection technique that allows the real-time in vivo 
assessment of functioning behaviors, including educational, employment, socialization, 
active leisure, self-care, and home-care activities.


RO6889450 (Ralmitaront) —F. Hoffmann-La Roche Ltd
68/Protocol BP40283, Version 6
In the present study, EMA will be used to assess the participants’ functioning associated 
to negative symptoms in Schizophrenia through the use of smartphones. A pop-up 
visualization will signal participants 3 times throughout the day, 5 days a week (not at the 
visit day) to respond to very brief (e.g., 3 minutes) questionnaires about their daily lives. 
Data are encrypted and uploaded to secure servers whenever the phone is connected to 
WiFi or if cellular data is available. If no WiFi network is available and cellular data is 
unavailable, the sensor data will be transferred during site visits.
The decision to install the app is strongly encouraged. The decision not to install the 
EMA app will not affect the participant’s eligibility for the study. Participants can decide 
at any time point to remove the EMA app from their smartphone.
This assessment will not be performed in countries without validated translation. If 
validated translations become available, they may be used.
8.2
SAFETY ASSESSMENTS
Planned time points for all safety assessments are provided in Section 1.3.
Safety assessments will consist of monitoring and recording AEs, including SAEs, 
measurement of protocol‑specified safety laboratory assessments, measurement of 
protocol-specified vital signs, ECGs, and other protocol-specified tests that are deemed 
critical to the safety evaluation of the study.
8.2.1
Physical Examinations
A complete physical examination will include, at a minimum, assessments of the 
cardiovascular, respiratory, gastrointestinal, dermatological, and neurological, 
musculoskeletal in addition to head, eyes, ears, nose, throat, neck, and lymph nodes 
systems. The physical examination will NOT include pelvic, rectal, or breast 
examinations. Further examination of other body systems may be performed in case of 
evocative symptoms at the Investigator’s discretion.
Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
Any abnormality identified at baseline should be recorded on the Medical History eCRF.
At subsequent visits (or as clinically indicated), limited, symptom-directed physical 
examinations should be performed. Changes from baseline abnormalities should be 
recorded in participant’s notes. New or worsened clinically significant abnormalities 
should be recorded as AEs on the AE eCRF.


RO6889450 (Ralmitaront) —F. Hoffmann-La Roche Ltd
69/Protocol BP40283, Version 6
8.2.2
Vital Signs
Vital sign measurements will include participant’s temperature, systolic and diastolic 
blood pressure and pulse. They will be taken before blood collection and will be 
measured in a supine position after the participant has been lying for at least five 
minutes. Additionally, blood pressure and pulse measurements will be taken again after 
two minutes in a standing position (orthostatic vital signs) at the time points indicated in
Section 1.3.
Blood pressure and pulse measurements will be assessed with a completely automated 
device. Manual techniques will be used only if an automated device is not available. 
When possible, the same arm should be used for all blood pressure measurements.
8.2.3
Electrocardiograms
Sites will be provided with ECG equipment by the central ECG analysis vendor. 
Twelve-lead ECG recordings will be obtained at the time points specified in the SoA 
(Section 1.3) with the following parameters: heart rate, PQ (PR), QRS, QT, RR and 
QTcF, along with information on T- and U-waves. Triplicate ECGs are required at 
screening, where the three individual ECG tracings should be obtained as closely as 
possible in succession, but no more than two minutes apart. The full set of triplicates 
should be completed in less than five minutes. At all other visits, single ECGs will be 
collected. Any clinically significant ECG abnormalities will be captured on the eCRF.
ECGs should be performed 2 hours or longer after the last meal (with meal-time 
recorded) and before any scheduled vital sign measurements and blood draws. To 
minimize variability, it is important that participants be in a resting position for at least 10 
minutes prior to each ECG evaluation. Body position should be consistently maintained
for each ECG evaluation to prevent changes in heart rate. Environmental distractions 
(e.g., television, radio, conversation) should be avoided during the pre‑ECG resting 
period and during ECG recording. In some cases, it may be appropriate to repeat 
abnormal ECGs to rule out improper lead placement as contributing to the ECG 
abnormality. Whenever possible, the same brand/model of a standard high‑quality, high-
fidelity electrocardiograph machine equipped with computer-based interval 
measurements should be used for each participant. The conditions should be as close 
as possible to baseline conditions; this includes but is not limited to food intake, activity 
level, stressors, and room temperature. 
For safety monitoring purposes, the Investigator or designee must review, sign, and date 
all ECG tracings. Paper or electronic copies will be kept as part of the participant’s 
permanent study file at the site. Any clinically relevant changes occurring during the 
study will be recorded in the AE section of the eCRF. The recordings will be 
electronically transferred to a central ECG analysis vendor. The following parameters will 
be obtained from the digital recordings: heart rate and rhythm, QRS duration, PQ (PR), 
RR and QT intervals (QTcF) as well as information on T-wave and U-wave. 


RO6889450 (Ralmitaront) —F. Hoffmann-La Roche Ltd
70/Protocol BP40283, Version 6
8.2.4
Clinical Safety Laboratory Assessments
A central laboratory designated by the Sponsor will be used for all laboratory testing 
required during the study. The central laboratory should be used for all laboratory testing 
whenever possible (including unscheduled and follow-up laboratory testing, if needed).  
Normal ranges for the study laboratory parameters will be supplied by the central 
laboratory to the Sponsor before the study starts. A list of clinical laboratory tests to be 
performed is provided in Appendix 4 and these assessments must be conducted in 
accordance with the separate Laboratory Manual and the SoA (Section 1.3).
The Investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the eCRF. The 
laboratory reports must be filed with the source documents. Clinically significant 
abnormal laboratory findings are those that are not associated with the underlying 
disease, unless judged by the Investigator to be more severe than expected for the 
participant's condition.

In the event of unexplained abnormal clinically significant laboratory test values, the 
tests should be repeated immediately and followed up until they have returned to the 
normal range and/or an adequate explanation of the abnormality is found.

If such values do not return to normal/baseline within a period of time judged 
reasonable by the Investigator, the etiology should be identified and the Sponsor 
notified.
Results of clinical laboratory testing will be received as electronically produced 
laboratory reports submitted directly from the central laboratory.
Additional blood or urine samples may be taken at the discretion of the Investigator if the 
results of any test fall outside the reference ranges, or clinical symptoms necessitate 
additional testing to monitor participant safety.
Where the clinical significance of abnormal lab results is considered uncertain, screening 
lab tests may be repeated before randomization to confirm eligibility.
If there is an alternative explanation for a positive urine or blood test for drugs of abuse, 
e.g., previous occasional intake of a medication or food containing for example, codeine, 
or opiates, the test may be repeated to confirm washout. 
Based on continuous analysis of the data in this study and other studies, any sample 
type not considered to be critical for safety may be stopped at any time if the data from 
the samples collected does not produce useful information.
8.2.5
Suicidal Risk Monitoring 
RO6889450 is a CNS-active study drug. There has been some concern that some 
CNS-active study drugs may be associated with an increased risk of suicidal ideation or 


RO6889450 (Ralmitaront) —F. Hoffmann-La Roche Ltd
71/Protocol BP40283, Version 6
behavior. Although this study drug or other similar drugs in this class have not been 
shown to be associated with an increased risk of suicidal thinking or behavior when 
given to healthy volunteers, the Sponsor considers it important to monitor for such 
events before or during this clinical study.
Participants being treated with RO6889450 will be monitored appropriately and observed 
closely for suicidal ideation and behavior or any other unusual changes in behavior. 
Consideration should be given to discontinuing RO6889450 in participants who 
experience signs of suicidal ideation or behavior.
Families and informants of participants being treated with RO6889450 should be 
instructed to monitor participants for the emergence of unusual changes in behavior, as 
well as the emergence of suicidal ideation and behavior, and to report such symptoms 
immediately to the study Investigator.
Baseline assessment of suicidal ideation and behavior or treatment-emergent suicidal 
ideation and behavior will be monitored during the study using the C-SSRS.
The C-SSRS is a tool used to assess the lifetime suicidality of a participant (C-SSRS
baseline) as well as any new instances of suicidality (C-SSRS since last visit). The 
C-SSRS incorporates a structured interview to prompt recollection of suicidal ideation, 
including the intensity of the ideation, behavior, and attempts with actual/potential 
lethality (Posner et al 2011). The “baseline/lifetime” version will be completed at the 
screening visit and a “since last visit” version will be completed at subsequent visits. This 
assessment takes approximately 5-10 minutes to complete.
8.2.6
Extrapyramidal Symptom Rating Scale- Abbreviated Version
The presence and severity of extrapyramidal symptoms will be evaluated using the 
ESRS-A as specified in the SoA (Section 1.3) (Alphs 2010). The reliability and validity of 
the ESRS has been demonstrated in antipsychotic-induced movement disorders 
(Chouinard et al 1980, Chouinard et al 2005).  Additionally, the ESRS-A has been found 
to specifically measure movement disorders independent of changes in psychiatric 
symptoms as measured by the PANSS. The scale is organized into two main 
components: (1) an assessment of specific symptoms of Parkinsonism, dyskinesia, 
akathisia, and dystonia (2) the clinician’s global impression of these symptoms. All are 
evaluated on a scale of 0 (absent) to 5 (extreme). The ESRS-A typically takes 
10 minutes to complete.
8.2.7
Medical History and Demographic Data
Medical history includes clinically significant diseases, smoking history, use of alcohol 
and drugs of abuse and all medications (e.g., prescription drugs, OTC drugs, herbal or 
homeopathic remedies, nutritional supplements) used by the participant within 28 days 
prior to the screening visit.


RO6889450 (Ralmitaront) —F. Hoffmann-La Roche Ltd
72/Protocol BP40283, Version 6
A detailed psychiatric history will be taken during the screening period. This will include 
information regarding specific symptoms, hospitalizations, and treatment history. In 
particular, information necessary to evaluate eligibility criteria will be noted. 
Demographic data will include age, sex, and self‑reported race/ethnicity. This includes 
collection of details on the relationship between the caregiver and participant.
During screening, the Eligibility Checklist Form (ECF) will be completed which will 
include the above mentioned demographic information along with other pertinent 
information as specified on the ECF. The completed ECF will be forwarded as soon as 
possible to the Site Clinical Team Manager (CTM) or Monitor via the clinical research 
organization (CRO) electronic Protocol Inquiry Platform (ePIP) for documentation and 
monitoring purposes. The Investigator will act as final decision maker regarding 
exclusion or inclusion of participants in the study.
8.3
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS
The definitions of an AE or SAE can be found in Appendix 2. The non-serious adverse 
events of special interest and disease-related events and/or disease-related outcomes 
not qualifying as AEs or SAEs are discussed in Sections 8.3.6.
The Investigator and any qualified designees are responsible for ensuring that all 
adverse events (including assessment of seriousness, severity and causality; see 
Appendix 2) are recorded on the AE eCRF and reported to the Sponsor in accordance 
with instructions provided in this section and in Appendix 2.
Procedures used for recording AEs are provided in Appendix 3.

Diagnosis versus signs and symptoms:

AEs occurring secondary to other events

Persistent or recurrent AEs

Abnormal laboratory values

Abnormal vital sign values

Abnormal liver function tests

Deaths

Preexisting medical conditions

Lack of efficacy or worsening of schizophrenia

Hospitalization or prolonged hospitalization

Patient-reported outcome data


RO6889450 (Ralmitaront) —F. Hoffmann-La Roche Ltd
73/Protocol BP40283, Version 6
8.3.1
Time Period and Frequency for Collecting Adverse Event and 
Serious Adverse Event Information
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix 2.
Investigators will seek information on AEs at each participant’s contact. All AEs, whether 
reported by the participant or noted by study personnel, will be recorded in the 
participant’s medical record and on the AE eCRF as follows:
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention should be reported 
(e.g., serious adverse events related to invasive procedures such as biopsies). Any 
other adverse event should not be reported.
After initiation of study drug, all adverse events, regardless of relationship to study 
drug, will be reported until 28 days after the last dose of study drug. 
Post-study AEs and SAEs: The Investigator is not required to actively monitor 
participants for adverse events after the end of the AE reporting period 28 days after the 
last dose of study drug.
However, if the Investigator learns of any SAE (including a death) or other AEs of 
concern that are believed to be related to prior treatment with study drug, at any time 
after a participant has been discharged from the study, and the Investigator considers 
the event to be reasonably related to the study drug or study participation, the 
Investigator must promptly notify the Sponsor. For the procedure of reporting, see 
Appendix 2.
8.3.2
Method of Detecting Adverse Events and Serious Adverse 
Events
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended 
and non-leading verbal questioning of the participant or caregiver/informant is the 
preferred method to inquire about AE occurrence.
A consistent methodology of non-directive questioning should be adopted for eliciting AE 
information at all participant evaluation time points.
8.3.3
Follow-Up of Adverse Events and Serious Adverse Events
8.3.3.1
Investigator Follow-Up
The Investigator should follow each AE until the event has resolved to baseline grade or 
better, the event is assessed as stable by the Investigator, the event is otherwise 
explained, the participant is lost to follow-up (Section 7.3), or the participant withdraws 
consent. Every effort should be made to follow all SAEs considered to be related to 
study drug or trial-related procedures until a final outcome can be reported.


RO6889450 (Ralmitaront) —F. Hoffmann-La Roche Ltd
74/Protocol BP40283, Version 6
During the study period, resolution of AEs (with dates) should be documented on the AE 
eCRF and in the participant’s medical record to facilitate source data verification. If, after 
follow-up, return to baseline status or stabilization cannot be established, an explanation 
should be recorded on the AE eCRF.
All pregnancies reported during the study should be followed until pregnancy outcome 
and reported according to the instructions provided in Section 8.3.5.
8.3.3.2
Sponsor Follow-Up
For SAEs, non-serious AEs of special interest, and pregnancies, the Sponsor or a 
designee may follow up by telephone, fax, electronic mail, and/or a monitoring visit to 
obtain additional case details and outcome information (e.g., from hospital discharge 
summaries, consultant reports, autopsy reports) in order to perform an independent 
medical assessment of the reported case.
8.3.4
Regulatory Reporting Requirements for Serious Adverse 
Events
Prompt notification by the Investigator to the Sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety 
of a study drug under clinical investigation are met.
The Sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study drug under clinical investigation. 
The Sponsor will comply with country-specific regulatory requirements relating to safety 
reporting to the regulatory authority, IRB/Independent Ethics Committees (IEC), and 
Investigators. 
Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and Sponsor policy and forwarded to Investigators as necessary. 
An Investigator who receives an Investigator safety report describing an SAE or other 
specific safety information (e.g., summary or listing of SAEs) from the Sponsor will 
review and then file, it along with the Investigator’s Brochure, and will notify the IRB/IEC, 
if appropriate, according to local requirements.
For immediate and expedited reporting requirements from Investigator to Sponsor and 
from Sponsor to Health Authority, Investigators, IRB, and EC, see Appendix 2.
8.3.4.1
Emergency Medical Contacts
To ensure the safety of study participants, access to the Medical Monitor is available 
24 hours a day, seven days a week. The Medical Monitor’s contact details will be 
available on a separate list generated by the study management team.


RO6889450 (Ralmitaront) —F. Hoffmann-La Roche Ltd
75/Protocol BP40283, Version 6
8.3.5
Pregnancy
Female participants of childbearing potential will be instructed to immediately inform the 
Investigator if they become pregnant during the study or within 28 days after the last 
dose of study drug.
If a pregnancy is reported, the Investigator should inform the Sponsor within 24 hours of 
learning of the pregnancy and should follow the pregnancy reporting process as detailed 
in Appendix 5.
Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs (Appendix 5).
8.3.6
Non-Serious Adverse Events of Special Interest 
Non-serious adverse events of special interest are required to be reported by the 
Investigator to the Sponsor immediately (i.e., no more than 24 hours after learning of the 
event; see Appendix 2 for reporting instructions).
Non-serious adverse events of special interest for this study include the following:

Cases of an elevated ALT or AST in combination with either an elevated bilirubin or
clinical jaundice, as defined in Appendix 3.

Suspected transmission of an infectious agent by the study drug, as defined below:
o
Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-
pathogenic, is considered an infectious agent. A transmission of an 
infectious agent may be suspected from clinical symptoms or laboratory 
findings that indicate an infection in a participant exposed to a medicinal 
product. This term applies only when a contamination of the study drug is 
suspected.
8.4
TREATMENT OF OVERDOSE
The MTD of RO6889450 has been defined as 
 QD (based on tolerability 
demonstrated when administered 
 [Phase I SAD study] 
and the occurrence of only two dose limiting events [DLEs] 
 
 Phase I MAD study in healthy volunteers). Any accidental or intentional overdose 
or incorrect administration of study drug should be reported as an AE (see Appendix 2
for further details).
For RO6889450, specific information regarding treatment of overdose is currently not 
available. In the event of any AE or overdose, appropriate supportive treatment should 
be initiated according to the participant’s clinical signs and symptoms.


RO6889450 (Ralmitaront) —F. Hoffmann-La Roche Ltd
76/Protocol BP40283, Version 6
Decisions regarding dose interruptions or modifications will be made by the Investigator 
in consultation with the Medical Monitor based on the clinical evaluation of the 
participant.
In the event of an overdose, the Investigator should:
1.
Contact the Medical Monitor immediately.
2.
Closely monitor the participant for AE/SAE and laboratory abnormalities until 
resolved.
3.
Document the quantity of the excess dose, as well as the duration of the overdose, 
in the eCRF.
8.5
PHARMACOKINETICS
Blood samples for measurement of plasma concentrations of RO6889450 and derived 
metabolite(s) will be collected at the time points specified in Section 1.3. Plasma 
concentrations will be measured by a specific and validated LC-MS/MS method. 
Population PK analyses using nonlinear mixed effects modeling will be performed to 
analyze the sparse dose-plasma concentration-time data of RO6889450 and, if feasible, 
of the derived metabolite(s). The influence of covariates (e.g., weight and gender) on 
selected PK parameters (clearance and volume of distribution) will be investigated in an 
exploratory way. If deemed necessary, data may be pooled with data from other studies 
with RO6889450 (and derived metabolite[s] if available) in order to improve the 
parameter estimates of the model. The results of the analysis will be reported separately 
from the clinical study report (CSR).
Any volume of blood samples remaining after the specified analyses may also be used 
for additional assay development/validation experiments and for metabolite 
investigations.
The blood samples will be destroyed no later than two years after the date of the final 
CSR. Details on sampling procedures, sample storage, and shipment are given in the 
Sample Handling Manual.
Drug concentration information that may unblind the study will not be reported to 
investigative sites or blinded personnel until the study has been unblinded.
8.6
PHARMACODYNAMICS
Pharmacodynamic effects will not be assessed in this study.
8.7
FURTHER ASSESSMENTS
8.7.1
Mini International Neuropsychiatric Interview
The MINI (Sheehan et al 1998) is a brief, semi-structured diagnostic interview used to 
assess DSM-5 disorders and will be used to confirm the diagnosis of schizophrenia for 


RO6889450 (Ralmitaront) —F. Hoffmann-La Roche Ltd
77/Protocol BP40283, Version 6
inclusion into this study. The MINI has been validated against the Structured Clinical 
Interview for DSM diagnoses. The interview with the participant will be conducted by a 
trained clinician or mental health professional. Administration time is approximately 20 
minutes at screening visit only.
8.7.2
Wide Range Achievement Test 4 
The Wide Range Achievement Test 4 (WRAT-4, Wilkinson et al 2006) measures basic 
reading skills. The test covers ages from 5 to 75 years old and takes approximately 15-
30 minutes to administer. The WRAT-4-reading test (or an equivalent test in non-English 
speaking countries, if available) will be administered according to standard instructions, 
at screening only. The age-corrected standard score obtained will be used as pre-morbid 
IQ estimate. This assessment will not be performed in countries without validated 
translation. If validated translations become available, they may be used. Equivalent 
scales may be used, if available.
8.7.3
Wechsler Abbreviated Scale of Intelligence – Second Edition
The Wechsler Abbreviated Scale of Intelligence, Second Edition (WASI-II) is an 
intelligence test designed to estimate IQ in individuals aged 6 to 90 years (Wechsler 
2011). The Full Scale Intelligence Quotient (FSIQ) score of the four-subtest form will be 
derived based on the total combined performance on the Vocabulary, Similarities, Block 
Design, and Matrix Reasoning subtests. A Verbal Comprehension Index (VCI) 
(Vocabulary and Similarities subtests) and a Perceptual Reasoning Index (Block Design, 
Matrix Reasoning subtests) will also be derived. The WASI-II four-subtest form should 
take approximately 30 minutes to administer. This assessment will not be performed in 
countries without validated translation. If validated translations become available, they 
may be used. Equivalent scales may be used, if available.
8.8
GENETICS
8.8.1
Clinical Genotyping
A mandatory whole blood sample will be taken for DNA extraction from every participant. 
If the sample is missed on baseline, it can be collected at any other scheduled visit. The 
DNA may be used for, but analysis is not limited to:

Genetic variants of cytochrome P450s (e.g., CYP3A4, CYP3A5, CYP2C19), 
transporters (e.g., multidrug resistance protein 1 [MDR1]), receptors, or other 
proteins that might affect the metabolism, pharmacokinetics, 
pharmacodynamics, or safety of RO6889450.

Genetic variants of the TAAR1 gene.

Genetic variants of pathways related to schizophrenia and schizoaffective 
disorder, including but not limited to, genes related to disease and safety of 
RO6889450.

Genes coding for human leukocyte antigens (i.e., human leukocyte antigen [HLA] 
gene family).


RO6889450 (Ralmitaront) —F. Hoffmann-La Roche Ltd
78/Protocol BP40283, Version 6
Data arising from all biosamples including samples for analyses of inherited DNA will be 
subject to the confidentiality standards described in Section 1.4 of Appendix 1. For 
participants who consent to research biosample repository (RBR), leftover samples will 
be transferred to RBR (see Section 8.9.1), otherwise the specimen will be destroyed 
after successful analysis.
The blood samples will be destroyed within two years after the date of the final CSR. 
Details on processes for collection and shipment of these samples can be found in 
Sample Handling Manual.
8.9
BIOMARKERS
8.9.1
Samples for Research Biosample Repository
8.9.1.1
Overview of the Research Biosample Repository
The Roche RBR is a centrally administered group of facilities for the long-term storage of 
human biologic specimens, including body fluids, solid tissues, and derivatives thereof 
(e.g., DNA, RNA, proteins, peptides). The collection, storage, and analysis of these 
specimens will facilitate the rational design of new pharmaceutical agents and the 
development of diagnostic tests, which may allow for individualized drug therapy for 
patients in the future.
Specimens will be collected from participants who give specific consent to participate in 
this optional RBR. Collected specimens will be used to achieve the following objectives:

To study the association of biomarkers with efficacy, AEs, or progressive disease.

To increase knowledge and understanding of disease biology.

To study treatment response, including drug effects and the processes of drug 
absorption and disposition.

To develop biomarker or diagnostic assays and establish the performance 
characteristics of these assays.
8.9.1.2
Sample Collection
Leftover blood samples will be stored in the RBR and for additional (assay) validation 
requirements or for other research purposes, including, but not limited to, research on 
biomarkers related to RO6889450 or schizophrenia.
For all samples, dates of consent and specimen collection should be recorded on the 
associated RBR page of the eCRF. For sampling procedures, storage conditions, and 
shipment instructions, see the separate Laboratory Manual.
RBR specimens will be stored and used until two years after the provision of the CSR. 
The RBR storage period will be in accordance with the IRB/EC‑approved Informed 
Consent Form (ICF) and applicable laws (e.g., Health Authority requirements).


RO6889450 (Ralmitaront) —F. Hoffmann-La Roche Ltd
79/Protocol BP40283, Version 6
The repository specimens will be subject to the confidentiality standards (as described 
under Confidentiality and in Appendix 1).
8.10
MEDICAL RESOURCE UTILIZATION AND HEALTH 
ECONOMICS
Medical Resource Utilization and Health Economics parameters are not evaluated in this 
study.
8.11
TIMING OF STUDY ASSESSMENTS
8.11.1
Screening and Pretreatment Assessments
Written informed consent for participation in the study must be obtained before 
performing any study‑specific screening tests or evaluations. Informed Consent Forms 
for enrolled participant and for participants who are not subsequently enrolled will be 
maintained at the study site.
All screening and pretreatment assessments must be completed and reviewed to 
confirm that participants meet all eligibility criteria. The Investigator will maintain a 
screening log to record details of all participants screened and to confirm eligibility or 
record reasons for screening failure.
Screening and pretreatment assessments will be performed within three to five weeks 
prior to start of study drug on Day 1. The screening period may be extended after 
discussion with the Sponsor (Medical Monitor/designee). During screening, the ECF 
will be completed and forwarded as soon as possible to the CTM or Monitor via the
CRO ePIP for documentation and monitoring purposes. The Investigator will act as 
final decision maker regarding exclusion or inclusion of participants in the study.
In Part A of the study, all antipsychotics will be washed-out for at least one week prior to 
baseline/Day 1 (see Appendix 6 for details on atypical antipsychotic PK). Participants in 
Part A will have the option of inpatient or partial hospitalization for the washout period 
and for an additional week if they wish. 
To enter the randomized, double-blind treatment period (Part A) there must be:

No significant new or worsening psychiatric or medical illness since screening 
that in the opinion of the Investigator would interfere with the participant’s ability 
to participate in the study.

No change in medications since screening except as allowed in the concomitant 
medication section.
The treatment period begins with the investigational site call into IxRS confirming the 
participant’s eligibility as per the confirmation of eligibility at baseline (see Section 5.3).


RO6889450 (Ralmitaront) —F. Hoffmann-La Roche Ltd
80/Protocol BP40283, Version 6
8.11.2
Assessments During Treatment
Under no circumstances will participants who enroll in this study and have completed 
treatment as specified, be permitted to be allocated a new randomization number and 
re-enroll in the study.
All assessments should be performed according to the SoA (see Section 1.3). All 
assessments should be performed on the day of the specified visit, unless a time 
window is specified in the SoA. Assessments scheduled on the day of study treatment 
administration should be performed prior to administration of study treatment, unless 
otherwise noted in the SoA. Patient-reported outcome (PRO) and Clinical outcome 
assessments (COA) performed by an Investigator/rater should be performed prior to the 
completion of any other study assessments (see Section 1.3).  
If the specified order of assessments cannot be followed, every effort should be made to 
conduct ECG and vital sign assessments prior to blood draws. Please refer to 
Section 8.2.2 and 8.2.3 for further guidance. Blood samples should be taken at least 
2 hours prior to PROs and COAs being performed. In exceptional situations, visits may 
be split over two consecutive days (as per SoA). In case the baseline visit is split over 
two consecutive days, study treatment administration must be performed after all 
assessments have been performed.
On baseline/Day1 participants will be randomized to one of the treatments as shown in 
Section 6.1. Study drug is to be administered on Day 1 as described in Section 6.1, only 
after all baseline procedures and assessments are completed. Subsequently, dosing will 
continue as once daily, preferably in the morning, throughout the treatment period.
During the outpatient periods, frequent telephone contacts with the participants by a 
clinician are planned to monitor for the emergence of any clinically significant AEs, 
including signs of relapse.
8.11.3
Assessments at Study Completion/Early Termination Visit
Participants who complete the study or discontinue from the study early are to return to 
the clinic for an end-of-treatment (EOT) visit with assessments as defined in the SoA 
(Section 1.3). They are then also to return for the required follow-up visits as described 
below.
8.11.4
Follow-Up Assessments
Follow-up phone calls will be made 7 and 14 days after the last dose of study drug or 
after early termination. An additional on-site follow-up visit will be performed 28 days
after the last dose of study drug or after early termination.
After the study completion/early termination visit, AEs should be followed as outlined in 
Sections 8.3.1 and 8.3.3. 


