Conditions: Schizophrenia, Schizoaffective Disorder
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 287
Healthy volunteers: no

Brief summary:
This study will investigate the efficacy and safety of RO6889450 as monotherapy in participants experiencing an acute exacerbation of symptoms of schizophrenia or schizoaffective disorder.

Detailed description:

Arms:
arm 1: Participants will receive 150 mg of RO6889450 QD for 4 weeks or 12 weeks or 48 weeks. arm 2: Participants will receive 45 mg of RO6889450 QD for 4 weeks or 12 weeks or 48 weeks. arm 3: Participants will receive oral placebo QD for 4 weeks. Participants from this arm that continue to the extension period will be randomized to either 45 mg or 150 mg QD of RO6889450 for up to an additional 8 weeks or additional 44 weeks (optional 36-Week Safety Extension Phase). arm 4: Participants will receive 4 mg of risperidone QD for 4 weeks or 12 weeks or 48 weeks.

Interventions: intervention 1: RO6889450 intervention 2: Placebo intervention 3: Risperidone
Intervention descriptions: intervention 1: Participants will receive oral RO6889450 QD. intervention 2: Participants will receive oral placebo QD. intervention 3: Participants will receive oral risperidone QD.

Protocol document:
Prot_000.pdf: 
 
Official Title: 
 
A Phase II, Multi-Center, Randomized, Double-Blind, Parallel Group, 
Placebo-Controlled Trial of The Efficacy and The Safety of 
RO6889450 (Ralmitaront) vs. Placebo in Patients With an Acute 
Exacerbation of Schizophrenia Or Schizoaffective Disorder 
NCT Number: NCT04512066 
Document Date: Protocol Version 5: 06-Oct-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The information contained in this document, especially any unpublished data, is the property of 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 —F. Hoffmann-La Roche Ltd
Protocol BP41743, Version 5
PROTOCOL
TITLE:
A PHASE II, MULTI-CENTER, RANDOMIZED, 
DOUBLE-BLIND, PARALLEL GROUP, PLACEBO-
CONTROLLED TRIAL OF THE EFFICACY AND THE 
SAFETY OF RO6889450 (RALMITARONT) VS. 
PLACEBO IN PATIENTS WITH AN ACUTE 
EXACERBATION OF SCHIZOPHRENIA OR 
SCHIZOAFFECTIVE DISORDER
PROTOCOL NUMBER:
BP41743
VERSION:
5
EUDRACT NUMBER:
2019-003788-23
IND NUMBER:
TEST PRODUCT:
RO6889450 
SPONSOR:
F. Hoffmann-La Roche Ltd
DATE FINAL:
Version 1: 20 October 2019 
DATE AMENDED:
Version 2: 16 April 2020
Version 3: 17 September 2020
Version 4: 3 June 2021
Version 5: See electronic date stamp below
 
Company Signatory
Approver's Name
Title
Date and Time (UTC)
06-Oct-2021 09:58:03


RO6889450 —F. Hoffmann-La Roche Ltd
2/Protocol BP41743, Version 5
PROTOCOL ACCEPTANCE FORM
TITLE:
A PHASE II, MULTI-CENTER, RANDOMIZED, 
DOUBLE-BLIND, PARALLEL GROUP, PLACEBO-
CONTROLLED TRIAL OF THE EFFICACY AND THE 
SAFETY OF RO6889450 (RALMITARONT) VS. 
PLACEBO IN PATIENTS WITH AN ACUTE 
EXACERBATION OF SCHIZOPHRENIA OR 
SCHIZOAFFECTIVE DISORDER
PROTOCOL NUMBER:
BP41743
VERSION NUMBER:
5
EUDRACT NUMBER:
2019-003788-23 
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 
Site Monitor.


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3/Protocol BP41743, Version 5
PROTOCOL AMENDMENT, VERSION 5
RATIONALE
Protocol BP41743 has been amended to allow:
-
enrollment of participants without prior approval by the Medical Monitor/Sponsor;
-
safety monitoring of vasculitis during 36-Week Safety Extension Phase. 
Changes to the protocol, along with a rationale for each change:

The schedule of the activities (SoA) without 36-Week Safety Extension Phase
(Table 1 in Section 1.3) has been amended to replace Eligibility Assessment Form 
by Eligibility Checklist Form (ECF) to remove the approval of eligibility by Medical 
Monitor. The SoA for the 36-Week Safety Extension Phase has been updated to 
include the Samples for vasculitis monitoring (Table 2 in Section 1.3).

Footnotes for SoA Table 1 and Table 2 have been updated as follows:
o
Footnote “e” has been amended to inform that the Erythrocyte 
sedimentation rate (ESR) samples will be processed locally. 
o
Footnote “h” has been amended to provide clarity on the timing of the PK 
sampling during the 36-Week Safety Extension Phase.
o
Footnotes “v”, “x”, “aa”, and “bb" have been updated to allow the following 
being used in the exceptional situation beyond COVID-19 pandemic:
assessments being performed remotely (Footnote “v”), study visit being 
split over 2 days (Footnote “x”), study drug being shipped directly from 
site to patient (Footnote “aa”), and the Home HealthCare system 
(Footnote “bb”). It has been also added that the Home HealthCare system 
will not be used in Japan as the services are not provided by the selected 
vendor in Japan (Footnote “bb”).
o
Footnote “gg” has been added to provide information on the tests that are 
to be performed as part of the vasculitis monitoring.

Section 2.3 (Benefit/Risk Assessment) has been amended to add a statement to 
clarify the impact of the COVID-19 pandemic on the benefit/risk assessment of this 
study protocol.