RO6889450 (Ralmitaront) —F. Hoffmann-La Roche Ltd
81/Protocol BP40283, Version 6
9.
STATISTICAL CONSIDERATIONS
9.1
STATISTICAL HYPOTHESES 
The primary efficacy analysis for this trial will compare each dose of RO6889450 with 
placebo at Week 12 for the primary endpoint. The following null (H0) and alternative (H1) 
hypotheses will be tested at a one-sided 0.05 level: 

H0: MEANRO6889450 ≤ MEANplacebo  versus

H1: MEANRO6889450 > MEANplacebo
for which the MEANRO6889450 and MEANplacebo refer to the mean change from baseline for 
RO6889450 and placebo, respectively.  In Part B, doses will be tested sequentially, 
starting with the higher and followed by the lower dose arm to maintain Type I error at 
5% one-sided.
9.2
SAMPLE SIZE DETERMINATION
Assuming a true effect size of 0.5, a number of 50 participants per arm will provide 80% 
power to see an effect with a one-sided type I error of 0.05. Thus, the goal is to have 
50 evaluable participants per arm in Part A. Allowing for about 20% of the participants 
randomized not completing 12 weeks of treatment, approximately 125 participants will 
be randomized to Part A of the study.
 
In Part B, 50 participants per treatment arm will provide 80% power for an effect size of 
0.5 and a one-sided type I error of 0.05. Allowing for about 25% of the participants 
randomized not completing 12 weeks of treatment, the goal is to have approximately 
200 participants over all three dose groups, leading to 50 evaluable participants per 
treatment arm. In case of an unexpectedly high proportion of participants not 
completing 12 weeks of treatment (i.e. more than 25%), the number of randomized 
participants may be increased to achieve 150 patients completing 12 weeks of treatment.
These 200 participants will be recruited outside Japan. In addition to these 200 
participants, approximately 20 participants will be recruited in Japan, leading to 
approximately additional 5 evaluable participants per treatment arm. The primary 
analysis will be based on all participants recruited outside Japan and in Japan and will 
be performed when all patients from outside Japan and in Japan complete the study. 
Based on data from previously conducted studies in negative symptoms, the standard 
deviation for the change from baseline in the BNSS Avolition/Apathy Subscale 
(consisting of the sum of the two items ‘Avolition/Apathy: Behavior’ and 
‘Avolition/Apathy: Internal Experience’) at Week 12 is about 2.8. Hence, an effect size of 
0.5 translates to a reduction (versus placebo) of 1.4 points for the primary endpoint. With 
an anticipated sample size of 50 participants per arm, statistical significance at the 
one-sided type I error of 0.05, any observed reductions (versus placebo) by 


RO6889450 (Ralmitaront) —F. Hoffmann-La Roche Ltd
82/Protocol BP40283, Version 6
approximately 0.92 or more points is expected to be statistically significant.  For these 
calculations, the BNSS items are assumed to be rated on a 7-point (0–6) scale, with 
anchor points ranging from the symptom’s being absent (0) to severe (6).
9.3
POPULATIONS FOR ANALYSES
For purposes of analysis, the following populations are defined in Table 7.
Table 7
Analysis Populations
Population
Description
Modified intent-to-treat (ITT)
All randomized participants who have received at least one 
dose of study drug will be included in the efficacy population.  
Per-protocol
All randomized participants who finished 12 weeks of 
treatment without any major protocol violations and acceptable 
compliance
Safety
Same as modified ITT population. 
Pharmacokinetic
All participants who have received at least one dose of study 
drug and who have data from at least one post-dose sample 
will be included in the PK analysis population. Participants will 
be excluded from the PK analysis population if they 
significantly violate the inclusion or exclusion criteria, deviate 
significantly from the protocol, or if data are unavailable or 
incomplete that may influence the PK analysis. Excluded 
cases will be documented together with the reason for 
exclusion. All decisions on exclusions from the analysis will be 
made prior to database closure.
9.4
STATISTICAL ANALYSES
9.4.1
Demographics and Baseline Characteristics
Demographic information and baseline characteristics will be summarized for all 
participants randomized. These summaries will be provided for the Safety Population.  
Summaries will be shown by randomized treatment arm.
9.4.2
Efficacy Analyses 
The primary and secondary efficacy analyses will be based on the efficacy population 
defined in Table 7.
For the primary analysis of the primary endpoint, the model Yijk = + bi + k + tj + (t)kj + 
ijk will be used. Therein Yijk denotes the change from baseline in participant i at visit j, 
denotes the general mean, k is the fixed effect of treatment k, tj is the fixed effect of visit 
j, and bi is the baseline value of the variable analyzed for participant i. The model also 
includes the treatment-by-visit interactions (t)kj. The random errors ijk are assumed to 
be independent across different participants, while within each participant an unspecified 


RO6889450 (Ralmitaront) —F. Hoffmann-La Roche Ltd
83/Protocol BP40283, Version 6
covariance structure will be modelled. Albeit not mentioned in the model equation, 
factors other than baseline used for stratification at the time of randomization will be 
added to the model. Baseline of the variable analyzed will be included as a continuous 
covariate.
Least squares means per treatment arm as well as visit will be reported with 2-sided 
90% confidence intervals in alignment with assumptions for the sample size 
considerations.  Likewise, at each visit, differences between each active treatment arm 
and placebo will be estimated and also reported with 2-sided 90% confidence intervals. 
The comparison at Week 12 will be used to test the statistical hypothesis described in 
Section 9.1.
Analysis methods for efficacy endpoints are summarized in Table 8.


RO6889450 (Ralmitaront) —F. Hoffmann-La Roche Ltd
84/Protocol BP40283, Version 6
Table 8
Efficacy Statistical Analysis Methods
Endpoint
Statistical Analysis Methods
Primary:

Change from baseline at Week 12 in the 
BNSS avolition/apathy subscore (sum of 
items “behavior” and “internal experience”)

Repeated Measures Model as described 
in Section 9.4.2.
Secondary:

CGI-I and CGI-I negative symptoms scores

CGI-S and CGI-S negative symptoms 
scores

Percent responders and percent 
deteriorating

Change from baseline in PANSS total and 
symptom factor scores

Change from baseline in BNSS total and 
subscores

Change from baseline in DPAS scores

Similar models as described in 
Section 9.4.2 will be used for change from 
baseline endpoints of approximately 
continuous variables (e.g., PANSS, 
BNSS, DPAS, etc).

Incidence, nature and severity of AEs

Incidence, nature and severity of SAEs

Incidence, nature and severity of treatment 
discontinuations due to AEs

Change from baseline in vital signs 

Change from baseline in electrocardiogram 
(ECG) intervals: heart rate, PQ (PR), QRS, 
QT, RR and QTcF along with information on 
T- and U-waves

Incidence of laboratory abnormalities, 
based on hematology, clinical chemistry, 
coagulation and urinalysis test results

AEs will be presented as frequency tables 
with the number and percentage of 
participants experiencing AEs.

Summary statistics of raw values as well 
as changes from baseline will be 
presented for continuous safety endpoints. 

Laboratory abnormalities will be presented 
as frequency tables with the number and 
percentage of participants experiencing 
these.

To evaluate the pharmacokinetics (PK) of 
RO6889450 and RO6889450-derived 
metabolite(s).

Concentration per time point

AUCss of RO6889450 and, if feasible, of 
RO6889450-derived metabolite(s)

Cmax of RO6889450 and, if feasible, of 
RO6889450-derived metabolite(s)

Other PK parameters as appropriate
9.4.3
Safety Analyses
All safety analyses will be based on the safety analysis population grouped according to 
the treatment assigned at randomization. Analysis methods are summarized in Table 9.


RO6889450 (Ralmitaront) —F. Hoffmann-La Roche Ltd
85/Protocol BP40283, Version 6
Table 9
Safety Statistical Analysis Methods
Endpoint
Statistical Analysis Methods
Adverse events
The original terms recorded on the eCRF by the Investigator for AEs will be 
coded by the Sponsor. AEs will be summarized by mapped term and 
appropriate thesaurus level.
Clinical laboratory 
tests
All clinical laboratory data will be stored on the database in the units in 
which they were reported. Participant listings and summary statistics at 
each assessment time will be presented using the International System of 
Units (SI units; Système International d’Unités). Laboratory data not 
reported in SI units will be converted to SI units before processing.
Laboratory test values will be presented by individual listings with flagging 
of values outside the normal ranges.
Vital signs
Vital signs data (including orthostatic changes) will be presented by 
individual listings with flagging of values outside the normal ranges and 
flagging of abnormalities. In addition, tabular summaries or averaged 
graphs will be used, as appropriate.
ECG data analysis ECG data will be presented by individual listings. In addition, tabular 
descriptive summaries for the change from baseline in ECG intervals: heart 
rate, PQ (PR), QRS, QT, RR, QTcF, T- and U-waves will be displayed
Concomitant 
medications
The original terms recorded on the participants’ eCRF by the Investigator 
for concomitant medications will be standardized by the Sponsor by 
assigning preferred terms.
Concomitant medications will be presented in summary tables and listings.
C-SSRS
C-SSRS data will be presented by individual listings.
ESRS-A
ESRS-A data will be presented by individual listings.
9.4.4
Pharmacokinetic Analyses 
Population PK analyses using nonlinear mixed effects modeling will be performed as 
described in Section 8.5.
The results of the analysis will be reported separately from the CSR.
9.5
INTERIM ANALYSES
The Sponsor may choose to conduct an interim efficacy analysis in Part A. The decision 
to conduct an optional interim analysis and the timing of the analysis will be documented 
in the Sponsor’s trial master file prior to the conduct of the interim analysis. The interim 
analysis will be performed and interpreted by members of the Sponsor study team and 
appropriate senior management personnel who will be unblinded at the treatment group 
level. Access to treatment assignment information will follow the Sponsor’s standard 
procedures.
The results of this analysis may support initiation of Part B enrollment during Part A if a 
positive results threshold is met as defined in the SAP. In case of very slow recruitment, 
Part A may be stopped and/or Part B may be started without the interim analysis.


RO6889450 (Ralmitaront) —F. Hoffmann-La Roche Ltd
86/Protocol BP40283, Version 6
The Sponsor may choose to conduct up to two additional interim efficacy analyses of 
Part B to determine the chance of final success. The decision to conduct an optional
interim analysis and its timing will be documented in the Sponsor’s trial master file prior 
to the conduct of the interim analysis. The interim analysis will be performed and 
interpreted by members of the Sponsor study team who will be unblinded at the 
treatment group level. The results of such an analysis may support an early termination 
of Part B. Access to treatment assignment information will follow the Sponsor’s standard 
procedures.
The planned interim analyses will be described in detail separately. An iDMC will review 
unblinded safety and efficacy (as appropriate) data, as outlined in the “iDMC charter”. 
Additional ad-hoc meetings may be convened to evaluate safety.
9.6
SUMMARIES OF CONDUCT OF STUDY
The number of participants screened and the total number of participants randomized 
will be reported. The number of participants prematurely withdrawn from study drug and 
the study will be reported.  


RO6889450 (Ralmitaront) —F. Hoffmann-La Roche Ltd
87/Protocol BP40283, Version 6
10.
REFERENCES
Addington J, Brooks BL, Addington D. Cognitive functioning in first episode psychosis: 
initial presentation. Schizophr Res 2003;62(1-2):59-64.
Alphs L, Bossie CA, Turkoz I. Validation of the Extrapyramidal Symptoms Rating Scale–
Abbreviated in Patients With Schizophrenia, presented at ISCTM in Washington 
DC, Feb 22, 2010: 
https://isctm.org/public_access/2010_22Feb_Posters_Abstracts.pdf
Bilder RM, Volavka J, Czobor P, et al. Neurocognitive correlates of the COMT 
Val(158)Met polymorphism in chronic schizophrenia. Biol Psychiatry 
2002;52(7):701-707.
Belmaker RH, Agam G. Major depressive disorder. N Engl J Med 2008;358:5568.
Ben-Zeev D, Brian R, Wang R, et al. CrossCheck: Integrating self-report, behavioral 
sensing, and smartphone use to identify digital indicators of psychotic relapse. 
Psychiatr Rehabil J 2017;40(3):266-275.
Berry MD. Mammalian central nervous system trace amines. Pharmacologic 
amphetamines, physiologic neuromodulators. J Neurochem 2004;90(2):25771.
Berry MD. The potential of trace amines and their receptors for treating neurological and 
psychiatric diseases. Rev Recent Clin Trials 2007;2(1):319.
Branchek TA, Blackburn TP. Trace amine receptors as targets for novel therapeutics: 
legend, myth and fact. Curr Opin Pharmacol 2003;3(1):90-97.
Buchanan RW. Persistent negative symptoms in schizophrenia: an overview. Schizophr 
Bull 2007;33(4):1013-1022.
Burchett SA, Hicks TP. The mysterious trace amines: protean neuromodulators of 
synaptic transmission in mammalian brain. Prog Neurobiol 2006;79(5-6):22346.
Chakos MH, Glick ID, Miller AL, et al. Baseline use of concomitant psychotropic 
medications to treat schizophrenia in the CATIE trial. Psychiatr Serv 2006; 
57(8):1094-1101.
Censits DM, Ragland JD, Gur RC, et al. Neuropsychological evidence supporting a 
neurodevelopmental model of schizophrenia: a longitudinal study. Schizophr Res 
1997;24(3):289-98.
Chouinard G, Ross-Chouinard A, Annable L, et al. Extrapyramidal Symptom Rating 
Scale. Can J Neurol Sci. 1980; 7:233.
Chouinard G, Margolese HC. Manual for the Extrapyramidal Symptom Rating Scale 
(ESRS). Schizophr Res. 2005;76(2-3):247-265.


RO6889450 (Ralmitaront) —F. Hoffmann-La Roche Ltd
88/Protocol BP40283, Version 6
Correll CU, Rummel-kluge C, Corves C, Kane JM, Leucht S. Antipsychotic combinations 
vs monotherapy in schizophrenia: a meta-analysis of randomized controlled trials. 
Schizophr Bull. 2009;35(2):443-457.
Gold, JM, Waltz JA, Prentice KJ, Morris SE and Heerey EA. Reward Processing in 
Schizophrenia: A Deficit in the Representation of Value. Schizophr Bull. 
2008;34(5): 835-847.
Gold JM, Waltz JA, Matveeva TM, et al. Negative symptoms and the failure to represent 
the expected reward value of actions: behavioral and computational modeling 
evidence. Arch Gen Psychiatry. 2012;69(2):129-138.
Gold JM, Strauss GP, Waltz JA, et al. Negative symptoms of schizophrenia are 
associated with abnormal effort-cost computations. Biol Psychiatry. 
2013;74(2):130-136.
Grant PM, Beck AT. Defeatist beliefs as a mediator of cognitive impairment, negative 
symptoms, and functioning in schizophrenia. Schizophr Bull. 2009;35(4):798–806.
Guy W., ed. Clinical Global Impressions: In ECDEU Assessment Manual for 
Psychopharmacology. 1976; 218-222. Revised DHEW Pub. (ADM) Rockville, MD: 
National Institute for Mental Health.
Harmeier A, Obermueller S, Meyer CA, et al. Trace amine-associated receptor 1 
activation silences GSK3beta signaling of TAAR1 and D2R heteromers. Eur 
Neuropsychopharmacol. 2015;25(11):2049–2061.
Haro JM, Kamath SA, Ochoa S, et al: The Clinical Global Impression-Schizophrenia 
scale: a simple instrument to measure the diversity of symptoms present in 
schizophrenia. Acta Psychiatr Scand Suppl 2003;416:16-23.
Heatherton TF, Kozlowski LT, Frecker RC, et al. The Fagerström Test for Nicotine 
Dependence: a revision of the Fagerström Tolerance Questionnaire. Br J Addict. 
1991;86(9):1119-1127.
Hobart MP, Goldberg R, Bartko JJ, et al. Repeatable battery for the assessment of 
neuropsychological status as a screening test in schizophrenia, II: 
convergent/discriminant validity and diagnostic group comparisons. Am J 
Psychiatry 1999;156(12):1951-1957.
Howes OD, Kapur S. The dopamine hypothesis of schizophrenia: version III--the final 
common pathway. Schizophr Bull 2009;35(3):549-562.
RO6889450 Investigator’s Brochure.
Kay SR, Fiszbein A, Opler LA. The positive and negative syndrome scale (PANSS) for 
schizophrenia. Schizophr Bull. 1987;13(2):261-276
Keefe RS, Goldberg TE, Harvey PD, et al. The Brief Assessment of Cognition in 
Schizophrenia: reliability, sensitivity, and comparison with a standard 
neurocognitive battery. Schizophr Res 2004;68(2-3):283-297.


RO6889450 (Ralmitaront) —F. Hoffmann-La Roche Ltd
89/Protocol BP40283, Version 6
Keefe RS, Poe M, Walker TM, et al. The relationship of the Brief Assessment of 
Cognition in Schizophrenia (BACS) to functional capacity and real-world functional 
outcome. J Clin Exp Neuropsychol 2006;28(2):260-269.
Krause M, Zhu Y, Huhn M, et al. Antipsychotic drugs for patients with schizophrenia and 
predominant or prominent negative symptoms: a systematic review and 
meta-analysis. Eur Arch Psychiatry Clin Neurosci 2018;10.1007/s00406-018-0869-
3.
Laughren T, Levin R. Food and Drug Administration perspective on negative symptoms 
in schizophrenia as a target for a drug treatment claim. Schizophr Bull 
2006;32(2):220-222.
Lehman AF, Lieberman JA and Dixon LB. Practice Guideline for the Treatment of 
Patients With Schizophrenia second edition. American Psychiatric Association 
2010.
Lindemann L, Hoener MC. A renaissance in trace amines inspired by a novel GPCR 
family. Trends Pharmacol Sci 2005;26(5):27481.
Marder SR, Alphs L, Anghelescu I-G, et al. Issues and perspectives in designing clinical 
trials for negative symptoms in schizophrenia. Schizophr Res 2013;150(2-3):328–
333.
Marder SR, Galderisi S. The current conceptualization of negative symptoms in 
schizophrenia. World Psychiatry. 2017; 16(1):14-24.
Mas S, Gassó P, Fernández de Bobadilla R, et al. Secondary nonmotor negative 
symptoms in healthy volunteers after single doses of haloperidol and risperidone: a 
double-blind, crossover, placebo-controlled trial. Hum Psychopharmacol 
2013;28:586-93.
McGuire P, Robson P, Cubala WJ et al. Cannabidiol (CBD) as an Adjunctive Therapy in 
Schizophrenia: A Multicenter Randomized Controlled Trial. Am J Psychiatry 2018; 
175:225–231
Mohamed S, Paulsen JS, O’Leary D, et al. Generalized cognitive deficits in 
schizophrenia: a study of first-episode patients. Arch Gen Psychiatry 
1999;56(8):749-754.
Nuechterlein KH, Barch DM, Gold JM, et al. Identification of separable cognitive factors 
in schizophrenia. Schiziphr Res 2004;72(1):29-39.
Perälä J, Suvisaari J, Saarni SI, et al. Lifetime prevalence of psychotic and bipolar I 
disorders in a general population. Arch Gen Psychiatry 2007;64(1):19-28.
Posner K, Brown GK, Stanley B, et al. The Columbia-Suicide Severity Rating Scale: 
initial validity and internal consistency findings from three multisite studies with 
adolescents and adults. Am J Psychiatry 2011;168(12):1266-1277.


RO6889450 (Ralmitaront) —F. Hoffmann-La Roche Ltd
90/Protocol BP40283, Version 6
Racagni G, Popoli M. Cellular and molecular mechanisms in the long-term action of 
antidepressants. Dialogues Clin Neurosci 2008;10(4):385400.
Rapado-Castro M, Soutullo C, Fraguas D, et al. Predominance of symptoms over time in 
early-onset psychosis: a principal component factor analysis of the Positive and 
Negative Syndrome Scale. J Clin Psychiatry 2010;71(3):327-337.
Rund BR, Barder HE, Evensen J, et al. Neurocognition and duration of psychosis: a 
10-year follow-up of first-episode patients. Schizophr Bull 2016;42(1):87-95.
Ruse SA, Davis VG, Atkins AS, et al. Development of a virtual reality assessment of 
everyday living skills. J Vis Exp 2014;86: doi: 10.3791/51405.
Saykin AJ, Gur RC, Gur RE, et al. Neuropsychological function in schizophrenia. 
Selective impairment in memory and learning. Arch Gen Psychiatry 
1991;48(7):618-624.
Sen S, Sanacora G. Major depression: emerging therapeutics. Mt Sinai J Med 
2008;75(3):20425.
Sheehan DV, Lecrubier Y, Sheehan KH, et al. The Mini-International Neuropsychiatric 
Interview (M.I.N.I.): the development and validation of a structured diagnostic 
psychiatric interview for DSM-IV and ICD-10. J Clin Psychiatry 1998;59(suppl 
20):22-33.
Stahl SM, Grady MM. A critical review of atypical antipsychotic utilization: comparing 
monotherapy with polypharmacy and augmentation. Curr Med Chem 
2004;11(3):313-327.
Stahl SM, Buckley PF. Negative symptoms of schizophrenia: a problem that will not go 
away. Acta Psychiatr Scand 2007;115(1):4-11.
Strauss GP, Keller WR, Buchanan RW, et al. Next-generation negative symptom 
assessmentfor clinical trials: validation of the Brief Negative Symptom Scale. 
Schizophr Res 2012;142(1-3):88–92.
Tandon R, Keshavan MS, Nasrallah HA. Schizophrenia, "just the facts" what we know in 
2008. 2. Epidemiology and etiology. Schizophr Res 2008;102(1-3):1-18.
Torous J, Kiang MV, Lorme J,et al. New tools for new research in psychiatry: a scalable 
and customizable platform to empower data driven smartphone research. JMIR 
Ment Health. 2016;3(2):e16.
Torous J, Keshavan M. A new window into psychosis: the rise digital phenotyping, 
smartphone assessment, and mobile monitoring. Schizophr Res. 2018; S0920-
9964(18)30005-7.
Tseng PT, Chen YW, Chung W, et al. Significant effect of valproate augmentation 
therapy in patients with schizophrenia: a meta-analysis study. Medicine (Baltimore) 
2016;95(4):e2475.


RO6889450 (Ralmitaront) —F. Hoffmann-La Roche Ltd
91/Protocol BP40283, Version 6
Wang R, Aung MSH, Abdullah S,et al. CrossCheck: toward passive sensing and 
detection of mental health changes in people with schizophrenia. In Proceedings of 
the 2016 ACM International Joint Conference on Pervasive and Ubiquitous 
Computing. 2016; p 886-897. 
Wang R, Wang W, Aung MSH, et al. Predicting Symptom Trajectories of Schizophrenia 
using Mobile Sensing. Proceedings of the ACM on Interactive, Mobile, Wearable 
and Ubiquitous Technologies 2017;1(3):110.
Wechsler D. Wechsler Abbreviated Scale of Intelligence-Second Edition (WASI-II). San 
Antonio, TX: NCS Pearson, 2011.
Wilkinson GS, Robertson GJ. Wide Range Achievement Test 4 professional manual.  
Psychological Assessment Resources 2006.
Zheng W, Xiang YT, Yang XH, et al. Clozapine augmentation with antiepileptic drugs for 
treatment-resistant schizophrenia: a meta-analysis of randomized controlled Trials. 
J Clin Psychiatry 2017;78(5):e498-e505.
Zucchi R, Chiellini G, Scanlan TS, et al. Trace amine-associated receptors and their 
ligands. Br J Pharmacol 2006;149(8):96778.


RO6889450 (Ralmitaront) —F. Hoffmann-La Roche Ltd
92/Protocol BP40283, Version 6
11.
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS
The following section includes standard appendices such as Appendix 1 (for regulatory, 
ethical, and study oversight considerations), Appendix 2 (for AE definitions, reporting) 
Appendix 3 (procedures of recording), Appendix 4 (clinical laboratory tests), and 
Appendix 5 (contraceptive guidance and collection of pregnancy information). Additional 
study-related appendices are in order of appearance in the protocol: Appendix 6 Atypical 
Antipsychotic Pharmacokinetics, Appendix 7 Antipsychotic Equivalencies, Appendix 8
Calculation of Body Mass Index, Appendix 9 Evaluation to Sign Consent (example form),
and Appendix 10 Assessment of Sleep, Mood, Well-being and Cognitive Functioning
and Treatment Expectancy.


RO6889450 (Ralmitaront) —F. Hoffmann-La Roche Ltd
93/Protocol BP40283, Version 6
Appendix 1
Regulatory, Ethical, and Study Oversight Considerations
1.
REGULATORY AND ETHICAL CONSIDERATIONS
1.1.
Compliance with Laws and Regulations
This study will be conducted in full conformance with the ICH E6 guideline for Good 
Clinical Practice and the principles of the Declaration of Helsinki, or the laws and 
regulations of the country in which the research is conducted, whichever affords the 
greater protection to the individual. The study will comply with the requirements of the 
ICH E2A guideline (Clinical Safety Data Management: Definitions and Standards for 
Expedited Reporting). Studies conducted in the United States or under a U.S. 
Investigational New Drug (IND) application will comply with U.S. Food and Drug 
Administration (FDA) regulations and applicable local, state, and federal laws. Studies 
conducted in the European Union(EU)/European Economic Area will comply with the EU 
Clinical Trial Directive (2001/20/EC).
1.2.
Institutional Review Board or Ethics Committee
This protocol, the ICFs, any information to be given to the participant (e.g., 
advertisements, diaries etc), and relevant supporting information must be submitted to 
the IRB/EC by the Principal Investigator and reviewed and approved by the IRB/ ethics 
committee (EC) before the study is initiated. 
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/EC annually or more frequently in accordance with the 
requirements, policies, and procedures established by the IRB/EC. Investigators are also 
responsible for promptly informing the IRB/EC of any protocol amendments 
(Section 2.3.1 of this Appendix).
The Investigator should follow the requirements for reporting all adverse events to the 
Sponsor. Investigators may receive written IND safety reports or other safety‑related 
communications from the Sponsor. Investigators are responsible for ensuring that such 
reports are reviewed and processed in accordance with Health Authority requirements 
and the policies and procedures established by their IRB/EC, and archived in the site’s 
study file.
1.3.
Informed Consent
The Sponsor’s Master Informed Consent Form (and ancillary sample ICFs such as a 
Child’s Assent or Caregiver's Informed Consent Form, if applicable) will be provided to 
each site. If applicable, it will be provided in a certified translation of the local language. 
Participants must be informed that their participation is voluntary. Participants or their 
legally authorized representative will be required to sign a statement of informed consent 


RO6889450 (Ralmitaront) —F. Hoffmann-La Roche Ltd
94/Protocol BP40283, Version 6
that meets the requirements of 21 CFR 50, local regulations, ICH guidelines, Health 
Insurance Portability and Accountability Act (HIPAA) requirements, where applicable, 
and the IRB/IEC or study center. The Sponsor or its designee must review and approve 
any proposed deviations from the Sponsor's sample ICFs or any alternate consent forms 
proposed by the site (collectively, the “Consent Forms”) before IRB/EC submission. The 
final IRB/EC‑approved Consent Forms must be provided to the Sponsor for Health 
Authority submission purposes according to local requirements. Participants must be re-
consented to the most current version of the ICF(s) during their participation in the study. 
A copy of the ICF(s) signed by all parties must be provided to the participant or the 
participant’s legally authorized representative.
The Consent Forms must be signed and dated by the participant or the participant’s 
legally authorized representative before his or her participation in the study. During the 
consent process, the ability to comply with the study protocol must be assessed using 
the Evaluation to Sign Consent (see Appendix 9) or similar local process. The case 
history or clinical records for each participant shall document the informed consent 
process and that written informed consent was obtained prior to participation in the 
study.
The Consent Forms should be revised whenever there are changes to study procedures 
or when new information becomes available that may affect the willingness of the 
participant to take part. The final revised IRB/EC-approved Consent Forms must be 
provided to the Sponsor for Health Authority submission purposes if required as per local 
regulations.
Participants must be re-consented to the most current version of the Consent Forms (or 
to a significant new information/findings addendum in accordance with applicable laws 
and IRB/EC policy) during their participation in the study. For any updated or revised 
Consent Forms, the case history or clinical records for each participant shall document 
the informed consent process and that written informed consent was obtained using the 
updated/revised Consent Forms for continued participation in the study.
A copy of each signed Consent Form must be provided to the participant or the 
participant’s legally authorized representative. All signed and dated Consent Forms must 
remain in each participant’s study file or in the site file and must be available for 
verification by study monitors at any time.
Participants who are re-screened are required to sign a new ICF.
In this study, the caregiver will be asked to provide information useful to assess patient 
eligibility and to complete clinician rated scales. A separate written informed consent will 
be obtained from this informant.


RO6889450 (Ralmitaront) —F. Hoffmann-La Roche Ltd
95/Protocol BP40283, Version 6
Consent to Participate in the Research Biosample Repository
A separate ICF will be required to document a participant's agreement to allow any 
remaining specimens to be used for optional exploratory research. The Investigator or 
authorized designee will explain to each participant the objectives, methods, and 
potential hazards of participation in the RBR. Participants will be told that they are free to 
refuse to participate and may withdraw their specimens at any time and for any reason 
during the storage period. A separate, specific signature will be required to document a 
participant’s agreement to provide optional RBR specimens. Participants who decline to 
participate will not provide a separate signature.
The Investigator should document whether or not the participant has given consent to 
participate by completing the RBR Sample Informed Consent eCRF.
In the event of death or loss of competence of a participant who is participating in the 
research, the participant's specimens and data will continue to be used as part of the 
RBR.
For sites in the United States, each Consent Form may also include patient authorization 
to allow use and disclosure of personal health information in compliance with the U.S. 
Health Insurance Portability and Accountability Act of 1996 (HIPAA). If the site utilizes a 
separate Authorization Form for patient authorization for use and disclosure of personal 
health information under the HIPAA regulations, the review, approval, and other 
processes outlined above apply except that IRB review and approval may not be 
required per study site policies.
Approval by the Institutional Review Board or Ethics Committee
Sampling for the RBR is contingent upon the review and approval of the exploratory 
research and the RBR portion of the Informed Consent Form by each site's Institutional 
Review Board or Ethics Committee (IRB/EC) and, if applicable, an appropriate 
regulatory body. If a site has not been granted approval for RBR sampling, this section 
of the protocol will not be applicable at that site
Withdrawal from the Research Biosample Repository
Participants who give consent to provide specimens for the RBR have the right to 
withdraw their specimens at any time for any reason. If a participant wishes to withdraw 
consent to the testing of his or her specimens, the Investigator must inform the Medical
Monitor and Site Monitor in writing of the participant’s wishes using the RBR 
Withdrawal Form and, if the trial is ongoing, must enter the date of withdrawal on the 
RBR Withdrawal of Informed Consent eCRF. The participant will be provided with 
instructions on how to withdraw consent after the trial is closed. A participant's 
withdrawal from Study BP40283 does not, by itself, constitute withdrawal of specimens 
from the RBR. Likewise, a participant’s withdrawal from the RBR does not constitute 
withdrawal from Study BP40283. Data already generated before time of withdrawal of 
consent to RBR will still be used.


RO6889450 (Ralmitaront) —F. Hoffmann-La Roche Ltd
96/Protocol BP40283, Version 6
1.4.
Confidentiality
Participants will be assigned a unique identifier by the Sponsor. Any participant records 
or datasets that are transferred to the Sponsor will contain the identifier only; participant 
names or any information that would make the participant identifiable will not be 
transferred. 
The participant must be informed that his/her personal study-related data will be used by 
the Sponsor in accordance with local data protection law. The level of disclosure must 
also be explained to the participant. 
Medical information may be given to a participant’s personal physician or other 
appropriate medical personnel responsible for the participant’s welfare, for treatment 
purposes.
The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
Sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory 
authorities.
Confidentiality for Research Biosample Repository
Data generated from RBR specimens must be available for inspection upon request by 
representatives of national and local Health Authorities, and Roche monitors, 
representatives, and collaborators, as appropriate.
Participant medical information associated with RBR specimens is confidential and may 
only be disclosed to third parties as permitted by the Informed Consent Form (or 
separate authorization for use and disclosure of personal health information) signed by 
the participant, unless permitted or required by law.
Data derived from RBR specimen analysis on individual participants will generally not be 
provided to study Investigators unless a request for research use is granted. The 
aggregate results of any conducted research will be available in accordance with the 
effective Roche policy on study data publication.
Genetic research data and associated clinical data may be shared with researchers who 
are not participating in the study or submitted to government or other health research 
databases for broad sharing with other researchers. Participants will not be identified by 
name or any other personally identifying information. Given the complexity and 
exploratory nature of these analyses, genetic data and analyses will not be shared with 
Investigators or participants unless required by law.
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of the RBR specimen data will become and remain the exclusive and 
unburdened property of Roche, except where agreed otherwise.


RO6889450 (Ralmitaront) —F. Hoffmann-La Roche Ltd
97/Protocol BP40283, Version 6
Monitoring and Oversight Research Biosample Repository
Specimens collected for the RBR will be tracked in a manner consistent with Good 
Clinical Practice by a quality-controlled, auditable, and appropriately validated laboratory 
information management system, to ensure compliance with data confidentiality as well 
as adherence to authorized use of specimens as specified in this protocol and in the 
Informed Consent Form. Roche monitors and auditors will have direct access to 
appropriate parts of records relating to participant participation in RBR for the purposes 
of verifying the data provided to Roche. The site will permit monitoring, audits, IRB/EC 
review, and Health Authority inspections by providing direct access to source data and 
documents related to the samples.
1.5.
Financial Disclosure
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate Health Authorities. 
Investigators are responsible for providing information on financial interests during the 
course of the study and for one year after completion of the study (i.e., last participant, 
last visit [LPLV]).
2.
Data Handling and Record
2.1.
Data Collection and Management Responsibilities
2.1.1.
Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF 
unless transmitted to the Sponsor or designee electronically (e.g., laboratory data). The 
Investigator is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the eCRF.
The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF.
The Investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.
The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data.
Study monitors will perform ongoing source data verification to confirm that data entered 
into the eCRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that 
the study is being conducted in accordance with the currently approved protocol and any 
other study agreements, ICH GCP, and all applicable regulatory requirements.


RO6889450 (Ralmitaront) —F. Hoffmann-La Roche Ltd
98/Protocol BP40283, Version 6
2.1.2.
Clinical Outcome Assessment Data
The study will use both electronic and paper to capture clinical outcome assessment 
(COA) data. 
2.1.2.1 Electronic Clinical Outcome Assessment Data 
Participants, central raters and site clinicians will use an electronic device to complete 
electronic clinical outcome assessments (eCOAs). Data will be transmitted electronically 
to a centralized database at the eCOA vendor. The data can be reviewed by site staff via 
secure access. Entries should be reviewed for completeness by the site staff during the 
visit. Sites should only use paper forms if there are issues with the electronic device. A 
backup device will be provided to each site in the event of device issues. Once the study 
is complete, the eCOA data, audit trail, and trial and system documentation will be 
archived. The Investigator will receive patient data for the site in both human- and
machine-readable formats on an archival-quality storage device (e.g., compact disc, 
USB drive) that must be kept with the study records as source data. Acknowledgement 
of receipt of the data is required. In addition, the Sponsor will receive all patient data in a 
machine-readable format.
eCOA data will be collected using an electronic device provided by an eCOA vendor. 
The device is designed for entry of data in a way that is attributable, secure, and 
accurate, in compliance with U.S. Food and Drug Administration (FDA) regulations for 
electronic records (21 CFR Part 11). The eCOA device data are available for view via 
secure access only. Only identified and trained users may view the data, and their 
actions become part of the audit trail. The Sponsor will have access only to data 
transferred by the eCOA vendors. System backups for data stored by the Sponsor and 
records retention for the study data will be consistent with the Sponsor’s standard 
procedures.
2.1.2.2. Paper Clinical Outcome Assessment Data
Participants and raters will use paper booklets to capture COA data. All item-level, score 
data will be entered into EDC. All original forms on which participants and raters first 
record responses are source documentation as described in Section 2.1.3. of this 
Appendix. Entries on the paper forms should be reviewed for completeness by the site 
staff during the visit.
2.1.3.
Source Data Records
Source documents (paper or electronic) are those in which participant data are recorded 
and documented for the first time. They include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, COAs (paper or eCOA), 
evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies of transcriptions that are certified after verification as being accurate 


RO6889450 (Ralmitaront) —F. Hoffmann-La Roche Ltd
99/Protocol BP40283, Version 6
and complete, microfiche, photographic negatives, microfilm or magnetic media, X-rays, 
patient files, and records kept at pharmacies, laboratories, and medico‑technical 
departments involved in a clinical trial.
Before study initiation, data to be entered directly into the eCRFs (i.e., no prior written or 
electronic record of the data) and considered source data must be defined in the Trial 
Monitoring Plan.
Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed and must be retained per 
the policy for retention of records described below.
To facilitate source data verification, the Investigators and institutions must provide the 
Sponsor and Sponsor designee direct access to applicable source documents and 
reports for trial‑related monitoring, Sponsor audits, and IRB/EC review. The 
investigational site must also allow inspection by applicable Health Authorities.
2.1.4.
Use of Computerized Systems
When clinical observations are entered directly into an investigational site’s 
computerized medical record system (i.e., in lieu of original hardcopy records), the 
electronic record can serve as the source document if the system has been validated in 
accordance with Health Authority requirements pertaining to computerized systems used 
in clinical research. An acceptable computerized data collection system allows 
preservation of the original entry of data. If original data are modified, the system should 
maintain a viewable audit trail that shows the original data as well as the reason for the 
change, name of the person making the change, and date of the change.
2.2.
Retention of Records
Records and documents, including signed ICF, pertaining to the conduct of this study 
must be retained by the Investigator for at least 15 years after study completion unless 
local regulations or institutional policies require a longer retention period. No records 
may be destroyed during the retention period without the written approval of the 
Sponsor. No records may be transferred to another location or party without written 
notification to the Sponsor.
2.3.
Study Records
The Investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully reconstructed, including but not limited to the protocol, protocol 
amendments, ICFs, and documentation of IRB/EC and governmental approval. 


RO6889450 (Ralmitaront) —F. Hoffmann-La Roche Ltd
100/Protocol BP40283, Version 6
Roche shall also submit an Annual Safety Report once a year to the IEC and CAs 
according to local regulatory requirements and timelines of each country participating in 
the study.
2.3.1.
Protocol Amendments
Any substantial protocol amendments will be prepared by the Sponsor. Substantial 
protocol amendments will be submitted to the IRB/EC and to regulatory authorities in 
accordance with local regulatory requirements.
Approval must be obtained from the IRB/EC and regulatory authorities (as locally 
required) before implementation of any changes, except for changes necessary to 
eliminate an immediate hazard to patients or any non-substantial changes, as defined by 
regulatory requirements.
2.3.2.
Publication Policy
The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the Investigator agrees to submit all manuscripts or abstracts to the Sponsor 
for approval prior to submission. This allows the Sponsor to protect proprietary 
information and to provide comments based on information from other studies that may 
not yet be available to the Investigator.
The Sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter trials only in their entirety and not as individual center 
data. In this case, a coordinating Investigator will be designated by mutual agreement.
Any formal publication of the study in which contribution of Sponsor personnel exceeded 
that of conventional monitoring will be considered as a joint publication by the 
Investigator and the appropriate Sponsor personnel.
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of data from this study will become and remain the exclusive and unburdened 
property of the Sponsor, except where agreed otherwise.
2.3.3.
Dissemination of Clinical Study Data
A clinical study report containing the results of this trial will be made available to anyone 
who requests a copy. A description of this clinical trial and a summary of its results will 
be available at http://www.ClinicalTrials.gov.


RO6889450 (Ralmitaront) —F. Hoffmann-La Roche Ltd
101/Protocol BP40283, Version 6
2.3.4.
Site Inspections
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, participants’ medical records, and eCRFs. The Investigator will 
permit national and local Health Authorities, Sponsor monitors, representatives, and 
collaborators, and the IRBs/ECs to inspect facilities and records relevant to this study.
3.
Study and Site Closure
The Sponsor (or designee) has the right to suspend or terminate this study at any time. 
Reasons may include, but are not limited to, the following:

The incidence or severity of adverse events in this or other studies indicates a 
potential health hazard to participants.

Participant enrollment is unsatisfactory.

The Sponsor decides to discontinue the development program.
The Sponsor will notify the Investigator and Health Authorities if the study is placed on 
hold, or if the Sponsor decides to discontinue the study or development program.
Study sites will be closed upon study completion. A study site is considered closed when 
all required documents and study supplies have been collected and a study-site closure 
visit has been performed.
The Investigator may initiate study-site closure at any time, provided there is reasonable 
cause and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the Sponsor or Investigator may include 
but are not limited to:

Failure of the Investigator to comply with the protocol, the requirements of the 
IRB/IEC or local Health Authorities, the Sponsor's procedures, or GCP 
guidelines.

Inadequate recruitment of participants by the Investigator.

Discontinuation of further study drug development.


RO6889450 (Ralmitaront) —F. Hoffmann-La Roche Ltd
102/Protocol BP40283, Version 6
Appendix 2
Adverse Events: Definitions and Procedures for Evaluating, 
Follow-up and Reporting
1.
DEFINITION OF ADVERSE EVENTS
According to the E2A ICH guideline for Good Clinical Practice, an adverse event is any 
untoward medical occurrence in a patient or clinical investigation subject administered a 
pharmaceutical product and which does not necessarily have to have a causal 
relationship with this treatment.
An adverse event can therefore be:

Any unfavorable 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.
Events Meeting the AE Definition:

Any deterioration in a laboratory value (hematology, clinical chemistry, coagulation
or urinalysis) or other clinical test (e.g., ECG, X-ray) that is associated with 
symptoms or leads to a change in study drug or concomitant treatment or 
discontinuation from study drug.

Exacerbation of a chronic or intermittent pre-existing condition, including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study drug administration even though it 
may have been present before the start of the study.

Adverse events that are related to a protocol-mandated intervention, including those 
that occur prior to assignment of study drug (e.g., screening invasive procedures 
such as biopsies).

"Lack of efficacy" or "failure of expected pharmacological action" per se will not be 
reported as an AE or SAE. Such instances will be captured in the efficacy 
assessments. However, the signs, symptoms, and/or clinical sequelae resulting 
from lack of efficacy will be reported as AE or SAE if they fulfill the definition of an 
AE or SAE.
Events NOT Meeting the AE Definition:

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments that are associated with the underlying disease, unless judged by the 
Investigator to be more severe than expected for the participant’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the 
participant’s condition.

Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is an AE.


RO6889450 (Ralmitaront) —F. Hoffmann-La Roche Ltd
103/Protocol BP40283, Version 6

Situations where an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen.
2.
DEFINITION OF SERIOUS ADVERSE EVENTS
If an event is not an AE per definition above, then it cannot be a serious adverse event 
(SAE) even if serious conditions are met (e.g., hospitalization for signs/symptoms of the 
disease under study, death due to progression of disease).
A serious adverse event is defined as any untoward medical occurrence that at any 
dose:

Results in death

Is life-threatening
The term "life-threatening" in the definition of "serious" refers to an event in which 
the participant was at risk of death at the time of the event; it does not refer to an 
event which hypothetically might have caused death if it was more severe.

Requires inpatient hospitalization or prolongation of existing hospitalization
(see Appendix 3).
In general, hospitalization signifies that the participant has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the 
physician’s office or outpatient setting. Complications that occur during 
hospitalization are AEs. If a complication prolongs hospitalization or fulfills any other 
serious criteria, the event is serious. When in doubt as to whether “hospitalization” 
occurred or was necessary, the AE should be considered serious.
Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE.

Results in persistent or significant disability/incapacity
Disability means substantial disruption of the participant’s ability to conduct normal 
life functions.
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (e.g., sprained ankle) which may interfere with or 
prevent everyday life functions but do not constitute a substantial disruption.

Is a congenital anomaly/birth defect

Other significant events:
Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that 


RO6889450 (Ralmitaront) —F. Hoffmann-La Roche Ltd
104/Protocol BP40283, Version 6
may not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 
one of the other outcomes listed in the above definition. These events should 
usually be considered serious.
Examples of such events include invasive or malignant cancers, intensive treatment 
in an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
3.
RECORDING OF ADVERSE EVENT AND/OR SERIOUS ADVERSE 
EVENT
When an AE/SAE occurs, it is the responsibility of the Investigator to review all
documentation (e.g., hospital progress notes, laboratory reports, and diagnostics 
reports) related to the event.
The Investigator will then record all relevant AE/SAE information in the eCRF.
It is not acceptable for the Investigator to send photocopies of the participant’s medical 
records to Medical Monitor in lieu of completion of the eCRF.
There may be instances when copies of medical records for certain cases are requested 
by the Sponsor. In this case, all participant identifiers, with the exception of the 
participant number, will be redacted on the copies of the medical records before 
submission to Sponsor.
The Investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.
3.1.
Assessment of Severity
The Investigator will make an assessment of severity for each AE and SAE reported 
during the study and assign it to one of the categories provided in Table 1 (as a 
guidance for assessing adverse event severity).
The terms “severe” and “serious” are not synonymous. Severity refers to the intensity of 
an adverse event (rated as mild, moderate, or severe, or according to a pre-defined 
grading criteria [e.g., National Cancer Institute Common Terminology Criteria for 
Adverse Events [NCI CTCAE] criteria); the event itself may be of relatively minor medical 
significance (such as severe headache without any further findings).
Severity and seriousness need to be independently assessed for each adverse event 
recorded on the eCRF.


RO6889450 (Ralmitaront) —F. Hoffmann-La Roche Ltd
105/Protocol BP40283, Version 6
Serious adverse events are required to be reported by the Investigator to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event.
Table 1
Adverse Event Severity Grading Scale
Severity
Description
Mild
Discomfort noticed, but no disruption of normal daily activity
Moderate
Discomfort sufficient to reduce or affect normal daily activity
Severe
Incapacitating with inability to work or to perform normal daily activity
Note: Regardless of severity, some events may also meet seriousness criteria. Refer to 
definition of a serious adverse event (see above).
3.2.
Assessment of Causality
Investigators should use their knowledge of the participant, the circumstances 
surrounding the event, and an evaluation of any potential alternative causes to 
determine whether or not an adverse event is considered to be related to the study drug, 
indicating "yes" or "no" accordingly. The following guidance should be taken into 
consideration:

Temporal relationship of event onset to the initiation of study drug.

Course of the event, considering especially the effects of discontinuation of study 
drug

Known association of the event with the study drug or with similar treatments.

Known association of the event with the disease under study.

Presence of risk factors in the participant or use of concomitant medications 
known to increase the occurrence of the event.

Presence of non-treatment-related factors that are known to be associated with 
the occurrence of the event.
For participant receiving combination therapy, causality will be assessed individually for 
each protocol-mandated therapy.
4.
FOLLOW-UP OF ADVERSE EVENTS AND SERIOUS ADVERSE 
EVENTS
The Investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the 
Sponsor to elucidate the nature and/or causality of the AE or SAE as fully as possible. 
This may include additional laboratory tests or investigations, histopathological
examinations, or consultation with other health care professionals.


RO6889450 (Ralmitaront) —F. Hoffmann-La Roche Ltd
106/Protocol BP40283, Version 6
If a participant dies during participation in the study or during a recognized follow-up 
period, the Investigator will provide the Sponsor with a copy of any post-mortem findings 
including histopathology.
New or updated information will be recorded in the originally completed eCRF.
The Investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information.
5.
IMMEDIATE REPORTING REQUIREMENTS FROM INVESTIGATOR 
TO SPONSOR
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical trial. The Investigator must report 
such events to the Sponsor immediately; under no circumstances should reporting take 
place more than 24 hours after the Investigator learns of the event. The following is a list 
of events that the Investigator must report to the Sponsor within 24 hours after learning 
of the event, regardless of relationship to study drug:

Serious adverse events

Non-serious adverse events of special interest (NSAESI)

Pregnancies (see Section 8.3.5)

Overdoses, medication errors, drug abuse, or drug misuse associated with a 
SAE (see Appendix 2, Section 5.2 for details on reporting requirements)
The Investigator must report new significant follow-up information for these events to the 
Sponsor immediately (i.e., no more than 24 hours after becoming aware of the 
information). New significant information includes the following:

New signs or symptoms or a change in the diagnosis.

Significant new diagnostic test results.

Change in causality based on new information.

Change in the event’s outcome, including recovery.

Additional narrative information on the clinical course of the event.
Investigators must also comply with local requirements for reporting serious adverse 
events to the local Health Authority and IRB/EC.
5.1
Reporting Requirements of Serious Adverse Events and 
Non-Serious Adverse Events of Special Interest
Events that Occur prior to Study Drug Initiation


RO6889450 (Ralmitaront) —F. Hoffmann-La Roche Ltd
107/Protocol BP40283, Version 6
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention should be reported. 
The Serious Adverse Event/Adverse Event of Special Interest Reporting Form provided 
to Investigators should be completed and submitted to the Serious Adverse Event 
responsible party immediately (i.e., no more than 24 hours after learning of the event).
Events that Occur after Study Drug Initiation
For reports of serious adverse events and non-serious adverse events of special interest 
(Section 8.3.6) that occur after initiation of study drug (Section 8.3.1), Investigators 
should record all case details that can be gathered immediately (i.e., within 24 hours 
after learning of the event) on the appropriate Adverse Event of Special Interest/Serious 
Adverse Event eCRF form and submit the report via the electronic data capture (EDC) 
system. A report will be generated and sent to the Sponsor’s Safety Risk Management 
department.
In the event that the EDC system is unavailable, the Serious Adverse Event/Adverse 
Event of Special Interest Reporting Form provided to Investigators should be completed 
and submitted to the Serious Adverse Event responsible party immediately (i.e., no more 
than 24 hours after learning of the event).
Once the EDC system is available, all information will need to be entered and submitted 
via the EDC system.
Reporting of Post-Study Adverse Events and Serious Adverse Events
If the Investigator becomes aware of any other serious adverse event occurring after the 
end of the AE reporting period and if the event is believed to be related to prior study 
drug, the event should be reported directly to the Sponsor or its designee, either by 
faxing or by scanning and emailing the SAE Reporting Form using the fax number or 
email address provided to Investigators.
5.2
Reporting Requirements for Cases of Overdose, Medication 
Error, Drug Abuse, or Drug Misuse
Overdose (accidental or intentional), medication error, drug abuse, and drug misuse 
(hereafter collectively referred to as "special situations"), are defined as follows:

Accidental overdose:  accidental administration of a drug in any quantity that is 
higher than the assigned dose in any arm.

Intentional overdose:  intentional administration of a drug in any quantity that is 
higher than the assigned dose in any arm.

Medication error:  accidental deviation in the administration of a drug 
o
In some cases, a medication error may be intercepted prior to 
administration of the drug.


RO6889450 (Ralmitaront) —F. Hoffmann-La Roche Ltd
108/Protocol BP40283, Version 6

Drug abuse:  intentional excessive use of a drug that may lead to addiction or 
dependence, physical harm, and/or psychological harm.

Drug misuse:  intentional deviation in the administration of a drug that does not 
qualify as drug abuse.
o
In cases where drug is to be self-administered by the patient, drug misuse 
could involve the drug being administered to someone other than the 
patient.
Special situations are not in themselves adverse events, but may result in adverse 
events.  All special situations associated with RO6889450 or matching placebo, 
regardless of whether they result in an adverse event, should be recorded on the 
Adverse Event eCRF and should be recorded as described below:

Accidental overdose:  Enter the drug name and "accidental overdose" as the 
event term.  Check the "Accidental overdose" and "Medication error" boxes.

Intentional overdose:  Enter the drug name and "intentional overdose" as the 
event term.  Check the "Intentional overdose" box.  If drug abuse is suspected, 
check the "Drug abuse" box.  If drug abuse is not suspected, check the "Drug 
misuse" box.

Medication error that does not qualify as an overdose:  Enter the name of the 
drug administered and a description of the error (e.g., wrong dose administered, 
wrong dosing schedule, incorrect route of administration, wrong drug, expired 
drug administered) as the event term.  Check the "Medication error" box.

Medication error that qualifies as an overdose:  Enter the drug name and 
"accidental overdose" as the event term.  Check the "Accidental overdose" and 
"Medication error" boxes.  Enter a description of the error in the additional case 
details.

Intercepted medication error:  Enter the drug name and "intercepted medication 
error" as the event term.  Check the "Medication error" box.  Enter a description 
of the error in the additional case details.

Drug abuse that does not qualify as an overdose:  Enter the drug name and 
"drug abuse" as the event term.  Check the "Drug abuse" box.

Drug abuse that qualifies as an overdose:  Enter the drug name and "intentional 
overdose" as the event term.  Check the "Intentional overdose" and "Drug abuse" 
boxes.

Drug misuse that does not qualify as an overdose:  Enter the drug name and 
"drug misuse" as the event term.  Check the "Drug misuse" box.

Drug misuse that qualifies as an overdose:  Enter the drug name and "intentional 
overdose" as the event term.  Check the "Intentional overdose" and "Drug 
misuse" boxes.

Drug administered to someone other than the patient:  Enter the drug name and 
"patient supplied drug to third party" as the event term.  Check the "Drug misuse" 
box.


RO6889450 (Ralmitaront) —F. Hoffmann-La Roche Ltd
109/Protocol BP40283, Version 6
For RO6889450 or matching placebo, each adverse event associated with a special 
situation should be recorded separately on the Adverse Event eCRF.  If the associated 
adverse event fulfills seriousness criteria, the event should be reported to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Appendix 2, 
Section 5.1).  For RO6889450 or matching placebo, adverse events associated with 
special situations should be recorded as described below for each situation:

Accidental overdose:  Enter the adverse event term.  Check the "Accidental 
overdose" and "Medication error" boxes.

Intentional overdose:  Enter the adverse event term.  Check the "Intentional 
overdose" box.  If drug abuse is suspected, check the "Drug abuse" box.  If drug 
abuse is not suspected, check the "Drug misuse" box.

Medication error that does not qualify as an overdose:  Enter the adverse event 
term.  Check the "Medication error" box.

Medication error that qualifies as an overdose:  Enter the adverse event term.  
Check the "Accidental overdose" and "Medication error" boxes.

Drug abuse that does not qualify as an overdose:  Enter the adverse event term.  
Check the "Drug abuse" box.

Drug abuse that qualifies as an overdose:  Enter the adverse event term.  Check 
the "Intentional overdose" and "Drug abuse" boxes.

Drug misuse that does not qualify as an overdose:  Enter the adverse event term.  
Check the "Drug misuse" box.

Drug misuse that qualifies as an overdose:  Enter the adverse event term.  
Check the "Intentional overdose" and "Drug misuse" boxes.
As an example, an accidental overdose that resulted in a headache would require the 
completion of two Adverse Event eCRF pages, one to report the accidental overdose 
and one to report the headache.  The "Accidental overdose" and "Medication error" 
boxes would need to be checked on both eCRF pages.
6.
EXPEDITED REPORTING TO HEALTH AUTHORITIES, INVESTIGATORS, 
INSTITUTIONAL REVIEW BOARDS, AND ETHICS COMMITTEES
The Sponsor will promptly evaluate all serious adverse events and NSAESI against 
cumulative product experience to identify and expeditiously communicate possible new 
safety findings to Investigators, IRBs, ECs, and applicable Health Authorities based on 
applicable legislation.
To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events using the following reference document{s}:

RO6889450 Investigator's Brochure


RO6889450 (Ralmitaront) —F. Hoffmann-La Roche Ltd
110/Protocol BP40283, Version 6
The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document.
Reporting requirements will also be based on the Investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed.
An iDMC will monitor the incidence of these expected events during the study. An 
aggregate report of any clinically relevant imbalances that do not favor the test product 
will be submitted to Health Authorities.


RO6889450 (Ralmitaront) —F. Hoffmann-La Roche Ltd
111/Protocol BP40283, Version 6
Appendix 3
Procedures for Recording Adverse Events
Investigators should use correct medical terminology/concepts when recording adverse 
events on the Adverse Event eCRF. Avoid colloquialisms and abbreviations.
Only one adverse event term should be recorded in the event field on the Adverse Event 
eCRF.
1.
DIAGNOSIS VERSUS SIGNS AND SYMPTOMS
A diagnosis (if known) should be recorded on the Adverse Event eCRF rather than 
individual signs and symptoms (e.g., record only liver failure or hepatitis rather than 
jaundice, asterixis, and elevated transaminases). However, if a constellation of signs 
and/or symptoms cannot be medically characterized as a single diagnosis or syndrome 
at the time of reporting, each individual event should be recorded on the Adverse Event 
eCRF. If a diagnosis is subsequently established, all previously reported adverse events 
based on signs and symptoms should be nullified and replaced by one adverse event 
report based on the single diagnosis, with a starting date that corresponds to the starting 
date of the first symptom of the eventual diagnosis.
2.
ADVERSE EVENTS OCCURRING SECONDARY TO OTHER EVENTS
In general, adverse events occurring secondary to other events (e.g., cascade events or 
clinical sequelae) should be identified by their primary cause, with the exception of 
severe or serious secondary events. However, medically significant adverse events 
occurring secondary to an initiating event that are separated in time should be recorded 
as independent events on the Adverse Event eCRF. For example:

If vomiting results in mild dehydration with no additional treatment in a healthy 
adult, only vomiting should be reported on the eCRF.

If vomiting results in severe dehydration, both events should be reported 
separately on the eCRF.

If a severe gastrointestinal hemorrhage leads to renal failure, both events should 
be reported separately on the eCRF.

If dizziness leads to a fall and subsequent fracture, all three events should be 
reported separately on the eCRF.
All adverse events should be recorded separately on the Adverse Event eCRF if it is 
unclear as to whether the events are associated.
3.
PERSISTENT OR RECURRENT ADVERSE EVENTS
A persistent adverse event is one that extends continuously, without resolution, between 
participant evaluation time points. Such events should only be recorded once on the 


RO6889450 (Ralmitaront) —F. Hoffmann-La Roche Ltd
112/Protocol BP40283, Version 6
Adverse Event eCRF. The initial severity of the event should be recorded, and the 
severity should be updated to reflect the most extreme severity any time the event 
worsens. If the event becomes serious, the Adverse Event eCRF should be updated to 
reflect this.
A recurrent adverse event is one that resolves between participant evaluation time
points and subsequently recurs. Each recurrence of an adverse event should be 
recorded separately on the Adverse Event eCRF.
4.
ABNORMAL LABORATORY VALUES
Not every laboratory abnormality qualifies as an adverse event. A laboratory test result 
should be reported as an adverse event if it meets any of the following criteria:

Accompanied by clinical symptoms.

Results in a change in study drug (e.g., dosage modification, treatment 
interruption, or treatment discontinuation).

Results in a medical intervention (e.g., potassium supplementation for 
hypokalemia) or a change in concomitant therapy.

Clinically significant in the Investigator’s judgment.
It is the Investigator’s responsibility to review all laboratory findings. Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory 
abnormality should be classified as an adverse event.
If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., alkaline phosphatase and bilirubin 5 times the ULN associated with cholecystitis), 
only the diagnosis (i.e., cholecystitis) should be recorded on the Adverse Event eCRF.
If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded on the Adverse Event eCRF, along with a 
descriptor indicating if the test result is above or below the normal range (e.g., "elevated 
potassium", as opposed to "abnormal potassium"). If the laboratory abnormality can be 
characterized by a precise clinical term per standard definitions, the clinical term should 
be recorded as the adverse event. For example, an elevated serum potassium level of 
7.0 mEq/L should be recorded as “hyperkalemia”.
Observations of the same clinically significant laboratory abnormality from visit to visit 
should not be repeatedly recorded on the Adverse Event eCRF, unless the etiology 
changes. The initial severity of the event should be recorded, and the severity or 
seriousness should be updated any time the event worsens.


RO6889450 (Ralmitaront) —F. Hoffmann-La Roche Ltd
113/Protocol BP40283, Version 6
5.
ABNORMAL VITAL SIGN VALUES
Not every vital sign abnormality qualifies as an adverse event. A vital sign result should 
be reported as an adverse event if it meets any of the following criteria:

Accompanied by clinical symptoms.

Results in a change in study drug (e.g., dosage modification, treatment 
interruption, or treatment discontinuation).

Results in a medical intervention or a change in concomitant therapy.

Clinically significant in the Investigator’s judgment.

It is the Investigator’s responsibility to review all vital sign findings. Medical and 
scientific judgment should be exercised in deciding whether an isolated vital sign 
abnormality should be classified as an adverse event.

If a clinically significant vital sign abnormality is a sign of a disease or syndrome 
(e.g., high blood pressure), only the diagnosis (i.e., hypertension) should be 
recorded on the Adverse Event eCRF.
Observations of the same clinically significant vital sign abnormality from visit to visit 
should not be repeatedly recorded on the Adverse Event eCRF, unless the etiology 
changes. The initial severity of the event should be recorded, and the severity or 
seriousness should be updated any time the event worsens.
6.
ABNORMAL LIVER FUNCTION TESTS
The finding of an elevated ALT or AST (3ULN) in combination with either an elevated 
total bilirubin (2ULN) or clinical jaundice in the absence of cholestasis or other 
causes of hyperbilirubinemia is considered to be an indicator of severe liver injury. 
Therefore, Investigators must report as an adverse event the occurrence of either of the 
following:

Treatment-emergent ALT or AST3ULN in combination with total 
bilirubin2ULN.

Treatment-emergent ALT or AST3ULN in combination with clinical jaundice.
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF and reported to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event), either as a 
serious adverse event or a non-serious adverse event of special interest.
7.
DEATHS
All deaths that occur during the protocol-specified adverse event reporting period (see 
Section 5 of Appendix 2), regardless of relationship to study drug, must be recorded on 


RO6889450 (Ralmitaront) —F. Hoffmann-La Roche Ltd
114/Protocol BP40283, Version 6
the Adverse Event eCRF and immediately reported to the Sponsor. This includes death 
attributed to progression of schizophrenia.
Death should be considered an outcome and not a distinct event. The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF. Generally, only one such event should be 
reported. If the cause of death is unknown and cannot be ascertained at the time of 
reporting, “unexplained death” should be recorded on the Adverse Event eCRF. If the 
cause of death later becomes available (e.g., after autopsy), “unexplained death” should 
be replaced by the established cause of death. The term "sudden death" should not be 
used unless combined with the presumed cause of death (e.g., "sudden cardiac death").
8.
PREEXISTING MEDICAL CONDITIONS
A preexisting medical condition is one that is present at the screening visit for this study. 
Such conditions should be recorded on the General Medical History and Baseline 
Conditions eCRF.
A preexisting medical condition should be recorded as an adverse event only if the 
frequency, severity, or character of the condition worsens during the study. When 
recording such events on the Adverse Event eCRF, it is important to convey the concept 
that the preexisting condition has changed by including applicable descriptors 
(e.g., “more frequent headaches”).
9.
LACK OF EFFICACY OR WORSENING OF SCHIZOPHRENIA
Medical occurrences or symptoms of deterioration that are anticipated as part of 
schizophrenia should be recorded as an adverse event if judged by the Investigator to 
have unexpectedly worsened in severity or frequency or changed in nature at any time 
during the study. When recording an unanticipated worsening of schizophrenia on the 
Adverse Event eCRF, it is important to convey the concept that the condition has 
changed by including applicable descriptors (e.g., “worsening of schizophrenia”).
10. HOSPITALIZATION OR PROLONGED HOSPITALIZATION
Any adverse event that results in hospitalization or prolonged hospitalization should be 
documented and reported as a serious adverse event (per the definition of serious 
adverse event in Appendix 2), except as outlined below.
An event that leads to hospitalization under the following circumstances should not be 
reported as an adverse event or a serious adverse event:

Hospitalization for respite care or social management

Planned hospitalization required by the protocol (e.g., for wash-out of previous 
medication) 


RO6889450 (Ralmitaront) —F. Hoffmann-La Roche Ltd
115/Protocol BP40283, Version 6

Hospitalization for a preexisting condition, provided that all of the following 
criteria are met:
o
The hospitalization was planned prior to the study or was scheduled 
during the study when elective surgery became necessary because of the 
expected normal progression of the disease.
o
The participant has not suffered an adverse event.
An event that leads to hospitalization under the following circumstances is not 
considered to be a serious adverse event, but should be reported as an adverse event 
instead:
1. Hospitalization for an adverse event that would ordinarily have been treated in an 
outpatient setting had an outpatient clinic been available.

11. PATIENT-REPORTED OUTCOME DATA (COA DATA REPORTED DIRECTLY BY 
PATIENT)
Adverse event reports will not be derived from PRO data by the Sponsor, and safety 
analyses will not be performed using PRO data. However, if any PRO responses 
suggestive of a possible adverse event are identified during site review of the PRO data, 
the Investigator will determine whether the criteria for an adverse event have been met 
and, if so, will report the event on the Adverse Event eCRF. 


RO6889450 (Ralmitaront) —F. Hoffmann-La Roche Ltd
116/Protocol BP40283, Version 6
Appendix 4
Clinical Laboratory Tests
The tests detailed in Table 1, with the exception of urinalysis, urine dipstick alcohol test, 
drugs of abuse, and urine pregnancy test, will be performed by the central laboratory.
Local laboratory results may be utilized in the event that the central laboratory results 
are not available in time for either study drug administration and/or response evaluation. 
If a local sample is required, with the exception of urinalysis, drugs of abuse, and urine 
pregnancy test. It is important that the sample for central analysis is obtained at the 
same time. 
Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Sections 5.1 and 5.2, respectively, of the protocol.
Additional tests may be performed at any time during the study as determined necessary 
by the Investigator or required by local regulations.
Table 1
Protocol-Required Safety Laboratory Assessments
All study-required laboratory assessments with the exception of urinalysis, urine dipstick 
alcohol test, drugs of abuse, and urine pregnancy test, will be performed by a central 
laboratory. In cases where an immediate result is required for a particular laboratory test, 
the sample can be divided and sent to both a local laboratory and the designated central 
laboratory.


RO6889450 (Ralmitaront) —F. Hoffmann-La Roche Ltd
117/Protocol BP40283, Version 6
Laboratory Assessments
Parameters
Hematology

Leucocytes, erythrocytes, hemoglobin, hematocrit, 
platelets, differential count (neutrophils, eosinophils, 
basophils, monocytes, lymphocytes, other cells).
Clinical Chemistry and Lipids

Sodium, potassium, chloride, bicarbonate, glucose, 
urea, creatinine, protein, albumin, phosphate, calcium, 
total and direct bilirubin, alkaline phosphatase, ALT, 
AST, urate, lactate dehydrogenase, glycated 
hemoglobin, fructosamine, C reactive protein (CRP).

Prolactin (all patients), follicle stimulating hormone 
(FSH, post-menopausal females, as applicable)

Cholesterol, low density lipoprotein cholesterol, high 
density lipoprotein cholesterol, triglycerides.
Coagulation

PT, aPTT and INR
Viral Serology

PCR COVID-19 testing, or other COVID-19 
diagnostic tests when available. HIV (specific tests 
HIV-1 antibody, HIV-1/2 antibody, HIV-2 antibody), 
HBsAg, HCV antibody. In cases where HCV was 
successfully treated, a positive HCV serology result 
can be followed by HCV RNA testing. 
Pregnancy Test

All WOCBP (including those who have had a tubal 
occlusion) will have a blood pregnancy test at 
screening. Urine pregnancy tests will be performed at 
specified subsequent visits. If a urine pregnancy test is 
positive, it must be confirmed by a blood pregnancy 
test.

Serum or urine human chorionic gonadotropin (hCG) 
pregnancy test (as needed for women of childbearing 
potential).
Urinalysis

Specific gravity

Dipstick: pH, glucose, protein, blood, ketones, bilirubin, 
urobilinogen, nitrite, leukocyte esterase

If there is a clinically significant positive result 
(confirmed by a positive repeated sample), urine will 
be sent to the laboratory for microscopy and culture. If 
there is an explanation for the positive dipstick results 
(e.g., menses), it should be recorded and there is no 
need to perform microscopy and culture.
Microscopic examination if deemed necessary will 
include sediment, RBCs, WBCs, casts, crystals, 
epithelial cells, and bacteria.
Other Screening Tests

Drugs of abuse will be measured in urine: 
cannabinoids, amphetamines, methamphetamines, 
opiates, buprenorphine, methadone, cocaine, 
benzodiazepines, and barbiturates.

Alcohol levels will be tested using a urine dipstick test.


RO6889450 (Ralmitaront) —F. Hoffmann-La Roche Ltd
118/Protocol BP40283, Version 6
Laboratory Assessments
Parameters
Antipsychotic drug level

Blood samples will be tested for the antipsychotic(s) 
noted at screening. Testing of blonanserin and 
perospirone cannot be performed by the central 
laboratory. Therefore, no blood samples to assess 
antipsychotic drug levels will be drawn for 
participants being currently treated with blonanserin 
and/ or perospirone. Participants currently treated 
with other antipsychotics in addition to blonanserin 
or perospirone will have blood samples taken to assess 
antipsychotic blood levels. Antipsychotic medication 
compliance of participants taking blonanserin or 
perospirone will be monitored via informant report 
and recorded in the eCRF. 
The results of each test will be transferred to Roche electronically by the laboratory 
vendor.
Investigators must document their review of each laboratory safety report.
Additional Statistical Considerations for Clinical Laboratory Data

Standard Reference Ranges and Transformation of Data
Roche standard reference ranges, rather than the reference ranges of the Investigator, 
will be used for all parameters. For most parameters, the measured laboratory test result 
will be assessed directly using the Roche standard reference range. Certain laboratory 
parameters will be transformed to Roche’s standard reference ranges.
A transformation will be performed on certain laboratory tests that lack sufficiently 
common procedures and have a wide range of Investigator ranges, e.g., enzyme tests 
that include AST, ALT, and alkaline phosphatase and total bilirubin. Since the standard 
reference ranges for these parameters have a lower limit of zero, only the upper limits of 
the ranges will be used in transforming the data.

Definition of Laboratory Abnormalities
For all laboratory parameters included, there exists a Roche predefined standard 
reference range. Laboratory values falling outside this standard reference range will be 
labeled “H” for high or “L” for low in participant listings of laboratory data.
In addition to the standard reference range, a marked reference range has been 
predefined by Roche for each laboratory parameter. The marked reference range is 
broader than the standard reference range. Values falling outside the marked reference 
range that also represent a defined change from baseline will be considered marked 
laboratory abnormalities (i.e., potentially clinically relevant). If a baseline value is not 
available for a participant, the midpoint of the standard reference range will be used as 
the participant’s baseline value for the purposes of determining marked laboratory 


RO6889450 (Ralmitaront) —F. Hoffmann-La Roche Ltd
119/Protocol BP40283, Version 6
abnormalities. Marked laboratory abnormalities will be labeled in the participant listings 
as “HH” for very high or “LL” for very low.


RO6889450 (Ralmitaront) —F. Hoffmann-La Roche Ltd
120/Protocol BP40283, Version 6
Appendix 5
Contraceptive Guidance and Collection of Pregnancy 
Information
1.
DEFINITIONS

Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile.

Women in the following categories are considered to be Woman of Non-
Childbearing Potential 
a)
Pre-menarchal
b)
Pre-menopausal female with one of the following:
–
Documented hysterectomy.
–
Documented bilateral salpingectomy.
–
Documented bilateral oophorectomy.
Note: Documentation can come from the site personnel’s: review of 
participant’s medical records, medical examination, or medical history interview.
c)
Post-menopausal female
–
A post-menopausal state is defined as no menses for 12 months without an 
alternative medical cause other than menopause. A high follicle-stimulating 
hormone (FSH) level in the post-menopausal range may be used to confirm a 
post-menopausal state in women not using hormonal contraception or hormonal 
replacement therapy (HRT). However, in the absence of 12 months of amenorrhea, 
a single FSH measurement is insufficient.
–
Females on HRT and whose menopausal status is in doubt will be required to use 
one of the non-hormonal highly effective contraception methods if they wish to 
continue their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of post-menopausal status before study enrollment.
2.
CONTRACEPTION GUIDANCE

Female Participants
The reliability of sexual abstinence should be evaluated in relation to the duration of the 
clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., 
calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not 
acceptable methods of contraception. Female participants of childbearing potential are 


RO6889450 (Ralmitaront) —F. Hoffmann-La Roche Ltd
121/Protocol BP40283, Version 6
eligible to participate if they agree to use an effective method of contraception 
consistently and correctly as described in Table 1 below.
Table 1
Acceptable Contraceptive Methods
Highly Effective Contraceptive Methods That Are User-Dependenta
(Failure rate of 1% per year when used consistently and correctly)
Combined (estrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulation

Oral

Intravaginal

Transdermal
Progestogen-only hormonal contraception associated with inhibition of ovulation

Oral

Injectable
Less Effective Contraceptive Methods That Are User Dependent 

Male or female condom with or without spermicide

Cap, diaphragm, or sponge with spermicide
Highly Effective Methods That Are User-Independenta
Implantable progestogen-only hormonal contraception associated with inhibition of ovulation

Intrauterine device (IUD)

Intrauterine hormone-releasing system (IUS)

Bilateral tubal occlusion
Vasectomized partner
A vasectomized partner is a highly effective contraception method provided that the partner is 
the sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. If 
not, an additional highly effective method of contraception should be used.
a) Typical use failure rates may differ from those when used consistently and correctly. Use 
should be consistent with local regulations regarding the use of contraceptive methods for 
participants participating in clinical studies.
3.
PREGNANCY TESTING
For WOCBP enrolled in the study, blood sample and urine pregnancy tests will be 
performed according to Schedule of Activity tables (see Section 1.3). If a urine 
pregnancy test is positive, it must be confirmed by a blood pregnancy test.
Pregnancy testing will be performed whenever a menstrual cycle is missed or when 
pregnancy is otherwise suspected and according to local practice.


RO6889450 (Ralmitaront) —F. Hoffmann-La Roche Ltd
122/Protocol BP40283, Version 6
4.
COLLECTION OF PREGNANCY INFORMATION

Female participants who become pregnant
The Investigator will collect pregnancy information on any female participant, who 
becomes pregnant while participating in this study (see Section 8.3.5 Pregnancy). 
Information will be recorded on the appropriate form and submitted to the Sponsor within 
24 hours of learning of a participant's pregnancy. The participant will be followed to 
determine the outcome of the pregnancy. The Investigator will collect follow-up 
information on the participant and the neonate, which will be forwarded to the Sponsor. 
Monitoring of the participant should continue until conclusion of the pregnancy. Any 
termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for procedure.
While pregnancy itself is not considered to be an AE or SAE, and should not be 
recorded on the AE eCRF, any pregnancy complication will be reported as an AE or 
SAE. A spontaneous abortion is always considered to be an SAE and will be reported as 
such. Any post-study pregnancy related SAE considered reasonably related to the study 
drug by the Investigator, will be reported to the Sponsor as described in Appendix 2.
While the Investigator is not obligated to actively seek this information in former study 
participants, he/she may learn of an SAE through spontaneous reporting.
Any female participant who becomes pregnant while participating in the study will be 
withdrawn from the study.
5
ABORTIONS
Any spontaneous abortion should be classified as a serious adverse event (as the 
Sponsor considers spontaneous abortions to be medically significant events), recorded 
on the Adverse Event eCRF, and reported to the Sponsor immediately (i.e., no more 
than 24 hours after learning of the event; see Section 5 of Appendix 2).
Any induced abortion due to maternal toxicity and/or embryo-fetal toxicity should also be 
classified as serious adverse event, recorded on the Adverse Event eCRF, and reported 
to the Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5 of Appendix 2).
Elective abortion not associated with toxicity (e.g., induced abortion for personal 
reasons) does not require expedited reporting but should be reported as outcome of 
pregnancy on the Clinical Trial Pregnancy Reporting Form.


RO6889450 (Ralmitaront) —F. Hoffmann-La Roche Ltd
123/Protocol BP40283, Version 6
6
CONGENITAL ANOMALIES/BIRTH DEFECTS
Any congenital anomaly/birth defect in a child born to a female participant exposed to 
study drug should be classified as a serious adverse event, recorded on the Adverse 
Event eCRF (prior to database lock), and reported to the Sponsor immediately (i.e., no
more than 24 hours after learning of the event; see Section 5 of Appendix 2).


RO6889450 (Ralmitaront) —F. Hoffmann-La Roche Ltd
124/Protocol BP40283, Version 6
Appendix 6
Atypical Antipsychotic Pharmacokinetics
Generic
Brand
Half-life
Washout 
duration 
needed
Testing 
Available 
from 
Central 
Lab
Permitted 
in Part A* 
(washout 
time 
compatibl
e)
Permitted in 
Part B** (IxRS 
stratification)
Aripiprazole
Abilify1
Abilify 
Maintena
Aristada
~75 hours, 
metabolite:  
~94 hours 
PM: ~146 
hours
LAI: 30-57 
days
2 weeks
LAI: 40 
weeks
X
X
LAI not 
permitted
D2 partial 
agonist
Asenapine
Saphris2
~24 hours
(mean)
1 week
X
X
D2/5HT2A 
antagonists
Brexpiprazole
Rexulti3
91 hours
3 weeks
X
Not 
permitted
D2 partial 
agonist
Blonanserin
Lonasen
~95.5 hours
approxim
ately 
20 days
X
Not 
permitted
D2/5HT2A 
antagonists
Cariprazine
Vraylar4
2-4 days, 
metabolite: 1-3 
weeks
15 weeks
X
Not 
permitted
D2 partial
agonist
Chlorpromazine5
Thorazine
30 hours
1 weeks
X
X
D2/5HT2A 
antagonists
Clozapine
Clozaril
Not permitted during the study. Not permitted within 5 years prior to 
screening for treatment of schizophrenia and within 12 months prior to 
screening for treatment of insomnia and dyskinesia (< 200 mg/day).
Fluphenazine6
Prolixin
~15 hours
LAI: 6.8-9.6 
days
1 weeks
LAI: 7 
weeks
X
X
LAI not 
permitted
D2/5HT2A 
antagonists
Haloperidol7
Haldol
IM: 20 hours
IV: 14-26 
Hours
PO: 14-37 
hours
LAI: 3 weeks
IM/IV/PO: 
1 week
LAI: 15 
weeks
X
X
LAI not 
permitted
D2/5HT2A 
antagonists
Iloperidone
Fanapt8
EM: 18 hours, 
metabolites: 
23-26 hours
PM: 33hrs, 
metabolites: 
31-37 hours
1 week
X
X
D2/5HT2A 
antagonists


RO6889450 (Ralmitaront) —F. Hoffmann-La Roche Ltd
125/Protocol BP40283, Version 6
Generic
Brand
Half-life
Washout 
duration 
needed
Testing 
Available 
from 
Central 
Lab
Permitted 
in Part A* 
(washout 
time 
compatibl
e)
Permitted in 
Part B** (IxRS 
stratification)
Loxapine
Adasuve, 
Loxitane9
~8 hours
1 week
X
X
D2/5HT2A 
antagonists
Lurasidone HCl
Latuda10
~18 hours 
(mean)
1 week
X
X
D2/5HT2A 
antagonists
Molindone11
Moban
2 hours
1 week
X
X
D2/5HT2A 
antagonists
Olanzapine
Zyprexa12
Zyprexa 
Relprevv
21-54 hours
LAI: 30 days
2 weeks
LAI: 20 
weeks
X
X
LAI not 
permitted
D2/5HT2A 
antagonists
Paliperidone
Invega13
(ext-rel 
tabs)
~23 hours
1 week
LAI: 35 
weeks
X
X
LAI not 
permitted
D2/5HT2A 
antagonists
Perphenazine
Trilafon14
9-12 hours, 
metabolite: 10-
19 hours
1 week
X
X
D2/5HT2A 
antagonists
Prochlorperazin
e15
Compazine
~9 hours
1 week
X
X
D2/5HT2A 
antagonists
Perospirone
Lullan
1 - ~8 hours
approxim
ately 40 h
X
X
D2/5HT2A 
antagonists
Quetiapine 
fumarate
Seroquel16
Seroquel 
XR17
~6 hours
~7 hours 
(quetiapine), 
metabolite: 12 
hours
1 week
X
X
D2/5HT2A 
antagonists
Risperidone
Risperdal18
Risperdal 
Consta
EM: 3 hours, 
PM: 20 hours
LAI: 3-6 days
1 week
LAI: 4 
weeks
X
X
LAI not 
permitted
D2/5HT2A 
antagonists
Trifluoperazine19
Stelazine
24 hours
1 week
X
X
D2/5HT2A 
antagonists
Ziprasidone HCl
Geodon20
~7 hours
1 week
X
X
D2/5HT2A 
antagonists
Key: EM = extensive metabolizers; ext-rel = extended-release; PM = poor metabolizers, LAI = long-acting 
injectable
Not an inclusive list of medications (Rev. 1/2018). 
(https://media.empr.com/documents/22/psyc_aap_0118_5255.pdf)
* Antipsychotics (AP) that require a washout of >2 weeks (i.e., LAIs, brexpiprazole, cariprazine) will not be 
permitted in Part A.  In Part A, AP treatment does not need to be stable for six months prior to enrollment as 


RO6889450 (Ralmitaront) —F. Hoffmann-La Roche Ltd
126/Protocol BP40283, Version 6
long as treatment changes are not related to a psychotic exacerbation. AP levels at screening in Part A are 
intended to be used by the investigator as one of several elements to assess the participant’s compliance, 
reliability and expected adherence to the study protocol. Patients without detectable blood levels of AP 
medication (or active metabolites) may be enrolled in Part A if they have not taken AP medication for a short 
time prior to screening (e.g., a period of several weeks). For patients without AP levels at baseline, the 
washout period may be skipped if considered appropriate by the investigator after discussion with the 
medical monitor or sponsor and a 1 week placebo compliance period monitored with the AiCure Adherence 
App may be considered appropriate. If a patient is taking one of the long-acting treatments marked as not 
permitted in Appendix 6 at the time of screening, the patient is not eligible since the treatment requires a 
washout period longer than the protocol allows. These treatments should not be stopped for the purpose of 
entering the study. If a patient has taken any of these medications in the 6 months prior to screening and 
stopped them for reasons unrelated to the study the patient may be eligible upon consultation with the 
medical monitor.
** Participants in Part B will be stratified based on their antipsychotic treatment (1:1 stratification ratio 
between D2/5HT2A antagonists and D2 partial agonist). In Part B, the screening sample is used as proxy of 
treatment compliance and if no blood concentration of the prescribed AP medication (or active metabolites) 
are detected, the participant should not be enrolled.
1.
Abilify [package insert]. Rockville, MD: Otsuka Pharmaceutical Co. 2014
2.
Saphris [package insert]. Parsippany, NJ: Actavis. 2015
3.
Rexulti [package insert]. Rockville, MD: Otsuka Pharmaceutical Co. 2018
4.
Vraylar [package insert]. Parsippany, NJ: Actavis. 2015
5.
"Chlorpromazine Hydrochloride". The American Society of Health-System Pharmacists. Archived 
from the original on 8 December 2015.
6.
"Fluphenazine decanoate". The American Society of Health-System Pharmacists. Archived from 
the original on 2015-12-08
7.
Kudo S, Ishizaki T. Pharmacokinetics of haloperidol: an update. Clin Pharmacokinet. 
1999;37(6):435-56.
8.
Fanapt [package insert]. Rockville, MD: Vanda Pharmaceuticals Inc. 2009
9.
Adasuve [package insert]. Mountain View, CA.  Alexza Pharmaceuticals, Inc. 2012.
10. Latuda [package insert]. Fort Lee, NJ: Sunovion Pharmaceuticals Inc. 2010
11. Zetin M, Cramer M, Garber D, et al. Bioavailability of oral and intramuscular molindone 
hydrochloride in schizophrenic patients. Clin Ther. 1985;7(2):169-75.
12. Zyprexa [package insert]. Indianapolis, IN: Eli Lilly and Co. 2009.
13. Invega [package insert]. Titusville, NJ: Janssen Pharmaceuticals Inc. 2010.
14. Trilafon [package insert]. Kenilworth, NJ: Schering Corporation. 2002.
15. Toxnet: Toxicology Data Network: Prochlorperazine. https://toxnet.nlm.nih.gov/cgi-
bin/sis/search/a?dbs+hsdb:@term+@DOCNO+3171
16. Seroquel [package insert]. Wilmington, DE: AstraZeneca. 2003
17. Seroquel XR [package insert]. Wilmington, DE: AstraZeneca. 2009
18. Risperdal [package insert]. Titusville, NJ: Janssen Pharmaceuticals Inc. 2009


RO6889450 (Ralmitaront) —F. Hoffmann-La Roche Ltd
127/Protocol BP40283, Version 6
19. American Psychiatric Association. Practice guideline for the treatment of patients with 
schizophrenia, second edition. Am J Psychiatry. 2004; 161(Suppl):1-56.
20. Geodon [package insert]. New York, NY: Pfizer Inc. 2008




RO6889450 (Ralmitaront) —F. Hoffmann-La Roche Ltd
129/Protocol BP40283, Version 6
Appendix 8
Calculation of Body Mass Index
Formula for calculation of BMI
BMI =
Weight (kg)
Height (m)2
Unit Conversion:    1 kg = 2.2 lbs
1 inch = 2.54 cm
Example: BMI of a participant being 1.70 m tall and weighing 80 kg:
80 kg
= 27.7 kg/m2
(1.70 m)2
The participant’s standing height will be measured in bare feet standing with his/her 
heels and back in contact with the vertical bar of a wall mounted measuring device. The 
head is held so the participant looks straight forward. A level will be placed on the 
participant’s head to ensure that the participant is looking straight forward. The point at 
which the lower surface of the level intersects with the vertical measuring device will be 
the standing height. BMI calculation will be rounded to the unit, so a BMI of 17.50 or 
40.49 will be rounded to 18 and 40, respectively.


RO6889450 (Ralmitaront) —F. Hoffmann-La Roche Ltd
130/Protocol BP40283, Version 6
Appendix 9
Evaluation to Sign Consent (example form)
Evaluation to Sign Consent (ESC)
Form Version: 1/15/16 JMP
MPRCID#:  ___ ___ ___ ___ ___ ___ ___
Program ID:  ___ ___ ___
Date of Rating: ____/____/____
Subject Initials:  ___ ___
Rater ID:  ___ ___
Rater Initials:  ___ ___
Protocol ID#:  
Protocol Name:  
PROCEDURE:
Make a subjective judgement regarding item 1 below.  Ask the patient questions 2-6.  The evaluator 
may select the language to use in asking the questions in order to help the patient understand them. 
ITEMS:
SCORE
1. Is the patient alert and able to communicate with the examiner?
_______
yes = 2
no = 0
2. Ask the patient to name at least two (2) potential risks incurred as a result of participating in 
the study. 0=not able to list potential risks,  1= able to list one risk,  2 =able to list two risks
_______
_____________________________________________________________________________
_____________________________________________________________________________
3. Ask the patient to name at least two (2) things that will be expected of him/her in terms of patient
cooperation during the study.  0=not able to list expectations,  1= able to list one expectation, 
2=able to list two expectations
_______
__________________________________________________________________________________
__________________________________________________________________________________
4.
Ask the patient to explain what he/she would do if he/she decides that they no longer wish to
participate in the study. 0=doesn’t know, 1=answers but not the most appropriate response, 
2=talk to any staff member
_______
__________________________________________________________________________________
__________________________________________________________________________________
5.
Ask the patient to explain what he/she would do if he/she is experiencing distress or discomfort. 
0=doesn’t know, 1=answers but not the most appropriate response, 2=talk to any staff member
_______
__________________________________________________________________________________
__________________________________________________________________________________
6.
Ask the patient to explain how medications (or treatments) are assigned during the study.
0=doesn’t know, 1=answers but not the most appropriate response, 
_______
   2=able to explain randomization procedures
__________________________________________________________________________________
__________________________________________________________________________________
SIGNATURE:
I hereby certify that the above patient is alert, able to communicate and able to give acceptable 
answers to items 2,3,4,5 and 6 above.
              
Total Score
_______
___________________
__ __/__ __/__ __ __ __ 
(Evaluator Signature)
(Date signed) 


RO6889450 (Ralmitaront) —F. Hoffmann-La Roche Ltd
131/Protocol BP40283, Version 6
Appendix 10
Assessment of Sleep, Mood, Well-being and Cognitive 
Functioning and Treatment Expectancy
Sleep (treatment period)
“How did you sleep last night?”
Mood & Well-being (treatment period)
“How are you feeling today?”
“How is your energy level today?”
Cognitive Functioning (treatment period)
“How is your concentration and memory today?”
Treatment Expectation (baseline visit only)
“Do you expect that the study drug will help you?”
Treatment Expectation (treatment period)
“Do you think the drug is helping you?”
Treatment Expectation (Day 84 ±2)
“Do you think you were taking placebo or study drug?”
Placebo 
☐
Study drug
☐

SAP_001.pdf: 
Official Title: Phase 2, Randomized, Double-Blind, Placebo-Controlled Study to 
Assess the Effects of RO6889450 (Ralmitaront) in Patients With 
Schizophrenia or Schizoaffective Disorder and Negative Symptoms 
NCT Number: NCT03669640 
Document Dates: SAP Version 1: 04-March-2020 






RO6889450—F. Hoffmann-La Roche Ltd 
2/Technical Document for Statistical Analysis BP40283 PART A 
 
 
TABLE OF CONTENTS 
1. 
BACKGROUND ............................................................................................ 5 
2. 
STUDY DESIGN ........................................................................................... 5 
2.1 
Protocol Synopsis .................................................................... 7 
2.2 
Objectives and endpoints ........................................................ 7 
2.3 
Determination of Sample Size ................................................. 9 
2.4 
Analysis Timing and Unblinding ............................................... 9 
2.4.1 
Interim Efficacy Analysis .......................................................... 9 
2.4.2 
Interim Safety Reviews ............................................................ 9 
2.4.3 
Final Analyses ....................................................................... 10 
3. 
STUDY CONDUCT ..................................................................................... 10 
3.1 
Randomization ....................................................................... 10 
3.2 
Independent Review Facility .................................................. 11 
3.3 
Data Monitoring ..................................................................... 11 
3.3.1 
Independent Data Monitoring Committee (iDMC) .................. 11 
4. 
STATISTICAL METHODS .......................................................................... 11 
4.1 
Analysis Populations ............................................................. 11 
4.2 
Analysis of Study Conduct ..................................................... 12 
4.2.1 
Disposition of Participants ..................................................... 12 
4.2.2 
Overview of Analysis Population ........................................... 12 
4.2.3 
Protocol Violations ................................................................. 12 
4.3 
Analysis of Treatment Group Comparability .......................... 12 
4.3.1 
Demographic Characteristics ................................................. 13 
4.3.2 
Baseline Disease Characteristics .......................................... 13 
4.3.3 
History of Schizophrenia ........................................................ 13 
4.3.4 
Previous and Current Diseases at Baseline .......................... 13 
4.3.5 
Previous and Concomitant Treatments (Other 
than Study Medication) ............................................................................ 14 
4.4 
Definition of Baseline ............................................................. 14 
4.5 
Efficacy Analysis .................................................................... 14 
4.5.1 
Primary Efficacy Endpoint ...................................................... 14 


RO6889450—F. Hoffmann-La Roche Ltd 
3/Technical Document for Statistical Analysis BP40283 PART A 
 
4.5.1.1 Definition of Primary Efficacy Endpoint ................................ 14 
4.5.2 
Secondary Efficacy Endpoints ............................................... 15 
4.5.2.1 CGI-S and CGI-I Overall and Negative 
Symptoms .......................................................................................... 16 
4.5.2.2 PANSS Total and Symptom Factor Scores .......................... 17 
4.5.2.3 BNSS Total and Subscores .................................................. 17 
4.5.2.4 DPAS Scores ....................................................................... 18 
4.5.3 
Exploratory Efficacy Endpoints .............................................. 18 
4.5.3.1 Effort-Choice Benefit Task  (ECBT)...................................... 18 
4.5.3.2 Reinforcement Learning Working Memory 
(RLWM) task ...................................................................................... 19 
4.5.3.3 Brief Assessment of Cognition in Schizophrenia 
(BACS) 24 
4.5.3.4 Virtual Reality Functional Capacity Assessment 
Tool (VRFCAT) ................................................................................... 25 
4.5.3.5 Smoking Dependence .......................................................... 26 
4.5.3.6 Levels and Patterns of Social and General 
Activity (optional) ................................................................................ 26 
4.5.3.7 CYP2C19 Status on PK Parameters .................................... 28 
4.5.4 
Other Efficacy Analyses......................................................... 28 
4.5.4.1 Sleep, Mood, Well-Being and Cognitive 
Functioning ......................................................................................... 28 
Pharmacokinetic and Pharmacodynamic Analyses .................................... 29 
4.6 
Safety Analyses ..................................................................... 29 
4.6.1 
Exposure of Study Medication ............................................... 29 
4.6.2 
Adverse Events ..................................................................... 30 
4.6.3 
Clinical Laboratory Tests ....................................................... 31 
4.6.4 
Electrocardiograms (ECG) data analysis ............................... 32 
4.6.5 
Concomitant Medications ...................................................... 33 
4.6.6 
Suicidality Assessment (C-SSRS) ......................................... 34 
4.6.7 
Extrapyramidal Symptom Rating Scale, 
Abbreviated Version (ESRS-A) ................................................................ 34 
4.6.8 
CGI-S MTS and CGI-I MTS ................................................... 35 
4.6.9 
Vital Signs Body Weight and BMI .......................................... 36 
4.7 
Missing Data .......................................................................... 37 


RO6889450—F. Hoffmann-La Roche Ltd 
4/Technical Document for Statistical Analysis BP40283 PART A 
 
4.8 
Interim Analyses .................................................................... 37 
 
 
LIST OF TABLES 
Es konnten keine Einträge für ein Abbildungsverzeichnis gefunden werden. 
 
LIST OF APPENDICES 
Appendix 1 
Protocol Synopsis ....................................................................... 38 
Appendix 2 
Schedule of Activities for Part A of the Study .............................. 45 
Appendix 3 
BNSS Items ................................................................................ 51 
Appendix 4 
PANSS Items and Scores ........................................................... 52 
Appendix 5 
CGI-S and CGI-I Questions ........................................................ 53 
Appendix 6 
DPAS Questions ......................................................................... 54 
Appendix 7 
Patients with Suicidal Ideation, Suicidal Behavior, and Self-
Injurious Behavior without Suicidal Intent Based on the C-
SSRS During Treatment ............................................................. 55 
Appendix 8 
Fagerstöm Nicotine Dependence Test (FTND) Scoring .............. 57 
Appendix 9 
Assessment of Sleep, Mood, Well-being and Cognitive 
Functioning, and Assumed Treatment Assignment ..................... 58 


RO6889450—F. Hoffmann-La Roche Ltd 
5/Technical Document for Statistical Analysis BP40283 PART A 
 
1. 
BACKGROUND 
This Technical Document for Statistical Analysis (TDSA) provides the data-handling 
rules, derivation rules, and statistical methods of summarizing and analyzing the efficacy 
and safety data that will be used for the data analysis and the reporting of the results 
from Part A of study BP40283.   
Recruitment rate in Part A has remained substantially below the original estimates 
despite the implementation of a protocol amendment and the addition of more sites. 
Therefore the Roche TAAR1 Project Team and the Clinical Team have decided to stop 
study Part A (monotherapy) and start Part B (add-on treatment).  In total 27 patients 
have been randomized into Part A.  
There will be a separate TDSA for Part B of the study. 
2. 
STUDY DESIGN 
This is a Phase 2, multicenter, randomized, double-blind, two-part, placebo-controlled, 
parallel-group study of 12 weeks of treatment in patients with schizophrenia or 
schizoaffective disorder. An overview of the study design is provided in Figure 1. The 
study is designed to collect potential efficacy data as well as safety and tolerability data 
in a patient population. 
This study is a proof of concept study (Part A) followed by a dose-ranging study (Part 
B): RO6889450 will first be evaluated in a monotherapy setting (Part A), i.e. the 
participants will withdraw from their antipsychotic treatment(s), then potential efficacy of 
two dose levels of RO6889450 in combination with usual antipsychotic treatments(s) will 
be evaluated.  
For both Parts A and B randomization occurs on Day 1 (Baseline), after screening period 
including placebo compliance period (inclusive of one-week-wash-out period for Part A). 
Treatment will be allocated by stratified block randomization on the bases of the three 
(Part A) or four (Part B) factors: baseline Brief Negative Symptoms Scale (BNSS) 
avolition/apathy subscores (≤6 vs. >6), age (18-35 years vs. 36-55 years), sex (Male vs. 
Female), and only for Part B antipsychotic treatment (full D2/5HT2A antagonist vs. 
partial D2 receptor agonist). 
Part A (monotherapy) 
Participants will be washed out (one week) from their antipsychotic therapy before being 
randomized 1:1 to either 
 QD of RO6889450 or placebo for 12 weeks. 
Part B (add-on therapy) 
Participants will be randomized 1:1:1 to 
 QD of RO6889450, 
 QD of 
RO6889450, or placebo for 12 weeks.  










RO6889450—F. Hoffmann-La Roche Ltd 
10/Technical Document for Statistical Analysis BP40283 PART A 
 
Two safety reviews are scheduled for the review of the safety data accrued in Part A of 
the study: 
1. Once approximately 10 participants per treatment arm reach the Week 2 visit, 
i.e., after the one-week-wash-out period. – This safety review was done at 14 
November 2019, the recommendation was to continue the study without 
modification. 
2. Once approximately 30 participants per treatment arm reach the Week 12 visit, 
i.e., during and after the Treatment Period with the main focus being on placebo 
arm. – This safety review will not be conducted as the Part A of the study was 
stopped before approximately 30 patients per treatment arm reached the Week 
12 visit. 
Additional safety reviews for the safety data may be conducted for study Part B at the 
request of the iDMC or the Study Team, e.g. if safety concerns arise.  
The Sponsor’s study statistician as well as statistical programmer will be unblinded to 
provide unblinded safety information to the iDMC. The data will be handled and cleaned 
in a secure area that is not accessible by any blinded SMT member. 
2.4.3 
Final Analyses 
The final analysis of data from the trial will be performed separately for Part A and Part 
B when all patients of the respective study part have either completed the study or 
discontinued early from the study, all data of the trial are in the database, have been 
cleaned and verified, and the database has been locked. 
3. 
STUDY CONDUCT 
3.1 
RANDOMIZATION  
An Interactive Voice/Web Response System (IxRS) is used to randomize the 
participants in equal proportion to the treatment arms.  
In Part A treatment will be allocated by stratified block randomization on the basis of 
the following factors: 
• 
Baseline BNSS avolition/apathy subscore (≤6 or >6) 
• 
Age (18-35 years vs. 36-55 years) 
• 
Sex (Male vs. Female) 
In Part A, on Day 1 (baseline) participants within each block stratum are randomly 
assigned in 1:1 ratio to either 
 QD of RO6889450 or placebo. Approximately 125 
participants will be randomized to ensure approximately 100 number of completers.  


RO6889450—F. Hoffmann-La Roche Ltd 
11/Technical Document for Statistical Analysis BP40283 PART A 
 
3.2 
INDEPENDENT REVIEW FACILITY 
PANSS and BNSS will be assessed live via secure videoconferece by an approved 
remote centralized rater. If a remote administration session cannot occur for an 
unforeseen reason, it will be rescheduled. 
3.3 
DATA MONITORING 
3.3.1 
Independent Data Monitoring Committee (iDMC) 
An iDMC will regularly review unblinded safety and efficacy (as appropriate) data. The 
iDMC will be composed of at least two psychiatrists external to the Sponsor and a 
statistician external to the Sponsor and will be responsible for monitoring safety data to 
help ensure that continuation of the trial in its current design does not pose unacceptable 
safety risks to participants. The iDMC will also assess safety as part of the planned 
interim safety analysis. 
A separate iDMC charter documents the roles, responsibilities, membership as well as 
scope of activities, time of meetings, and communication plan. Planned and ad hoc 
safety reviews will be performed as described in the iDMC charter. 
4. 
STATISTICAL METHODS 
The final analysis of data from the trial will be performed separately for Part A and Part 
B. This TDSA describes the analyses for Part A.   
 
 Data for study Part A will be listed and summarized 
descriptively. No formal hypothesis test will be performed. 
4.1 
ANALYSIS POPULATIONS 
For purposes of analysis, the following populations are defined in Table 2. 
Table 2 
Analysis Populations 
Population 
Description 
Modified intent-to-treat (ITT) All randomized participants who have received at least 
one dose of study drug, including participants who were 
withdrawn prematurely, will be included in the efficacy 
population. The modified ITT analysis population will be 
the primary analysis population for all efficacy data 
analyses.  
Per-protocol (PP) 
No PP analysis population is defined for Part A 
Safety evaluable (SE) 
Same as modified ITT analysis population.  


RO6889450—F. Hoffmann-La Roche Ltd 
12/Technical Document for Statistical Analysis BP40283 PART A 
 
Pharmacokinetic (PK) 
All participants who have received at least one dose of 
study drug and who have data from at least one post-
dose sample will be included in the PK analysis 
population. Participants will be excluded from the PK 
analysis population if they significantly violate the 
inclusion or exclusion criteria, deviate significantly from 
the protocol, or if data are unavailable or incomplete that 
may influence the PK analysis. Excluded cases will be 
documented together with the reason for exclusion. All 
decisions on exclusions from the analysis will be made 
prior to database closure. 
 
4.2 
ANALYSIS OF STUDY CONDUCT 
4.2.1 
Disposition of Participants 
For all patients in the modified ITT analysis population enrollment in the study, 
discontinuation of study drug and from the study, and reason for discontinuation will be 
summarized per treatment arm to which participants are randomized. In addition, 
protocol violations will be summarized by treatment arm.  
4.2.2 
Overview of Analysis Population 
The number (percentage) of participants excluded from the analysis populations will be 
summarized by reason for exclusion per treatment arm  
4.2.3 
Protocol Violations 
The major protocol violations will be identified before database lock. The number and 
percentage of participants with major protocol violations will be summarized per protocol 
violation criterion and treatment arm to which participants are randomized.   
4.3 
ANALYSIS OF TREATMENT GROUP COMPARABILITY 
The evaluation of treatment arm comparability between the two treatment arms in study 
Part A will include summaries of demographics, baseline disease characteristics, and 
participant medical history. Data will be summarized by treatment arm to which 
participants were randomized.  
Descriptive statistics (mean, standard deviation, median, and minimum-maximum) will 
be presented by treatment arm for continuous variables. Frequency counts and 
proportions will be presented by treatment arm for categorical variables.  


RO6889450—F. Hoffmann-La Roche Ltd 
13/Technical Document for Statistical Analysis BP40283 PART A 
 
4.3.1 
Demographic Characteristics 
Summary tables of demographics will be produced for the modified ITT analysis 
population by treatment arm to which participants were randomized. The following 
variables will be summarized: 
Categorical variables: 
• 
Sex (Male vs. Female) 
• 
Age group (18-35 years vs. 36-55 years) at baseline 
• 
Race (Black or African American vs. White) or Ethnicity (Hispanic or Latino vs. non-
Hispanic or Latino) 
Continuous variables: 
• 
Weight [kg], Height [cm], Body Mass Index (BMI) [kg/m2] at baseline 
• 
Age (years) at baseline 
and others if appropriate.  
4.3.2 
Baseline Disease Characteristics 
Baseline data for BNSS total- subscores, PANSS total- and symptom factor scores, CGI-
S and CGI-S NS scores will be included in the respective efficacy outputs. No separate 
outputs will be presented for baseline.  
4.3.3 
History of Schizophrenia 
Summary statistics will be generated for each treatment group and will include each 
patient’s history of schizophrenia. The key variables from the electronic Case Report 
Form (eCRF) listed in the psychiatric history page will be summarized. The time (in 
months) since the diagnosis of schizophrenia and the time (in months) since the most 
recent hospitalization for worsening of Schizophrenia will be calculated relative to the 
randomization date. 
4.3.4 
Previous and Current Diseases at Baseline 
For all diseases at baseline (other than schizophrenia), the term entered by the 
investigator describing the disease (the “verbatim term”) will be assigned to a 
standardized term (the “preferred term”) and System Organ Class from MedDRA. All 
analyses will be performed using these preferred terms and body systems. Diagnoses 
will be categorized by condition at baseline (ongoing with treatment/ongoing without 
treatment/resolved) with use of the responses from the medical history page of the 
eCRF. 


RO6889450—F. Hoffmann-La Roche Ltd 
14/Technical Document for Statistical Analysis BP40283 PART A 
 
The number and percentage of patients with previous (resolved) diseases will be 
summarized by treatment group. Diseases concurrent (ongoing with or without 
treatment) at baseline will be summarized similarly in a separate table. Multiple 
occurrences of a disease (i.e., same coded term) will be counted only once. 
4.3.5 
Previous and Concomitant Treatments (Other than Study 
Medication) 
For all medications, the term entered by the investigator describing the medication (the 
“verbatim term”) will be assigned to a standardized term (the “preferred term”) and drug 
class from the WHO drug dictionary. All analyses will use these preferred terms and 
medication classes. 
The number and percentage of patients who received previous or concomitant treatment 
(medication, medical procedure, or non-medical therapy) will be summarized by 
treatment group.  
Multiple occurrences of a medication in an individual (i.e., same coded term) will be 
counted only once. All summary tables will be sorted by medication class (in decreasing 
order of overall incidence), then by preferred term (in decreasing order of overall 
incidence). 
4.4 
DEFINITION OF BASELINE 
Baseline for all efficacy and safety analyses is define das the last non-missing value 
recorded prior to or on the first day of randomized double-blind study drug 
administration. 
4.5 
EFFICACY ANALYSIS 
Endpoints will be summarized descriptively for the modified ITT analysis population, no 
statistical modelling will be perfomed, no statistical hypothesis will be tested. 
 
4.5.1 
Primary Efficacy Endpoint 
4.5.1.1 
Definition of Primary Efficacy Endpoint 
The primary efficacy endpoint of the study is the change from baseline in the BNSS 
Avolition/Apathy subscore at Week 12.  
The BNSS (Strauss et al 2012) is a 13-item instrument designed for clinical trials and 
other studies that measure the severity of negative symptoms in six domains 
(subscales), inclusive of one single-item domain of ‘Distress’ (see Appendix 3):  
• 
Blunted Affect (three items): facial expression, vocal expression, expressive 
gestures; 
• 
Alogia (two items): quantity of speech, spontaneous elaboration; 


RO6889450—F. Hoffmann-La Roche Ltd 
15/Technical Document for Statistical Analysis BP40283 PART A 
 
• 
Asociality (two items): asociality - behavior, asociality - internal experience; 
• 
Anhedonia (three items): intensity of pleasure during activities, frequency of 
pleasure during activities, intensity of expected pleasure from future activities; 
• 
Avolition/Apathy (two items): avolition - behavior, avolition - internal experience; 
• 
Distress (single item): distress.  
All ratings are based on a semi-structured interview with prompts and queries. Items are 
rated on a 7-point scale, ranging from the symptom being no impairement/normal (0), 
very slight deficit/questionable (1), mild deficit/mild (2), moderate deficit/moderate (3), 
moderately severe deficit/moderately severe (4), marked deficit/severe (5) to severe 
deficit/extremely severe (6). A total BNSS score is calculated by summing the 13 
individual items so that the possible total score ranges from 0 to 78. Subscores are 
calculated by summing the individual items within each domain (subscale). The primary 
efficacy endpoint, the change in avolition/apathy subscale ranges from 0 to 12.  
Higher scores indicate more negative symptoms. Hence negative values for change 
from baseline indicate improvement. 
In study Part A, the BNSS is assessed by an approved remote centralized rater at 
Week -4, Day 1 (Baseline), Day 14, Day 28, Day 42, Day 56, Day 70, Day 84/EOT and 
Day 112 (FU). All assessments will be assigned to analysis study days according to the 
following table. 
Assessment Days 
Assigned Analysis Study Day 
>88 or >4 days after last study medication  
FU, will not be included in statistical analysis 
78-88 
84 
64-77 
70 
50-63 
56 
36-49 
42 
22-35 
28 
2-21 
14 
-2-1 
1 
<-2 
-35, will not be included in statistical analysis 
 
Descriptive summary statistics and listings will be presented for the BNSS 
Avolition/Apathy subscore by visit and treatment arm for the modified ITT analysis 
population by treatment arm to which participants were randomized. The same 
descriptive summary statistics and will be presented for the change from baseline in 
BNSS Avolition/Apathy subscore. 
4.5.2 
Secondary Efficacy Endpoints 
Descriptive summary statistics will be presented for all secondary efficacy endpoints by 
visit and treatment arm for the modified ITT analysis population by treatment arm to 


RO6889450—F. Hoffmann-La Roche Ltd 
16/Technical Document for Statistical Analysis BP40283 PART A 
 
which participants were randomized. The same descriptive summary statistics and will 
be presented for the change from baseline. 
Descriptive summary statistics will include the number of patients contributing to the 
summary statistic as well as the mean, median, lower and upper quartile, standard 
deviation, minimum and maximum. 
In general, if at least one item score is missing or not ratable, the total/factor/subscale 
scores that include the item will be set to missing.  
4.5.2.1 
CGI-S and CGI-I Overall and Negative Symptoms 
The CGI rating scales are tools used to evaluate both the severity of illness and change 
from baseline. It provides an overall clinician-determined summary measure that takes 
into account all available information, including a knowledge of the participants’ history, 
psychological circumstances, symptoms, behavior, and the impact of the symptoms on 
the participant’s ability to function. 
CGI-S and CGI-S NS 
The CGI-S is a 7-point scale ranging from 1 (normal, not at all ill) to 7 (among the most 
extremely ill patients) (see Appendix 5). τn the scale, the value 0 corresponds to ‘σot 
assessed’, which will be excluded from the analyses. The values 1 to 7 will be 
transformed into the 0 to 6 range prior to statistical analysis. The CGI-S is an absolute 
measure assessing how mentally ill the participant is at the time of the assessment.  
Smaller values indicate less severity of illness. Hence negative values for change from 
baseline indicate improvement.  
The CGI-S NS is very similar to the CGI-S and will be analyzed in the similar manner. 
In study Part A CGI-S along with CGI-S NS will be evaluated at Day 1 (baseline), Day 
14, Day 28, Day 42, Day 56, Day 70, Day 84 /EOT, Day 112 (FU) by an experienced 
clinician. All assessments will be assigned to analysis study days as described for the 
primary endpoint.  
The CGI-S and CGI-S NS scores and change from baseline will be summarized. 
CGI-I and CGI-I NS 
The CGI-I, a 7-point scale rating, is used to assess the clinical changes as compared to 
symptoms at baseline. The scale requests an assessment by how much, compared to 
baseline, the condition of the participant has changed (see Appendix 5). Values range 
from 1 (very much improved) to 7 (very much worse) where the value 0 corresponds to 
‘σot assessed’, which will be excluded from any analyses. The values 1 to 7 will be 
centered prior to analysis so that 0 becomes ‘no change’ and the values -3 and +3 
correspond to ‘very much improved’ and ‘very much worse’, respectively.  


RO6889450—F. Hoffmann-La Roche Ltd 
17/Technical Document for Statistical Analysis BP40283 PART A 
 
The CGI-I NS is very similar to the CGI-I and will be analyzed in the similar manner.  
In study Part A CGI-I along with CGI-I NS will be evaluated at Day 14, Day 28, Day 42, 
Day 56, Day 70, Day 84 /EOT, Day 112 (FU) by an experienced clinician. All 
assessments will be assigned to analysis study days as described for the primary 
endpoint. 
The The CGI-I and CGI-I NS scores will be summarized. There is not baseline value for 
CGI-I and CGI-I NS, therefore no change from baseline can be derived. 
4.5.2.2 
PANSS Total and Symptom Factor Scores  
PANSS assessments are performed by an approved remote centralized rater.  
The PANSS is a 30-item clinician-rated instrument for assessing positive, negative and 
other symptoms in partients with schizophrenia (see Appendix 4). The symptoms are 
rated on a 7-point scale capturing absent to extreme psychopathology, and the tool 
demonstrated sensitivity to effects seen with medication. The assessment for each of the 
30 items is to allow calculation of a total score describing overall symptomatology as well 
as the factor scores (the classification of symptoms into five factors: negative symptoms; 
positive symptoms; disorganized thought; uncontrolled hostility/excitement; and 
anxiety/depression) which are calculated for each factor. Additonally, negative and 
positive symptom factore scores according to Marder (PANSS-NSFS, PANSS-PSFS, 
see Table 5 in protocol V2) are used.  
Each item of the PANSS is rated on a 7-point scale on the basis of the following 
anchors: 1 = Absent, 2 = Minimal, 3 = Mild, 4 = Moderate, 5 = Moderately Severe, 6 = 
Severe, and 7 = Extreme. For the analyses of PANSS data, the scores will be 
transformed into 0 to 6 points with “Absent” expressed as 0.  
Higher scores indicate more positive and negative symptoms. Hence negative values for 
change from baseline indicate improvement in symptoms. 
In study Part A, the PANSS is assessed at Week -4, Day 1 (Baseline), Day 14, Day 28, 
Day 42, Day 56, Day 70, Day 84/EOT, Day 112 (FU). All assessments will be assigned 
to analysis study days as described for the primary endpoint. 
The PANSS total factor and symptom factor scores and change from baseline will be 
summarized. 
4.5.2.3 
BNSS Total and Subscores 
See section 4.4.1.1. 
The BNSS total and subscores (other than Avolition/Apathy) and change from baseline 
will be summarized. 


RO6889450—F. Hoffmann-La Roche Ltd 
18/Technical Document for Statistical Analysis BP40283 PART A 
 
4.5.2.4 
DPAS Scores 
The DPAS is a 15-item, patient-reported assessment that evaluates expectations of 
failures or self-defeating beliefs related to prior failed experiences as well as illness on a 
7-point Likert scale ranging from disagree totally (1), disagree very much (2), disagree 
slightly (3), neutral (4), agree slightly (5), agree very much (6), to agree totally (7) (for 
items see Appendix 6). For the analyses of DPAS data, the scores will be transformed 
into 0 to 6 points with “disagree totally” expressed as 0. 
Higher scores indicate higher expectation of failure or self-defeating beliefs. Hence 
negative values for change from baseline indicate improvement. 
In study Part A DPAS is assessed at Day 1 (baseline), Day 42, and Day 84/EOT. All 
assessments will be assigned to analysis study days according to the following table: 
Assessment Day 
Assigned Study Day 
>88 or >4 days after last study medication  
FU, will not be included in statistical analysis 
64-88 
84 
2-63 
42 
-2-1 
1 
<-2 
-35, will not be included in statistical analysis 
 
The DPAS sum score and change from baseline will be summarized. 
4.5.3 
Exploratory Efficacy Endpoints 
4.5.3.1 
Effort-Choice Benefit Task  (ECBT) 
The ECBT assesses the degree to which participants are willing to engage in effortful 
responding as a function of the probability and magnitude of potential rewards. 
Participants with negative symptoms show reduced willingness to engage in effortful 
behavior. The ECBT task is assigned to the participants to complete.  
In the experiment, participant has the choice between a low effort task and a high effort 
task. When making a choice, the participant will be aware of the number of pumps 
(‘effort’) required for the low (always 20 pumps) and the high (100, 120, or 150 pumps) 
effort task. Also, the participant is informed about the maximum possible reward (1 point 
for the low effort task and 3, 5, 7 points for the high effort task). Each set of cumulated 
20 points covert to a e.g. $1 bonus: i) if the low effort task is selected, the participant 
needs to complete all 20 pumps to obtain his reward; ii) if the high effort task is selected, 
the participant will obtain the reward after 25 seconds, and the reward will be in 
proportion to the required amount of effort. For example, if the participant selects the 
task for 5 points and 120 pumps, and end up pumping 90 times, he receives a reward of 
5 × 90/120 points. The participant can earn more than 5 points if pumping more than 
120 times. The participant will be told the certainty with which the reward will be paid 
(100% or 50%). This certainty applies equally to the low and high effort task. 
Furthermore, the high effort task (in balloon) may appear on the left or the right side of 


RO6889450—F. Hoffmann-La Roche Ltd 
19/Technical Document for Statistical Analysis BP40283 PART A 
 
the screen. In total this leads to 3 × 3 × 2 × 2 = 36 different combinations of ‘number of 
pumps for high effort task (# of pumps required for maximum reward in high effort task, 
‘100’, ‘120’, ‘150’)’, ‘reward of high effort task (3, 5, 7 points)’, ‘reward certainty (100% or 
50%)’, and ’side of display of high effort task (‘left’ or ‘right’)’. Each combination is 
presented twice (variable ‘trialno’, 1 or 2), leading to the total of 72 experiments per 
session.  
In study Part A the ECB task will be performed at Day 1 (baseline), Day 14, Day 2, Day 
42, and Day 84/EOT.  
Descriptive Summaries:  
Overall and separately for all levels of the factors ‘reward’ (levels 3, 5, or 7) and within 
each patient, the percentage how often the high effort task was selected will be derived. 
These percentages obtained for each patient will then be summarized by treatment per 
assessment. The summaries will show the mean, median, lower and upper quartile as 
well as minimum and maximum.  
Exclusion of data from analysis:  
In all analyses, data from a session will only be included if the first two of the following 
three QC criteria applied to the data collected from a patient in a session are met:  
1. The proportion of failed trials must be below or equal to 20%;  
2. The proportion of same side choices must be below or equal to 85%; and  
3. The proportion of same balloon type choices must be below or equal to 85%.  
 
4.5.3.2 
Reinforcement Learning Working Memory (RLWM) task 
The RLWM task assesses the ability to learn from positive reward and establish 
corresponding mental value representations, functions that are deficient in patients with 
negative symptoms. The RLWM task is assigned to the participants to complete.  
Task Description: 
Learning Phase (LP): To complete the RLWM task, at the learning phase, participants 
have to learn to select one out of three button presses for each stimulus (=image): on 
each presentation (trial), a single stimulus is presented to which participants can 
respond with one of three responses (button presses). Participants have to learn over 
time which of those responses is the correct one for each stimulus, based on the binary 
deterministic feedback they receive.  
The stimuli are presented in blocks. The number of stimuli in the block to be learned at 
a time ranges from 2, 3, 4, 5, 6. There are two blocks of size ns =2 (i.e., two blocks 
containing two stimuli each), three blocks of size ns= 3, two blocks or size ns= 4, three 
blocks of size ns =5. The total number of blocks is 10. The stimuli in each block 
correspond to a different category of images (e.g., sports, fruits, places, etc.) leading to a 


RO6889450—F. Hoffmann-La Roche Ltd 
20/Technical Document for Statistical Analysis BP40283 PART A 
 
total of 2×2 + 3×3 + 2×4 + 3×5= 36 different stimuli. Within each block, stimuli are 
presented in a pseudo-randomly intermixed order, with 10 presentations of each 
stimulus within a block, i.e., a total of 360 presentations within a session. When 
participants select the incorrect action for a stimulus, they receive feedback indicating 
they have won 0 points, but if they select the correct action, they obtain a reward of 1 or 
2 points. Each stimulus has a fixed probability q of resulting in 2 (vs. 1) points of reward 
for correct actions (q is 0.25, 0.50, and 0.75); the probabilities are pre-assigned to 
counterbalance across set sizes and other factors1. The correct action is always correct 
and the incorrect one is always incorrect. The participant would not know the probability 
q of receiving 2 points (rather than 1 point) in case of a correct answer. Although the 
participants have no control over the reward values, their striatal reinforcement learning 
system is expected to learn to represent higher expected reward values for those stimuli 
associated with higher probability of two points, which can be assessed in the test 
phase.  
Test Phase (TP): After the learning phase, participants face a test phase, in which they 
are presented with pairs of stimuli they previously encountered. They are asked to 
choose the stimulus that they perceive to have given them most points in the learning 
phase. Instead of selecting the response that had been ‘correct’ for each of the individual 
stimuli, in this phase participants are asked to select among pairs of stimuli and to 
indicate their preferences (more likely to choose ones they think had led to more points). 
They receive no reward. The test phase includes 156 trials, i.e., 156 pairs of stimuli. 
These 156 pairs are selected among all 1176 (49 choose 2) possible pairs. The 
selection is based on the actual responses of the participant in the learning phase and 
done in a way to ensure that sufficient pairs with a range of ‘Value Differences’ but also 
‘Value Means’ (see below) are included. Participants are more likely to select the more 
rewarding stimuli, and they do so more reliably as the difference between their reward 
values grows. This test also allows us to assess whether participants perform better 
either at choosing the most rewarding stimuli or at avoiding the least rewarding 
stimuli, when each of these are paired with neutral stimuli. Such difference in 
performance in these two situations is related to striatal dopaminergic measures in 
various studies. 
With lower set sizes, participants can rely on (fast but subject to decay in time and 
capacity-limited) working memory (WM). As set size exceeds their WM capacity, they 
have to rely on incremental (slow, cumulative learning) reinforcement learning (RL). The 
paradigm can thus isolate WM from RL processes that are striatal dependent.  
 
1 As an example, there are 2 blocks of size 2 each, leading to a total of 4 different images across these two 
blocks. Among these 4, two each may be assigned probability 0.25, 0.50, and 0.75; the remaining two may 
be assigned either of the three. Similarly, there are 3 blocks of size 3. Across the 9 images, each probability 
is assigned to three images, but not all images from the same block need to have distinct probabilities.   
 


RO6889450—F. Hoffmann-La Roche Ltd 
21/Technical Document for Statistical Analysis BP40283 PART A 
 
Assessment schedule are at Weeks 1 (baseline), 2, 6, 12 for both Parts A and B. No 
assessment is planned for Screening or Follow-up. 
Statistical Analyses  
At the RLWM Learning Phase the proportion of correct choices in late trials and for 
large blocks of stimuli is investigated while at the RLWM Testing Phase the interaction 
‘value difference modulated by value mean’ is investigated to assess the ‘choose A 
avoid B’ paradigm.  
Repeated presentations of a stimulus within a block are referred as ‘iteration’: iteration 
1 refers to the first presentation of a stimulus, iteration 2 to the second presentation of a 
stimulus etc. There are 10 iterations per stimulus. Iterations 2 and 3 are referred to as 
‘early trials’, whereas the iterations 8 to 10 are referred to as ‘late trials’. All stimuli are 
presented 10 times, but there may be on occasion less than 10 responses by a 
participant e.g., due to the participant not responding within the required time. Such 
records are retained in the data set with a missing value for participant response. The 
records will be excluded from any analysis. 
RLWM LP: The percentages of correct choices will be calculated for each iteration 
within each block size. These will be derived in a sequential manner: first, across all 
blocks of the same size, i.e., separately for blocks of size 2, 3, 4, and 5, the percentage 
of correct choices per each iteration will be derived for each participant. Then those 
percentages per iteration within each block size per participant will be averaged across 
all participants by treatment arm. Descriptive statistics for the percentages in late trials 
(iteration 8, 9, 10) and for large blocks (block size 4, 5) will be displayed by treatment 
arm.  
RLWM TP: For the RLWM Testing Phase the following factors will be considered in the 
analysis: 
• 
Value Difference (F1). The ‘mean value’ of a stimulus is derived based on the 
average number of points the participant gained in the LP for this stimulus: the sum 
of all points gained for the stimulus divided by the total number of responses made 
(typically 13 but may be less). The value difference is derived by (‘mean value’ of 
right stimulus) – (‘mean value’ of left stimulus) for the given pair of stimuli. ‘Value-
difference’ ranges between -2 (the left is more rewarding) and 2 (the right is more 
rewarding). Value difference is an indicator of RL value learning.  
• 
Value Mean (F2). The ‘value mean’ of a pair of stimuli is the average of the two 
mean values of the pair in the presentation. Values range from 0 to 2.  
• 
Value Difference Modulated by Value Mean (F12). Factor F12 will assess the 
interaction between value difference (F1) and value mean (F2). F12 is an indicator of 
value learning bias, corresponding to the classic Probabilistic Selection Task (PST) 


RO6889450—F. Hoffmann-La Roche Ltd 
22/Technical Document for Statistical Analysis BP40283 PART A 
 
“choose A vs. avoid B” measure (assessing whether participants perform better 
either at choosing the most rewarding stimuli or at avoiding the least rewarding 
stimuli, when each of these are paired with neutral stimuli). 
• 
Block Size Mean (F3) is the mean of the sizes of the blocks the two stimuli 
originated from in the learning phase. For example, if one stimulus (image) in a pair 
stems from a block of size 2 and the other stimulus stems from a block of size 4, the 
set size mean is 3. Possible values are from 2 to 5 in steps of 0.5. 
• 
Value Difference Modulated by Block Size Mean (F13). Factor F13 will assess the 
interaction between value difference (F1) and block size mean (F3). High values for 
block size mean (e.g., 5 or 6) imply that both stimuli in a pair are from rather large 
blocks (e.g., of sizes 5 or 6). In such cases the effect of value difference may be less 
pronounced compared to what might be observed if both stimuli in a pair are from 
smaller blocks. Smaller block sizes might enable more robust learning leading to a 
more pronounced effect of value difference for smaller compared to large block size 
means. Alternatively, larger block sizes might require more use of RL over WM and 
thus lead to a more pronounced effect of value difference. 
• 
Block Size Difference (F4) is the difference in the sizes of the blocks the two stimuli 
originated from in the LP. For example, if one stimulus in a pair stems from a block of 
size 2 and the other image stems from a block of size 4, the block size difference is 
2. Block size differences will also be calculated as ‘block size right stimulus 
originated from’ minus ‘block size left stimulus originated from’; hence results can 
range from -4 to 4 in steps of 1.  
• 
Learning Block Difference (F5). 13 blocks are used in the LP. If e.g. the left image 
was learned in the 2nd block and the right image in the 6th block, the learning block 
difference will be 4 (=6-2). Differences will be derived as ‘right’ minus ‘left’. Values 
can thus range from -12 to 12 in steps of 1.  
• 
Previous Trial Choice (F6). The factor is coded as ‘L’ or ‘R’ and indicates the side 
of the previously chosen stimulus. Significant effects on this factor may be 
interpreted as an increase in choice stickiness, and thus possibly a decrease in 
involvement in the task. 
For each pair of stimuli, denote by z the binary response taking values 1 (if the 
participant chose the right stimulus in the pair) and 0 (if the participant chose the left 
stimulus in a pair).  
Logistic regression analysis modelling the likelihood the participant chooses the right 
stimulus of a pair (variable z) will be performed for each session with model  
log(p/(1-p)) = β0 + β1·F1 + β12·F12 + β13·F13 + β4·F4 + β5·F5 + β6 ·F6 + ε. 


RO6889450—F. Hoffmann-La Roche Ltd 
23/Technical Document for Statistical Analysis BP40283 PART A 
 
Factor F2 will not included because there is no reason to believe why value mean should 
be systematically associated with the likelihood to choose the right stimulus of the pair. 
Only the three parameters β0, β1, and β12 are of primary interest. The other factors have 
been added to the model to improve the model fit but (even if significant) are not of 
scientific interest. Any records where any of the six covariates is missing or where 
information on the side chosen is not available will be excluded from analysis. Based on 
the resulting data set,  
a) Each variable of F1 to F6 will be standardized within each participant and visit by 
subtracting the within participant and visit mean and dividing by the within participant 
and visit standard deviation.  
b) The two interaction terms F12 and F13 will then be derived as the product of the 
corresponding standardized variables F1 and F2 as well as F1 and F3.  
c) Subsequently, the two interaction terms F12 and F13 will again be standardized 
using the same approach as described in a).  
The regression coefficients will allow the following interpretation: 
Factor F1 (Value Difference): Positive values for β1 will mean that the likelihood to 
choose the right side will increase with the (right minus left) value difference F1. Positive 
value differences imply that the right side is the correct choice; hence positive values for 
β1 imply increasing likelihood to make a correct choice with increasing difference 
between stimuli.  
F1 and F2 (Value Mean) Interaction (F12, Value Difference modulated by Value 
Mean): Effect of F1 (value difference) on p depends on the level of F2 (value mean): F2 
being close to 0 or close to 2 imply that there can only be very small value differences in 
such pairs whereas F2 being close to 1 allows F1 (right minus left) to range from -2 to 2. 
Hence, a positive association between p is expected for F2 around 1 but less so for F2 
close to 0 or 2 and should manifest itself in the β12 interaction term associated with F12. 
Positive values of β12 are assiociated with “choose A (choose one with better reward)” 
being improved over "avoid B (avoid one with less reward)", while negative values would 
correspond to “choose A” being worse than “avoid B”. An increase in β12 is expected for 
an effective treatment. 
F1 and F3 (Block Size Mean) Interaction (F13): Like F12 smaller block size means are 
expected to lead to a stronger association of value difference (F1) with the likelihood to 
choose the right stimulus.  
Note that main effects for F2 and F3 are not included. The value mean (F2) of a pair 
should not impact the likelihood to choose R or L. Same applies to F3, which also as 
such is not expected to have an effect.  


RO6889450—F. Hoffmann-La Roche Ltd 
24/Technical Document for Statistical Analysis BP40283 PART A 
 
Factor F4 (Block Size Difference): Significant effects of F4 (i.e., positive coefficients for 
β4) could be interpreted as a change in effort avoidance, as it indicates a tendency to 
prefer those stimuli encountered from easier blocks independently of learned value. In 
other words, F4 measures to what extent the choice of the participant is driven by block 
size beyond value they have gained.  
Factor F5 (Learning Block Difference): i) In case a participant would always correctly 
choose the higher value stimulus and ii) assuming the higher value stimulus is equally 
often on the right or left side, the coefficient β5 associated with factor F5 in the model 
above is expected to zero. Hence, significant effect of F5 could be interpreted as a 
change in long term memory use, as it indicates a tendency to be sensitive to recency. 
F5 is intended to capture effects on learning that are independent of objective value. 
Decision making literature shows that many other factors may influence choice, beyond 
strict economic preference. A preference based on how recently the stimulus was seen 
is a possible factor, which F5 is attempting to capture. 
The analysis will focus on the evaluation of the coefficient β12 associated with the 
interaction ‘value difference modulated by value mean’ in the model above. This is 
considered to capture the “choose A/avoid B” paradigm. Model  
Yijk = µ + Ĳi + πj+ εijk, 
where µ is the general mean, Ĳi are the effects of treatment, πj are the effects of visit, 
and εijk are random errors assumed to be correlated across visits within each participant, 
i.e., Cov(εi1k, εi’2k) = Cov(εi2k, εi’3k) = ı1 and Cov(εi1k, εi’3k) = ı2 and Var(εijk)= ı2, will be 
applied to the coefficients β12. Results will be reported as least squares means by 
treatment arm as well as differences between treatment arms together with 90% 
confidence intervals.  
4.5.3.3 
Brief Assessment of Cognition in Schizophrenia (BACS) 
To explore the effects of RO6889450 on overall functioning/cognition, the Brief 
Assessment of Cognition in Schizophrenia (BACS) is employed. 
The BACS is designed to measure cognition in schizophrenia. The domains of cognitive 
function measured by the BACS include:  
• 
verbal memory (measure: number of items recalled total, range: 0–75, ZDSCAT= 
VERBAL MEMORY; VERBAL MEMORY TSCORE),  
• 
working memory (measure: digit sequencing, number of correct sequences, 
range: 0–28, ZDSCAT=DIGIT SEQUENCING; DIGIT SEQUENCING TSCORE),  
• 
motor speed (measures: the number of tokens correctly placed into the 
container, range: 0–xx, ZDSCAT=TOKEN MOTOR TASK; TOKEN MOTOR 
TASK TSCORE),  


RO6889450—F. Hoffmann-La Roche Ltd 
25/Technical Document for Statistical Analysis BP40283 PART A 
 
• 
attention and speed of processing (measure: symSbol coding - number of correct 
numerals, range: 0–110, ZDSCAT=SYMBOL CODING; SYMBOL CODING 
TSCORE),  
• 
executive functions (measure: tower of london, number of correct responses, 
range: 0–22, ZDSCAT=TOWER OF LONDON; TOWER OF LONDON TSCORE), 
and  
• 
verbal fluency (measure: number of words generated = verbal fluency total, 
range: 0-xx, ZDSCAT=VERBAL FLUENCY; VERBAL FLUENCY TSCORE)  
The BACS domains found to be impaired in schizophrenia. The BACS is found to be a 
valid outcome measure for the effects of medication, and therapy on cognitive function, 
and is an indicator of functional relevance with respect to independent living skills, 
performance-based assessments of everyday living skills, and interview-based 
assessments of cognition in participants with schizophrenia. The BACS is administered 
by qualified site raters using the tablet-based BACS App.  
In study Part A, the assessments for BACS are performed at Day 1 (baseline), Day 42, 
and Day 84/EOT. All assessments will be assigned to analysis study days according to 
the following table: 
Assessment Day 
Assigned Study Day 
>88 or >4 days after last study medication  
FU, will not be included in statistical analysis 
64-88 
84 
2-63 
42 
-2-1 
1 
<-2 
-35, will not be included in statistical analysis 
 
In general, if at least one item score is missing or not ratable, the total/factor/subscale 
scores that include the item will be set to missing. 
The BACS measure from each of the 6 test (number of items recalled total, number of 
correct sequences, number of tokens correctly placed, cat) will be provided by absolut 
values and standardized t-scores (verbal memory, digit sequencing, token motor, verbal 
fluency, symbol coding, tower of London, BACS composite score) will be provided.  
BACS t-scores and change from baseline in t-scores will be summarized by assessment 
visit. 
4.5.3.4 
Virtual Reality Functional Capacity Assessment Tool (VRFCAT) 
To explore the effects of RO6889450 on overall functioning/cognition, the Virtual Reality 
Functional Capacity Assessment Tool (VRFCAT) is employed. 
The VRFCAT is a computerized measure of functional capacity, with the potential to 
demonstrate real-world functional improvements associated with cognitive change. It 
presents participants with a realistic simulated environment to recreate routine activities 


RO6889450—F. Hoffmann-La Roche Ltd 
26/Technical Document for Statistical Analysis BP40283 PART A 
 
of daily living (Ruse et al 2014). It consists of four mini-scenarios that follow a story, 
including: (1) exploring a kitchen, (2) catching a bus to a grocery store, (3) 
finding/purchasing food in a grocery store, and (4) returning home on a bus.  
In study Part A, the assessments for VRFCAT are performed at Day 1 (baseline), Day 
42, and Day 84/EOT. All assessments will be assigned to analysis study days according 
to the following table: 
Assessment Day 
Assigned Study Day 
>88 or >4 days after last study medication  
FU, will not be included in statistical analysis 
64-88 
84 
2-63 
42 
-2-1 
1 
<-2 
-35, will not be included in statistical analysis 
 
VRFCAT adjusted total time, errors and forced progressions t-scores and change from 
baseline in t-scores will be summarized. 
4.5.3.5 
Smoking Dependence 
To explore the effects of RO6889450 on changes in smoking dependence Fagerstrom 
Test for Nicotine Dependence (FTND) total score is employed. 
The Fagerstrom Tolerance Scale is used to assess nicotine consumption during the 
study. The Fagerstrom test is a standard instrument for assessing the intensity of 
physical addiction to nicotine providing an ordinal measure of nicotine dependence 
related to cigarette smoking. It contains six items that evaluate the quantity of cigarette 
consumption, the compulsion to use, and dependence. Yes/No items are scored from 0 
to 1 and multiple choices are scored from 0 to 3. The items are summed to yield a total 
score of 0 to 10, see Appendix 8). The higher the total Fagerstrom score, the more 
intense is the participant’s physical dependence on nicotine.  
In study Part A, FTND is assessed at Day 1 (baseline), Day 42, Day 84/EOT and Day 
112 (FU)..  
In general, if at least one item score is missing or not ratable, the total/factor/subscale 
scores that include the item will be set to missing. 
The FTND total score and the change from baseline in total score will be summarized by 
assessment visit. 
4.5.3.6 
Levels and Patterns of Social and General Activity (optional) 
‘Phone Usage Monitoring’ will be carried out as an exploratory and optional tool to help 
understand a potential therapeutic effect of RO6889450, regarding participant’s 
functioning and behavior and to refine such outcome measures for future studies. 


RO6889450—F. Hoffmann-La Roche Ltd 
27/Technical Document for Statistical Analysis BP40283 PART A 
 
Participants who have a personal Android-based smartphone will be asked to download 
a Phone Usage Monitoring App.Through the Smartphone App the phone usage of the 
participants will be monitored and evaluated, from which levels and patterns of social 
and general activity of the participants can be inferred. The App will record: 
• 
Time spent on the phone and on different Apps: the power state of the phone 
(screen on/off, power connected/disconnected, and shutdown/restart/boot) and all 
screen touch events will be recorded. Given the wide variety of apps, each app is 
grouped into one of the three broad categories: social, engagement, and entertainment. 
Every 15 mins the total number of apps that belong to each of these three categories will 
be computed from the process stack. Then the increases in the number of apps for each 
of categories will be computed.  
• 
Number and timing of phone calls, and their duration: the number and duration 
of incoming and outgoing calls per day will be recorded  
• 
Number and timing of messages: the number of incoming and outgoing text 
messages per day will be recorded 
• 
Number of contacts and level of interaction with contacts 
• 
Ambient noise: the mean audio amplitude will be computed to determine the 
acoustic conditions raging from quiet to loud environments. Also the standard deviation 
of the audio amplitude will be computed to gauge if the audio environment is ambient 
(e.g., loud air conditioning) or active (e.g., people talking). 
• 
Location: the GPS chip will be used to record the spatial location of the phone over 
time. Total distance traveled, maximum displacement from the home, standard deviation 
of distances, location entropy, and duration of time spent at primary location and at 
secondary location will be recorded on a daily basis. A locational routine index over a 
period of time will be computed to quantify the degree of repetition in terms of places 
visited. The number of new locations visited in a day that have not been seen previously 
can be also monitored. Sampled location readings/coordinates will be clustered into 
primary, secondary or other location over the entirety of a participant’s data. The first 
and second largest clusters are labeled as the primary and secondary locations, 
respectively. 
Collected data will be immediately encrypted and buffered on the device until a Wi-Fi 
connection becomes available, at which point the data are uploaded to a database on 
the study server. The data can be analyzed using an evolving suite of software. 
The decision to install the App is optional but encouraged. Participants can at any time 
point decide to remove the App from the smartphone.  


RO6889450—F. Hoffmann-La Roche Ltd 
28/Technical Document for Statistical Analysis BP40283 PART A 
 
The phone usage is continuously monitored from the placebo compliance period up to 
end of the follow-up, i.e., continuously from Week -2 to Day 112 (FU) 
4.5.3.7 
Due to the small number of patients no analysis will be done 
for Part A.CYP2C19 Status on PK Parameters  
To assess CYP2C19 status on PK parameters, genotyping of CYP2C19 will be 
performed. 
A mandatory whole blood sample will be taken for DNA extraction from every participant. 
The DNA may be used for the anaylsis of genetic variants of cytochrome P450, such as 
CYP2C19, that might affect the metabolism, PK, pharmacodynamics, or safety of 
RO6889450. 
It has been suggested that genetic variation of CYP2C19 associated with decreased 
CYP2C19 enzyme activity might be related to an altered PK response to the study 
treatment. Therefore, to assess the affect of genetic variation of CYP2C19 on PK 
responses to RO6889450 the genotyping for CYP2C19 will be performed. Genotyping of 
CYP2C19 would allow for assay of the alleles frequencies. The different alleles of 
CYP2C19 that make up a genotype of a participant would indicate poor or enhanced 
metabolizer status.  
 Due to the small number of patients no analysis will be done for Part A. 
4.5.4 
Other Efficacy Analyses 
4.5.4.1 
Sleep, Mood, Well-Being and Cognitive Functioning 
Sleep, mood, cognition and treatment expectation questions will be presented on the 
AiCure app at selected time points between Day 1 and Day 112 that will appear as 
random to the participant. Likert scales assessing sleep quality, mood / well-being, and 
cognitive functioning will be administered via the smartphone (see Appendix 9). 
Participant will be instructed to fill in the Likert scales (made of six smiley icons) at 
defined time points during the trial. In addition, participants will be asked to answer the 
following question at the end of the study: “Do you think you were taking placebo or 
drug?”. 
The Likert scale is a 6-point scale rating values range from 0 to 5.  The higher the 
values, the better is the subjective well-being and cognitive functioning. Hence positive 
values for change from baseline indicate improvement.  
The Likert scale data will be aggregated in 3-weeks intervals, i.e. ≤ Day 1, (Day 1, Day 
21], (Day 21, Day 42], (Day 42, Day 63], (Day 63. Day 84], (Day 84, Day 112]. If more 
than one value is in an interval, the last value in the interval will be used.  
The Likert scale scores and change from baseline will be summarized by time interval. 


RO6889450—F. Hoffmann-La Roche Ltd 
29/Technical Document for Statistical Analysis BP40283 PART A 
 
PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSES 
To evaluate the PK of RO6889450 and RO6889450-derived metabolite(s), concentration 
per time point, AUCss and Cmax of RO6889450 and RO6889450-derived metabolite(s), 
and other PK parameters as appropriate will be collected.  
Blood samples for measurement of plasma concentrations of RO6889450 and derived 
metabolite(s) will be collected at Day 7, Day 14, Day 42, Day 84/EOT, Day 112 (FU). 
Plasma concentrations will be summarized descriptively by treatment arm per time 
points: the number of non-missing values, arithmetic mean, geometric mean, coefficient 
of variation, standard deviation, minimum and maximum will be reported.   
AUCss, Cmax of RO6889450 and, if feasible, of RO6889450-derived metabolite(s) and 
other PK parameter as appropriate will be analyzed.  
Population PK analyses will only be performed after Part B is completed. 
Pharmacodynamic effects will not be assessed in this study. 
4.6 
SAFETY ANALYSES 
The safety analysis will be conducted to compare the safety and the tolerability of 12 
weeks of treatment with RO6889450 as monotherapy (Part A) with placebo. Safety 
assessments will consist of monitoring and recording AEs, including SAEs, 
measurement of protocol-specified safety laboratory assessments, measurement of 
protocol-specified vital signs, ECGs, and other protocol-specified tests that are deemed 
critical to the safety evaluation of the study. 
All safety analyses will be based on the safety analysis population grouped according to 
the treatment assigned at randomization. 
4.6.1 
Exposure of Study Medication 
The following extent of exposure to randomized study medication will be summarized by 
randomized treatment arm: 
• 
Duration of treatment (weeks), which will be calculated from the first day of 
randomized double-blind study medication intake as recorded with AICURE to the 
last day of randomized double-blind study treatment intake as recorded with 
AICURE, i.e. last dosing date minus first dosing date plus 1 day (divided by 7 to get 
weeks). 
• 
Number of doses over the whole double-blind treatment period derived from the 
number of days at which randomized double-blind treatment was taken as recorded 
with AICURE. 
• 
Total cumulative dose (mg) over the whole double-blind treatment period as 


RO6889450—F. Hoffmann-La Roche Ltd 
30/Technical Document for Statistical Analysis BP40283 PART A 
 
recorded with AICURE. 
• 
Extent of compliance with randomized double-blind treatment (%). Treatment 
compliance for each participant will be calculated as actually taken dose divided by 
planned dose of double-blind treatment. The actually taken dose will be the total 
cumulative dose. The planned dose is the cumulative planned dose over 84 days, 
i.e., 
×84 days. 
4.6.2 
Adverse Events 
The original terms recorded on the eCRF by the Investigator for AEs will be assigned by 
the Sponsor to a standardized term (the “preferred term”) based on MedDRA. All data 
displays of AE will be performed using the system organ class and preferred terms. All 
AEs will be presented as frequency tables by randomized treatment arm with numbers 
and percentage of participants experiencing AEs.  
AEs will be separately summarized for the following analysis periods: 
• 
Screening/Wash-out period for antipsychotics includes the AEs with onset before 
the first day of study medication in the randomized double-blind treatment period 
(Baseline Sign and Symptoms).  
• 
Double-blind treatment period including follow-up includes all AEs from day of 
first onset of study medication in the double-blind treatment period until end of 
follow-up.  
Intensity and relationship to study treatment will be summarized for the double-blind 
treatment period including follow-up as assigned by the investigator.  
In the summary table of AEs by intensity, if a participant has more than one occurrence 
of an event, the event with the most severe intensity will be counted. If the intensity of an 
AE is missing, then the AE will be included only in the total number of events column 
and not in the count of participants with the event by intensity.  
In the summary table of AEs by relationship to trial treatment, if a participant has more 
than one occurrence of an event, the most closely related event will be counted. If the 
relationship of an AE is missing, then the AE will be included only in the total number of 
events column and not in the count of participants with the event by relationship.  
All SAEs and AEs that led to death, and AEs that led to withdrawal of study treatment 
will also be summarized by treatment arm.  
The following rules will be applied for AEs with missing onset or end dates: 


RO6889450—F. Hoffmann-La Roche Ltd 
31/Technical Document for Statistical Analysis BP40283 PART A 
 
• 
Events that are missing both, onset and end dates, will be considered as emerging 
from treatment, given the participant had at least one dose of study medication.  
• 
If the onset date is missing and the end date is on or after the first dosing date, then 
the event will be considered as emerging from treatment. 
• 
If the end date is missing and the onset date is on or after the first dosing date of a 
specific period, then the event will be considered as emerging from treatment.  
• 
If the end date is missing and the most extreme intensity is worse than the initial 
intensity and the onset date is before the first dosing date of a specific period, then 
the event will be considered as emerging from treatment. 
• 
If the onset or end dates are missing, the duration will be set to missing. 
The analysis will be based on the safety analysis population grouped according to the 
treatment assigned at randomization. 
Time to onset of exacerbation of schizophrenia (AE preferred terms Schizophrenia, 
Psychotic dissorder) will be evaluated by summary statistics. 
4.6.3 
Clinical Laboratory Tests 
The Investigator will review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the eCRF.  
In study Part A, hematology, chemistry and lipids are assessed at Week -4, Day 1, Day 
14, Day 42, Day 84/EOT, Day 112 (FU). Urinalysis is additionally assessed at Day 28 
and Day 56, but not at Day 42. Hematology, chemistry and lipids assessments will be 
assigned to analysis study days according to the following table: 
Assessment Day 
Assigned Study Day 
>88 or >= 1 day after last study medication  
FU, will not be included in statistical analysis 
64-88 
84 
28-63 
42 
2-28 
14 
-2-1 
1 
<-2 
-35, will not be included in statistical analysis 
 
Urinalysis assessments will be assigned to analysis study days according to the 
following table: 
Assessment Day 
Assigned Study Day 
>88 or >=1 day after last study medication  
FU, will not be included in statistical analysis 
71-88 
84 
43-70 
56 
22-42 
28 
2-21 
14 


RO6889450—F. Hoffmann-La Roche Ltd 
32/Technical Document for Statistical Analysis BP40283 PART A 
 
-2-1 
1 
<-2 
-35, will not be included in statistical analysis 
 
Clinical laboratory data are stored on the database in the units in which they were 
reported. For analysis laboratory data will be converted using the International System of 
Units (SI units; Système International d’Unités). Laboratory data not reported in SI units 
will be converted to SI units before processing and will be transformed to common 
reference range using Roche Safety Lab Standardisation.  
Summary statistics for converted values and changes from baseline at each assessment 
time will be presented. Baseline is the patient’s last observation prior to initiation of 
randomized double-blind study treatment.  
The number of patients with a laboratory value abnormality in the direction specified 
(low/high) among patients during randomzed double-blind treatment without this 
abnormality at baseline will be summarized.  
Mean (+/- SEM) plots including single values will be presented by scheduled time point 
and randomized treatment arm. 
Safety laboratory test values will be presented by individual listing with flagging of values 
outside the normal range.  
The analysis will be based on the safety analysis population grouped according to the 
treatment assigned at randomization. 
4.6.4 
Electrocardiograms (ECG) data analysis 
Triplicate ECGs are required at screening, where the three individual ECG tracings 
should be obtained as closely as possible in succession, but no more than two minutes 
apart. The full set of triplicates should be completed in less than five minutes. At all other 
visits, single ECGs are collected. Any clinically relevant changes or abnormalities 
occurring during the study should be recorded in the AE section of the eCRF. 
In study Part A, twelve-lead ECG recording will be obtained at Week -4, Day 1, Day 14, 
Day 56, Day 84/EOT, Day 112 (FU). ECG assessments will be assigned to analysis 
study days according to the following table: 
Assessment Day 
Assigned Study Day 
>88 or >=1 day after last study medication  
FU, will not be included in statistical analysis 
71-88 
84 
36-70 
56 
2-35 
14 
-2-1 
1 
<-2 
-35, will not be included in statistical analysis 
 


RO6889450—F. Hoffmann-La Roche Ltd 
33/Technical Document for Statistical Analysis BP40283 PART A 
 
Summary statistics for actual heart rate, PQ (PR), QRS, QT, RR, and QTcF values and 
changes from baseline at each assessment time will be presented. Baseline is the 
patient’s last observation prior to initiation of randomized double-blind study treatment.  
The number of patients with a ECG value abnormality in the direction specified 
(low/high) during randomzed double-blind treatment will be summarized.  
QTcF intervals will be classified into categories ≤450 msec, >450-≤480 msec, >480-
≤500 msec and >500 msec, change from baseline will be classified into categories ≤30 
msec, >30-≤60 msec, >60 msec; both will be summarized by scheduled time point and 
overall for the maximum post-baseline interval. 
ECG data will be presented by individual listings. In addition, tabular descriptive 
summaries for the change from baseline in ECG intervals: heart rate, PQ (PR), QRS, 
QT, RR, and QTcF. T- and U-waves abnormalities will be displayed. 
ECG data will be presented by individual listing with flagging of values outside the 
normal range.  
Mean (+/- SEM) plots including single values will be presented by scheduled time point 
and randomized treatment arm. 
The analysis will be based on the safety analysis population grouped according to the 
treatment assigned at randomization. 
4.6.5 
Concomitant Medications  
Concomitant therapy includes any medication, e.g., prescription drugs, over-the-counter 
[OTC] drugs, approved dietary and herbal supplements, nutritional supplements and any 
nonmedication interventions (e.g., individual psychotherapy, cognitive behavioural 
therapy, smoking cessation therapy, and rehabilitative therapy). As a general rule no 
new concomitant medications are permitted, with the exception of medications to treat 
AEs.  
The original terms (the “verbatim term”) recorded on the participants’ eCRF by the 
investigator will be assigned to a standardized term (the “preferred term”) and 
Anatomical Therapeutic Chemical (ATC) classification using WHODrug Global B3 
Format dictionary. Analyses will use preferred terms and grouped by ATC2 
(pharmacological or therapeutic properties) levels. Note: If a generic is assigned 
multiple classes ATC Class paths in WHODrug , it may be listed multiple times. 
Previous/Concomitant medications (started before first randomized double-blind 
treatment intake), concomitant medications (started after first randomized double-blind 
treatment intake) and medications to treat AEs.will be presented by treatment arm in 


RO6889450—F. Hoffmann-La Roche Ltd 
34/Technical Document for Statistical Analysis BP40283 PART A 
 
summary tables and listings. Multiple occurrences of a medication in an individual (i.e., 
same coded term) will be counted only once in summary tables.  
The analysis will be based on the safety analysis population grouped according to the 
treatment assigned at randomization. 
4.6.6 
Suicidality Assessment (C-SSRS) 
The C-SSRS is a tool used to assess the lifetime suicidality of a participant (C-SSRS 
baseline) as well as new instances of suicidality (C-SSRS since last visit). It incorporates 
a structured interview to prompt recollection of suicidal ideation, including the intensity of 
the ideation, behavior, and attempts with actual/potential lethality. 
In study Part A, the “baseline” version will be completed at the Screening visit (Week -4) 
and a “since last visit” version will be completed at subsequent visits at Day -7, Day 1, 
Day 7, Day 14, Day 28, Day 42, Day 56, Day 70, Day 84/EOT, Day 112 (FU). 
The items of the C-SSRS will be listed. The number and percentage of patients with 
suicidal ideation, suicidal behavior, and self-injurious behavior without suicidal intent 
based on the C-SSRS during treatment will be summarized (see Appendix 7).  
The analysis will be based on the safety analysis population grouped according to the 
treatment assigned at randomization. 
4.6.7 
Extrapyramidal Symptom Rating Scale, Abbreviated Version 
(ESRS-A) 
The presence and severity of extrapyramidal symptoms are evaluated using ESRS-A. 
The reliability and validity of the ESRS have been demonstrated in antipsychotic-induced 
movement disorders. The scale is organized into two main components: (1) an 
assessment of specific symptoms of Parkinsonism, dyskinesia, akathisia, and dystonia 
(2) the Clinician’s Global Impression (CGI) of these symptoms. All are evaluated on a 
scale of 0 (absent) to 5 (extreme).  
In study Part A, the assessments will be carried out at the Screening visit (Week -4), 
and subsequent visits Day 1, Day 14, Day 28, Day 84/EOT, Day 112 (FU). Assessments 
will be assigned to analysis study days according to the following table: 
Assessment Days 
Assigned Analysis Study Day 
>88 or >=1 day after last study medication  
FU, will not be included in statistical analysis 
57-88 
84 
22-56 
28 
2-21 
14 
-2-1 
1 
<-2 
-35, will not be included in statistical analysis 
 


RO6889450—F. Hoffmann-La Roche Ltd 
35/Technical Document for Statistical Analysis BP40283 PART A 
 
The movement related rating scales (ESRS-A) will be summarized for the total score of 
each domain (i.e., Parkinsonism, Akathisia, Dystonia, Dyskinesia) and the associate 
CGIS score by treatment group using descriptive statistics at each scheduled 
assessment visit. Change from baseline will be summarized by timepoint using 
descriptive statistics. In addition, patients (n, %) with clinically relevant severity in each 
of the four symptoms will be summarized. 
The analysis will be based on the safety analysis population grouped according to the 
treatment assigned at randomization. 
4.6.8 
CGI-S MTS and CGI-I MTS 
At screening, clinicians will gather information from the patient’s past psychiatric history, 
caregiver feedback, and clinical judgement to determine two to three prodromal or MTS 
(most troubling symptoms) historically associated with a signal of the patient’s relapse. 
The patient’s MTS (including frequency, intensity, interference with daily function or 
family life, and other salient consequences) will be recorded and these symptoms 
evaluated using the CGI-S MTS. At post-baseline visits, the clinician will use the MTS 
description and re-evaluate the MTS using the CGI-S and CGI-I. This re-assessment of 
the patient’s prodromal symptoms will support with the ongoing clinical evaluation of 
relapse risk. 
In study Part A CGI-S MTS will be evaluated at Week -4, Day -7, Day 1 (baseline), Day 
7, Day 14, Day 21, Day 28, Day 35, Day 42, Day 49, Day 56, Day 63, Day 70, Day 77, 
Day 84 /EOT, Day 112 (FU) by an experienced clinician. All assessments will be 
assigned to analysis study days according to the following table: 
Assessment Days 
Assigned Analysis Study Day 
>88 or >=1 day after last study medication  
FU, will not be included in statistical analysis 
81-88 
84 
74-80 
77 
67-73 
70 
60-66 
63 
53-59 
56 
46-52 
49 
39-45 
42 
32-38 
35 
25-31 
28 
18-24 
21 
11-17 
14 
2-10 
07 
-2-1 
1 
-8- -14 
-7, will not be included in statistical analysis 
<-14 
-35, will not be included in statistical analysis 
 
The The CGI-S MTS and and change from baseline will be summarized. 


RO6889450—F. Hoffmann-La Roche Ltd 
36/Technical Document for Statistical Analysis BP40283 PART A 
 
In study Part A CGI-I MTS will be evaluated at Day 7, Day 14, Day 21, Day 28, Day 35, 
Day 42, Day 49, Day 56, Day 63, Day 70, Day 77, Day 84 /EOT, Day 112 (FU) by an 
experienced clinician. All assessments will be assigned to analysis study days as 
described for CGI-S MTS. 
The CGI-I MTS scores will be summarized. 
4.6.9 
Vital Signs Body Weight and BMI 
Orthostatic vital signs are vital signs taken when the patient moves from supine to 
standing position. In the Phase I study BP30134 Postural Orthostatic Tachycardia was 
the most often observed change in vital signs which occurred at multiple timepoints, 
including pretreatment in all cohorts and placebo in both Part A (SAD) and Part B 
(MAD). The definition of POT is a heart rate > 120 bpm on standing or an increase in 
heart rate by 30 bpm from a resting heart rate without clinically significant orthostatic 
hypotension. 
In study Part A, systolic blood pressure, diastolic blood pressure and heart rate are 
assessed in supine as well as standing position at Week -4, Day 1, Day 14, Day 28, Day 
56, Day 84/EOT, Day 112 (FU). Weight is collected at at Week -4, Day 1, Day 56, Day 
84/EOT, Day 112 (FU). BMI is calculated as weight (kg) / height (m)2 (height as 
measured at baseline).  
Blood pressure and heart rate assessments will be assigned to analysis study days 
according to the following table: 
Assessment Days 
Assigned Analysis Study Day 
>88 or >=1 day after last study medication  
FU, will not be included in statistical analysis 
71-88 
84 
43-70 
56 
22-42 
28 
2-21 
14 
-2-1 
1 
<-2 
-35, will not be included in statistical analysis 
 
Weight assessments will be assigned to analysis study days according to the following 
table: 
Assessment Days 
Assigned Analysis Study Day 
>88 or >4 day after last study medication  
FU, will not be included in statistical analysis 
71-88 
84 
2-70 
56 
-2-1 
1 
<-2 
-35, will not be included in statistical analysis 
 
Summary statistics for values and changes from baseline at each assessment time will 
be presented. Baseline is the patient’s last observation prior to initiation of randomized 


RO6889450—F. Hoffmann-La Roche Ltd 
37/Technical Document for Statistical Analysis BP40283 PART A 
 
double-blind study treatment. Blood pressure and heart rate will be presented in units as 
collected (mmHg and beats/min), while body weight will be converted to kg.  
The definition of POT is a heart rate > 120 bpm on standing or an increase in heart rate 
by 30 bpm from a resting heart rate without clinically significant orthostatic hypotension. 
To support assessment of POT, the difference between standing and supine heart rate 
will be calculated and summarized. Patients with a heart rate > 120 bpm in standing 
position or an increase in heart rate by 30 bpm from a supine heart rate will be listed. 
Mean (+/- SEM) plots including single values will be presented by scheduled time point 
and randomized treatment arm. 
The analysis will be based on the safety analysis population grouped according to the 
treatment assigned at randomization. 
4.7 
MISSING DATA 
Generally, in summaries, all data from the respective analysis population regardless of 
completeness by Week 12 will be included; participants who have taken the study 
medication or have visited the sites only partially will be included in the summaries. No 
imputation will be applied for missing data will be applied. 
For all rating scales, if any item score contributing to the total/factor/subscale score is 
missing, then the total/factor/subscale will be set to missing.  
4.8 
INTERIM ANALYSES 
See section 2.4. 
 
 


RO6889450—F. Hoffmann-La Roche Ltd 
38/Technical Document for Statistical Analysis BP40283 PART A 
 
Appendix 1 Protocol Synopsis 
PROTOCOL TITLE: 
PHASE 2, RANDOMIZED, DOUBLE-BLIND, PLACEBO-
CONTROLLED STUDY TO ASSESS THE EFFECTS OF 
RO6889450 IN PATIENTS WITH SCHIZOPHRENIA OR 
SCHIZOAFFECTIVE DISORDER AND NEGATIVE SYMPTOMS 
PROTOCOL NUMBER: 
BP40283 
VERSION: 
2 
TEST PRODUCT: 
RO6889450 
PHASE: 
2 
 
RATIONALE 
The trace amine-associated receptor 1 (TAAR1) partial agonist RO6889450, a modulator of 
dopaminergic transmission, leads to a normalization of behaviors in rodent models of negative 
symptoms of schizophrenia. Results of a clinical study with RO6889450 in healthy volunteers 
suggest performance improvements in tasks that probe reward-based learning and motivated 
behavior, functions that are deficient in patients with negative symptoms (e.g., blunted affect, 
avolition/apathy). These results indicate a potential utility of RO6889450 in the treatment of 
negative symptoms associated with schizophrenia or schizoaffective disorder. 
 
OBJECTIVES AND ENDPOINTS 
Objectives 
Endpoints 
Primary 
Part A: To compare the efficacy of 
 
once daily (QD) of RO6889450 as 
monotherapy with placebo on negative 
symptoms in patients with schizophrenia or 
schizoaffective disorder. 
Part B: To compare the efficacy of 
 
 QD of RO6889450 as add-on therapy 
with placebo on negative symptoms in 
patients with schizophrenia or schizoaffective 
disorder. 
Part A & B: Change from baseline at Week 12 
in the Brief Negative Symptoms Scale (BNSS) 
avolition/apathy subscore (sum of items 
“behavior” and “internal experience”). 
 


RO6889450—F. Hoffmann-La Roche Ltd 
39/Technical Document for Statistical Analysis BP40283 PART A 
 
Objectives 
Endpoints 
• 
Secondary 
To compare the effect of RO6889450 with 
placebo on: 
• 
Clinical Global Impression Severity 
(CGI-S) and change (CGI-I) (overall and 
negative symptoms) 
• 
Change from baseline in CGI-S and CGI-
S negative symptoms scores 
• 
CGI-I, and CGI-I negative symptoms 
scores 
To compare the effect of RO6889450 with 
placebo on: 
• 
Symptoms of schizophrenia or 
schizoaffective as assessed with the 
Positive and Negative Syndrome Scale 
(PANSS), BNSS, and Defeatist 
Performance Attitude Scale (DPAS) 
• 
Change from baseline in PANSS total and 
symptom factor scores 
• 
Change from baseline in BNSS total and 
subscores 
• 
Change from baseline in DPAS scores 
• 
To compare the safety and tolerability of 
12 weeks of treatment with RO6889450 
as monotherapy (Part A) or add-on 
therapy with placebo (Part B)  
• 
Incidence, nature, and severity of adverse 
events (AEs) 
• 
Incidence, nature, and severity of serious 
AEs (SAEs) 
• 
Incidence, nature, and severity of 
treatment discontinuations due to AEs 
• 
Change from baseline in orthostatic vital 
signs recordings 
• 
Change from baseline in 
electrocardiogram (ECG) intervals: heart 
rate, PQ (PR), QRS, QT, RR and QTcF 
along with information on T- and U-waves  
• 
Incidence of laboratory abnormalities, 
based on hematology, clinical chemistry, 
coagulation and urinalysis test results 
• 
Change from baseline in Columbia-
Suicide Severity Rating Scale (C-SSRS) 
and Extrapyramidal symptom rating scale, 
abbreviated (ESRS-A) 
• 
To evaluate the pharmacokinetics (PK) of 
RO6889450 and RO6889450-derived 
metabolite(s). 
• 
Concentration per time point 
• 
AUCss of RO6889450 and RO6889450-
derived metabolite(s) 
• 
Cmax of RO6889450 and RO6889450-
derived metabolite(s)  
• 
Other PK parameters as appropriate 
 
OVERALL DESIGN 
This is a Phase 2, multicenter, randomized, double-blind, two-part, placebo-controlled, parallel-
group, study in patients with schizophrenia or schizoaffective disorder. 
Study Design 
Part A (monotherapy):  
Participants will be washed out (one week) from their antipsychotic therapy before being 
randomized to either 
 QD of RO6889450 or placebo for 12 weeks. Stratification will be 
based on baseline BNSS avolition/apathy subscore (BNSS ≤6 vs >6), age (18-35 years vs. 36-
55 years), and sex. The participants will have the option of an inpatient stay or partial 
hospitalization during the washout period as well as the first week of study drug. 
 


RO6889450—F. Hoffmann-La Roche Ltd 
40/Technical Document for Statistical Analysis BP40283 PART A 
 
Part B (add-on therapy):  
Participants will be randomized 1:1:1 to 
 QD of RO6889450, 
 QD of RO6889450, 
or placebo for 12 weeks. Stratification will be based on BNSS avolition/apathy subscore (sum of 
items “behavior” and “internal experience”; ≤6 vs. >6), age (18-35 years vs. 36-55 years), sex, 
and antipsychotic treatment (1:1 stratification ratio between dopamine 2 receptor [D2]/serotonin 
2A [5HT2A] receptor antagonists and D2 partial agonist).  
Participants who are not enrolled in Part A, can be screened for Part B only after approval by the 
Medical Monitor or delegate. The reason(s) for the decision must be documented. 
 
Part B is planned to start after Part A. If the result of Part A is negative, the Sponsor may choose 
not to conduct Part B.  
 
Interim analyses:  
The Sponsor may choose to conduct an interim efficacy analysis in Part A. The decision to 
conduct an optional interim analysis and the timing of the analysis will be documented in the 
Sponsor’s trial master file prior to the conduct of the interim analysis. The interim analysis will be 
performed and interpreted by members of the Sponsor study team and appropriate senior 
management personnel who will be unblinded at the treatment group level. Access to treatment 
assignment information will follow the Sponsor’s standard procedures.  
The results of this analysis may support initiation of Part B enrollment during Part A if a positive 
results threshold is met as defined in the statistical analysis plan (SAP). In case of very slow 
recruitment, Part A may be stopped and/or Part B may be started without the interim analysis. 
 
The Sponsor may choose to conduct an interim analysis of Part B to determine the chance of 
final success. The results of such an analysis may support an early termination of Part B. 
 
Treatment Groups and Duration 
The investigational medicinal product (IMP) is RO6889450 (and matching placebo) and will be 
given orally QD at a daily dose of 
 in Part A and at a daily dose of either 
 
in Part B.  
 
Length of Study 
Part A: The total duration will be approximately 147 days (from screening through study 
completion) for each enrolled participant as follows: 
• 
Screening: up to 35 days (including the placebo compliance and a 7-day washout 
period) 
• 
Treatment period: 84 days (12 weeks) 
• 
Follow up: 28 days 
 
Part B: The total duration will be up to approximately 147 days (from screening through study 
completion) for each enrolled participant as follows:  
• 
Screening: up to 35 days (including the placebo compliance period) 
• 
Treatment period: 84 days (12 weeks) 
• 
Follow up: 28 days 
 
End of Study 
The end of the study is defined as the date when the last participant last observation (LPLO) 
occurs. LPLτ is expected to occur approximately 28 days after the last participant’s last dose. 
 
Data Monitoring Committee 
An independent Data Monitoring Committee (iDMC) will regularly review unblinded safety and 
efficacy (as appropriate) data. The iDMC will be composed of at least two psychiatrists external 
to the Sponsor and will be responsible for monitoring safety data to help assure that continuation 


RO6889450—F. Hoffmann-La Roche Ltd 
41/Technical Document for Statistical Analysis BP40283 PART A 
 
of the study in its current design does not pose unacceptable safety risks to participants. 
Planned and ad hoc safety reviews will be performed as described within the iDMC charter.   
PARTICIPANT POPULATION 
The participants of this study will be male and female outpatients between 18 to 55 years of age 
with a Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) diagnosis of 
schizophrenia or schizoaffective disorder with negative symptoms, who are stable. For Part B, 
participants also need to be stable on antipsychotic treatment. Participants who are in a 
residential inpatient setting are eligible for this study. 
 
Inclusion/Exclusion Criteria 
Unless otherwise stated, inclusion and exclusion criteria refer to evaluations or assessments at 
screening. 
Inclusion Criteria: 
Informed Consent 
1. Able and willing to provide written informed consent according to International Council for 
Harmonisation (ICH) and local regulations as assessed using the Evaluation to Sign 
Consent. If the participant has a legal representative, the informed consent must be signed 
by this person as well. 
 
Patient and Disease Characteristics 
2. Male or female participants aged 18-55 years (inclusive). 
3. Patients with a DSM-5 diagnosis of schizophrenia or schizoaffective disorder as confirmed 
by the Mini International Neuropsychiatric Interview (MINI). 
4. Part B only: Stable treatment with a D2/5HT2A antagonists or a D2 partial agonist for a 
minimum of six months and receiving no more than two antipsychotics (if no blood 
concentration of the prescribed AP medication [or active metabolites] is detected, the 
participant, should not be enrolled.). Antipsychotic regimen: Patients must be on a 
"primary" antipsychotic and may be on a secondary antipsychotic. The amount of the 
secondary antipsychotic has to be equal to or less than the equivalent dose of the primary 
antipsychotic and the sum of the primary and secondary antipsychotics must be ≤6 mg of 
risperidone equivalents (see Appendix 7). 
5. Medically stable during the prior six months. 
6. Outpatient with no hospitalization for worsening of schizophrenia or schizoaffective disorder 
within the six prior months (hospitalization for social management within this time is 
acceptable). 
7. PANSS negative symptom factor score of 18 or higher. 
8. The following rating on items of the PANSS:  
(a) 
less than 5 on G8 (uncooperativeness), P1 (delusions), P3 (hallucinations), P4 
(excitement/hyperactivity), and P6 (suspiciousness/persecution) 
(b) 
less than 4 on P7 (hostility) and G14 (poor impulse control) 
9. Has an informant who is considered reliable by the Investigator to provide support to the 
participant and to help ensure compliance with study visits and protocol procedures; who 
preferably is also able to provide input helpful for completing study rating scales and is in 
regular contact with the participant in order to be able to alert the Investigator of worsening 
signs and symptoms for the participant. 
10. Body mass index (BMI) between 18 and 40 kg/m2 inclusive. 
Reproductive 
11. A female is eligible to participate if she is not pregnant, not breastfeeding, and at least one 
of the following conditions applies:  
(a) Not a woman of childbearing potential (WOCBP). 
(b) WOCBP, who  


RO6889450—F. Hoffmann-La Roche Ltd 
42/Technical Document for Statistical Analysis BP40283 PART A 
 
- agree to remain abstinent (refrain from heterosexual intercourse) or use 
acceptable contraceptive methods during the treatment period and for at least 28 days 
after the last dose of study drug. 
- The following are acceptable contraceptive methods: bilateral tubal occlusion, male 
sterilization, established proper use of hormonal contraceptives that inhibit ovulation, 
hormone-releasing intrauterine devices and copper intrauterine devices, male or female 
condom with or without spermicide; and cap, diaphragm, or sponge with spermicide. 
 
The contraception and abstinence requirements are intended to prevent exposure of an embryo 
to the study treatment. The reliability of sexual abstinence for female enrollment eligibility needs 
to be evaluated in relation to the duration of the clinical study and the preferred and usual 
lifestyle of the participant. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or 
post-ovulation methods) and withdrawal are not acceptable methods of preventing drug 
exposure. 
 
Exclusion Criteria: 
Medical Conditions 
1. 
Part A only: Confirmed suicidal behavior based on Investigator judgment or violent 
behavior resulting in injury or property damage in the prior five years. A history prior to the 
last five years requires approval by the Patient Review Committee (PRC) on a case-by-
case basis. 
2. 
Part A only: Lifetime history of homicidal behavior 
3. 
Moderate to severe substance use disorder within six months (excluding nicotine or 
caffeine) as defined by DSM-5. 
4. 
Other current DSM-5 diagnosis (e.g., bipolar disorder, major depressive disorder). 
5. 
PANSS item G6 (depression) greater than or equal to 5. 
6. 
Significant risk of suicide or harming him- or herself or others according to the Investigator’s 
judgment. 
7. 
A prior or current general medical condition that might be impairing cognition or other 
psychiatric functioning (e.g., migraine headaches requiring prophylaxis treatment, head 
trauma, dementia, seizure disorder, stroke; or neurodegenerative, inflammatory, infectious, 
neoplastic, toxic, metabolic, endocrine etc. conditions). 
8. 
Positive result at screening for hepatitis B surface antigen (HBsAg), hepatitis C (HCV, 
untreated), or human immunodeficiency virus (HIV)-1 and -2. HCV patients who have been 
successfully treated and who test negative for HCV RNA, may be considered eligible for 
entry into the study. 
9. 
Tardive dyskinesia that is moderate to severe or requires treatment.  
10. History of neuroleptic malignant syndrome. 
11. Average triplicate QTcF interval greater than 450 msec for males and 470 msec for females 
or other clinically significant abnormality on screening electrocardiogram (ECG) based on 
centralized reading. 
12. Clinically significant abnormalities in laboratory safety test results (including hepatic and 
renal panels, complete blood count, chemistry panel, coagulation and urinalysis), including:  
o 
Aspartate transaminase (AST), alanine transaminase (ALT) 2  upper limit of 
normal (ULN) 
o 
Total bilirubin >1.5 ULN with the exception of Gilbert syndrome 
o 
Serum creatinine 1.5 ULN 
In case of uncertain or questionable results, tests performed during screening may be 
repeated before randomization to confirm eligibility or may be accepted if they are, in the 
opinion of the Investigator and the Medical Monitor, not clinically significant. 


RO6889450—F. Hoffmann-La Roche Ltd 
43/Technical Document for Statistical Analysis BP40283 PART A 
 
13. Significant or unstable physical condition that in the Investigator’s judgment might require a 
change in medication or hospitalization during the course of the study. 
 
Prior/Concomitant Therapy 
14. On more than one antidepressant, or if on one antidepressant, a change in dose within 28 
days prior to screening. 
15. History of clozapine treatment. 
16. Concomitant use of prohibited medications. 
17. Positive urine drug screen for amphetamines, methamphetamines, opiates, buprenorphine, 
methadone, cannabinoids (including cannabidiol), cocaine and barbiturates. In case of 
uncertain or questionable results, the urine drug screen may be repeated once during the 
screening period to confirm eligibility. 
Other Exclusions 
18. Receipt of an investigational drug within 28 days or five times the half-life of the 
investigational drug (whichever is longer) before the first study drug administration 
19. Donation of blood over 400 mL within three months prior to screening. 
 
Confirmation of Eligibility at Baseline 
1. 
Part A only: Patient will be excluded if unable to taper off an antipsychotic in the one week 
prior to baseline (e.g., in the case of symptom exacerbation or antipsychotics with a longer 
half-life). 
2. 
Female participants who are of childbearing potential must have a negative pregnancy test 
result at baseline. 
 
NUMBER OF PARTICIPANTS 
Overall, it is planned to have approximately 500 participants randomized in this study in order 
to achieve 400 evaluable participants.  
In Part A, approximately 125 participants will be randomized to one of two treatment arms to 
ensure that approximately 100 participants complete the treatment phase as described in this 
protocol, with the primary endpoint assessed at Week 12. In Part B, approximately 375 
participants will be randomized to one of three treatment arms to ensure that approximately 300 
participants complete the treatment phase as described in this protocol with the primary endpoint 
assessed at Week 12. 
 
CONCOMITANT MEDICATIONS 
Rescue Medicine During Part A  
If early signs of relapse requiring treatment are noticed/recorded by the Investigator, an 
antipsychotic should be prescribed and the participant will be immediately withdrawn from the 
study drug. 
Permitted Therapy 
The use of stable, scheduled doses of benzodiazepines are permitted. The use of stable, 
scheduled doses of non-benzodiazepine hypnotics are permitted. 
If deemed necessary by the Investigator to treat occasional anxiety, agitation or sleep problems, 
lorazepam, alprazolam, or oxazepam are allowed as needed (PRN) (up to a maximum daily 
dose of lorazepam 6 mg, alprazolam 3 mg, or oxazepam 90 mg). If PRN treatment of more than 
five consecutive days is necessary, this should be discussed with the Medical Monitor. PRN 
doses of benzodiazepines should not be administered within 12 hours of a clinic visit. 
Non-prohibited medications used for the treatment of stable medical conditions other than 
schizophrenia (e.g., hypertension, diabetes, oral contraceptives, hormone-replacement therapy) 
are allowed during the study, provided that they have been stable for 28 days prior to screening 
and are intended to remain stable throughout the study up to the follow-up visits. 


RO6889450—F. Hoffmann-La Roche Ltd 
44/Technical Document for Statistical Analysis BP40283 PART A 
 
Patients in Part B of the study must be on stable treatment (i.e., no medication changes or 
significant dose adjustments) with D2/5HT2A antagonists or D2 partial agonist for a minimum of 
six months prior to screening. Co-administration of RO6889450 and P-gp substrates, such as 
risperidone, amisulpride, aripiprazole, and paliperidone, though permitted may result in slight 
elevations of the P-gp substrate so continued monitoring is suggested. 
Prohibited Therapy 
Use of the following therapies (non-topical formulation where applicable) is prohibited during the 
study unless otherwise specified: 
• 
Clinically relevant substrates of P-gp, including quinidine and loperamide. 
 
In Part A, all antipsychotic treatment as well as medications used to treat extrapyramidal 
symptoms (EPS) (e.g., anticholinergics) will be discontinued before randomization. 
Antipsychotic medications that require longer washout periods (i.e., more than two weeks), such 
as cariprazine, brexpiprazole, or long-acting injectable antipsychotics are exclusionary.   
Patients receiving treatment for tardive dyskinesia (e.g., valbenazine or deutetrabenazine) are 
excluded. As a general rule, no new concomitant medications will be permitted, with the 
exception of medications to treat AEs, unless the rationale for exception is discussed and 
accepted by the Sponsor or designee and clearly documented between the Investigator and the 
Sponsor. 
 




RO6889450—F. Hoffmann-La Roche Ltd 
46/Technical Document for Statistical Analysis BP40283 PART A 
 
Period 
Screening 
Treatment Period 
Follow-Up Visits 
 
 
Placebo Compliance 
 
 
Week 
Week -4 
Week -2 
Week -1 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
16 
Day 
Day -35 to 
Day -19 
Day -14 
Day -7 
Baseline1/
Day 1 
Day 
7 
Day 
14 
Day 
21 
Day 
28 
Day 
35 
Day 421 
Day 
49 
Day 
56 
Day 
63 
Day 
70 
Day 
77 
Day 84/ 
EOT1, 2 
Day 
91 
Day 
98 
Day 
1121 
Visit window (days) 
 
±1 
±1 
-1 
±1 
±1 
±1 
±2 
±2 
±2 
±2 
±2 
±2 
±2 
±2 
±2 
±2 
±2 
±4 
Orthostatic vital signs 
X 
 
 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
Viral serology 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prolactin sample 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Alcohol levels 
X 
 
 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
Drugs of abuse 
X 
 
 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
Urinalysis 
X 
 
 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
Pregnancy test 7 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Blood chemistry and lipids  
X 
 
 
X 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
Hematology 
X 
 
 
X 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
X 
Coagulation parameters 
X 
 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Antipsychotic blood 
levels  
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
PK sample 
 
 
 
 
X9 
X 9,10 
 
 
 
X 9,10 
 
 
 
 
 
X 9,10 
 
 
X 
Genotyping 
 
 
 
X 11 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
RBR DNA (optional) 
 
 
 
X 11 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MINI 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
WASI-II  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 






RO6889450—F. Hoffmann-La Roche Ltd 
49/Technical Document for Statistical Analysis BP40283 PART A 
 
 
1 To decrease patient burden, some assessments may be split within the visit window days. Baseline assessments should be done pre-dose on Day 1 or within 
24 hours prior to the first double-blind dose (i.e., on Day -1). 
2 If treatment is discontinued early, the Week 12 visit assessments as well as the follow-up visit assessments (four weeks after last dose) should be performed. 
3 Phone calls listed are for scheduled visits. Informal calls by a case manager up to three times per week to follow up with patients, especially during the 
washout period, are encouraged. 
4 Eligibility will be confirmed at baseline (see Section 
 
). 
 
5 Complete physical exam includes height and weight at screening. Limited physical exams (symptom driven) and weight will be done at subsequent visits 
including the follow-up visit (see Section 
). 
6 Triplicate ECGs will be performed at screening and a single ECG at subsequent visits ECGs should be performed prior to meals or any scheduled vital sign 
measurements and blood draws. 
7 Pregnancy testing will be using a blood sample at screening and urine sample at subsequent visits.  If urine test is positive, pregnancy must be confirmed by 
blood test.  
8 Washout may start earlier for antipsychotics with long half-life (2 week washout for aripiprazole, olanzapine, see 
 
). 
9 Sample should be taken prior to the morning dose (pre-dose/trough). 
 
 
 
 
 
10 One additional sample should be taken two hours (± 0.5) post-dose. 
 
 
 
 
 
 
11 Samples can be taken at any time between baseline and follow-up. 
 
 
 
 
 
12 Phone usage monitoring will be used only with screened patients who have android phones and agree to the assessment. 
 
 
13 After informed consent, but prior to initiation of study drug, only SAEs caused by a protocol-mandated intervention will be collected. After initiation of study 
drug, all adverse events, regardless of relationship to study drug, will be reported until 28 days after the last dose of study drug.  
14 The placebo compliance period will start with a visit reviewing instructions with the patient.   
 
 
15 Study drug is three capsules administered once daily, preferably in the morning. The last dose is given at the Day 84/EOT visit. 
16 Sleep, mood, cognition and treatment expectation questions will be presented on the AiCure app at select time points that will appear as random to the 
participant. 
17 The exploratory endpoints Brief Assessment of Cognition in Schizophrenia (BACS) (digital version), Wechsler Abbreviated Scale of Intelligence – Second 
Edition (WASI-II), Wide Range Achievement Test (WRAT-4) and Virtual Reality Functional Capacity Assessment Tool (VRFCAT) are not available as 
validated Spanish translation. Therefore, sites will not be required to administer these tests to Spanish only speaking patients. If validated versions become 
available, they may be used. 
 


RO6889450—F. Hoffmann-La Roche Ltd 
50/Technical Document for Statistical Analysis BP40283 PART A 
 


RO6889450—F. Hoffmann-La Roche Ltd 
51/Technical Document for Statistical Analysis BP40283 PART A 
 
Appendix 3 BNSS Items 
 
 


RO6889450—F. Hoffmann-La Roche Ltd 
52/Technical Document for Statistical Analysis BP40283 PART A 
 
Appendix 4 PANSS Items and Scores 
 
PANSS Negative Symptoms, Disorganized Thoughts and Positive Symptoms Factors 
 
PAσSS factors based on “Marder” PAσσS factor analysis published in J Clin Psych 
58:12, December 1997 p538. 
 


RO6889450—F. Hoffmann-La Roche Ltd 
53/Technical Document for Statistical Analysis BP40283 PART A 
 
 
Appendix 5 CGI-S and CGI-I Questions 
Clinical Global Impression 
Clinical Global Impression – Severity of Illness Scale (CGI-S) 
 
 
Clinical Global Impression – Improvement Scale (CGI-I) 
 
 
Adapted from Guy W. ECDEU Assessment manual for Psychopharmacology, US 
Department of Health, Education, and Welfare publication (ADM) 76-338, Rockville, MD; 
National Institute of Mental Health, 1976. 
 
 


RO6889450—F. Hoffmann-La Roche Ltd 
54/Technical Document for Statistical Analysis BP40283 PART A 
 
Appendix 6 DPAS Questions 
1. It is difficult to be happy unless one is good-looking, intelligent, rich and creative. 
2. People will probably think less of me if I make a mistake. 
3. If I do not do well all the time, people will not respect me. 
4. Taking even a small risk is foolish because the loss is likly to be a disaster 
5. If a person asks for help, it is a sign of weakness. 
6. If I do not do as well as other people, it means I am an inferior human being. 
7. If I fail at my work, then I am a failure as a person. 
8. If you cannot do something well, there is little point in doing it atall. 
9. Making mistakes is fine because I can learn from them. 
10. If I fail partly, it is as bad as being a complete failure.  
11. People should have a reasonable likelihood of success before undertaking 
anything. 
12. If I don’t set the highest standards for myself, I am likey to end up a second-rate 
person. 
13. If I am to be a worthwhile person, I must be truly outstanding in one major 
respect. 
14. People who have good ideas are more worthy than those who do not. 
15. If I ask a question, it makes me look inferior. 
 


RO6889450—F. Hoffmann-La Roche Ltd 
55/Technical Document for Statistical Analysis BP40283 PART A 
 
Appendix 7 Patients with Suicidal Ideation, Suicidal Behavior, 
and Self-Injurious Behavior without Suicidal Intent Based on the 
C-SSRS During Treatment 
 
Notes: N = number of enrolled patients with at least one post-baseline C-SSRS 
assessment. In this table, n and (%) refer to the number and percent of patients who 
experience the event at least once during treatment. For the composite endpoint of 
suicidal ideation (1-5), n and (%) refer to the number and percent of patients who 
experience any one of the five suicidal ideation events at least once during treatment. 
For the composite endpoint of suicidal behavior (6-10), n and (%) refer to the number 
and percent of patients who experience any one of the five suicidal behavior events at 
least once during treatment. For the composite endpoint of suicidal ideation or behavior 
(1-10), n and (%) refer to the number and percent of patients who experience any one of 
the ten suicidal ideation or behavior events at least once during treatment. 


RO6889450—F. Hoffmann-La Roche Ltd 
56/Technical Document for Statistical Analysis BP40283 PART A 
 
 
1=Wish to be Dead, 2=Non-specific Active Suicidal Thoughts, 3=Active Suicidal Ideation 
with Any Methods (Not Plan) without Intent to Act, 4=Active Suicidal Ideation with Some 
Intent to Act, without Specific Plan, 5=Active Suicidal Ideation with Specific Plan and 
Intent, 6=Preparatory Acts or Behavior, 7=Aborted Attempt, 8= Interrupted Attempt, 
9=Actual Attempt (non-fatal), 10=Completed Suicide. 
Only patients with suicidal ideation, suicidal behavior, or self-injurious behavior without 
suicidal intent are displayed. For patients with suicidal ideation, suicidal behavior, or self-
injurious behavior without suicidal intent at any time, data from all visits are displayed. 
Self-Inj Beh wo SI = Self-injurious Behavior without Suicidal Intent. 
 


RO6889450—F. Hoffmann-La Roche Ltd 
57/Technical Document for Statistical Analysis BP40283 PART A 
 
Appendix 8 Fagerstöm Nicotine Dependence Test (FTND) 
Scoring 
 
 
 


RO6889450—F. Hoffmann-La Roche Ltd 
58/Technical Document for Statistical Analysis BP40283 PART A 
 
Appendix 9 Assessment of Sleep, Mood, Well-being and 
Cognitive Functioning, and Assumed Treatment Assignment