Section 3 (Objectives and Endpoints) Table 3 has been amended to add clarification 
on the time points of the secondary analysis planned and that both PANSS total and 
factor scores changes from baseline will be assessed up to week 12. 

Section 5.1 (Inclusion Criteria) has been amended to 
o
remove the possibility to enroll subjects with the duration of exacerbation 
at screening longer than 8 weeks (Inclusion criterion 5);
o
remove the possibility to enroll subjects with hospitalization duration at 
screening longer than 7 days, except for in exceptional situations (e.g.,
delay due to the administrative procedures) where the maximum may be


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4/Protocol BP41743, Version 5
10 days prior to screening (prior discussion with the Medical Monitor is 
recommended) (Inclusion criterion 6);
o
add Inclusion criterion E for the 36-Week Safety Extension Phase 
specifying the requirement for no clinically significant abnormality in 
laboratory assessments performed for evaluation of the confirmed or
suspected presence of vasculitis.

Section 5.2 (Exclusion Criteria) has been amended to:
o
limit the hospitalization duration for current exacerbation of schizophrenia 
to 1 week at screening visit or in exceptional situations (e.g., delay due to 
the administrative procedures) to 10 days (Exclusion criterion 1);
o
remove Medical Monitor approval requirement for the decision made for 
the laboratory results at screening (Exclusion criterion 12);
o
remove Medical Monitor approval requirement for the use of low doses of 
clozapine (< 200 mg/day) to treat insomnia or dyskinesia more than 
12 months prior to screening visit. Further clarification has been provided 
that any use of clozapine (any dose regimen/ any indication) is prohibited 
within 12 months prior to screening visit (Exclusion criterion 17).
o
remove the possibility to enroll subjects with regular use of cannabis 
(including cannabidiol) meeting criteria for substance use disorder for 
cannabis in case of positive urine drug screen (only sporadic use of 
cannabis is allowed) (Exclusion criterion 19). 

Section 5.5 (Screen Failures) has been amended to remove Sponsor/Medical 
Monitor approval requirement for the decision on subject re-screening. Potential 
re-screenings should be discussed with the Medical Monitor/delegate.

Section 6.4 (Treatment Compliance) has been amended to allow the use of direct 
site-to-patient drug delivery in the exceptional situation beyond COVID-19 pandemic
upon Sponsor/Medical Monitor approval. Further clarification has been added that 
compliance below 80% on a weekly basis should be brought to the Sponsor’s
attention.

Section 7.1 (Discontinuation of study treatment) has been amended to add the 
condition indicating confirmed presence of vasculitis as requirement for 
discontinuation of the participant entering the 36-Week Safety Extension Phase
from the study treatment. In addition, the participant may be discontinued if 
vasculitis is suspected.

Section 8 (Study Assessments and Procedures) has been amended to allow the use 
of remote assessments and use of the Home HealthCare system in the exceptional 
situation beyond COVID-19 pandemic upon Sponsor/Medical Monitor approval. It 
has been also added that the Home HealthCare system will not be used in Japan as 
the services are not provided by the selected vendor in Japan. 

Section 8.2.1 (Physical Examination) has been amended to add that the
Investigators should pay special attention to clinical signs of rash, myalgia, arthritis,


RO6889450 —F. Hoffmann-La Roche Ltd
5/Protocol BP41743, Version 5
and fever, and report those as adverse events (AEs) as part of the evaluation of a 
confirmed or suspected presence of vasculitis. 

Section 8.2.4 (Clinical Safety Laboratory Assessments) has been amended to 
provide the details on tests for vasculitis monitoring.

Section 8.2.7 (Psychiatric/Medical History and Demographic Data) has been 
amended to:
o
remove Medical Monitor/Sponsor approval requirement for eligibility 
during screening. 
o
replace the Eligibility Assessment Form with the ECF. 
o
require completion and submission to the Clinical Research Organization 
(CRO) electronic Protocol Inquiry Platform (ePIP) system of the ECF 
during screening for documentation and monitoring purposes.

Section 8.7 (Pharmacodynamics and Biomarker Samples) has been amended to 
add the requirement for mandatory blood sample collection for the assessment of 
suspected vasculitis.

Section 8.10.1 (Screening and Pre-treatment Assessments) has been amended to 
remove the requirement of Eligibility Assessment Form submission and Medical 
Monitor/Sponsor approval prior to randomization. Instead, an ECF should be 
completed and submitted to the CRO ePIP system during screening as per 
guidance provided in the protocol for documentation and monitoring purposes.

Section 8.10.2 (Assessment during Treatment) has been amended to provide 
clarification of the order of assessments.

Section 9.2 (Sample size determination) has been amended to allow an increase of 
a number of randomized participants in case of an unexpectedly high proportion of 
participants not completing initial 4 weeks of treatment (i.e., more than 25%).

Section 9.4.2 (Efficacy Analyses) Table 7 has been amended to clarify that both 
total and factor PANSS score changes from baseline will be assessed.

Section 9.4.3 (Safety Analyses) Table 8 has been amended to clarify that tabular 
summaries will be used to present clinical laboratory test results.

Appendix 4:
o
has been amended to provide information on which tests for vasculitis 
monitoring are to be performed locally.
o
Table 1 (Laboratory Assessments) has been amended to include a list of 
tests to be performed for vasculitis monitoring

Appendix 6 Table 1 has been amended to 
o
remove Medical Monitor approval requirement for the use of single doses 
of aripiprazole, brexpiprazole, and blonanserin administered to control 
current exacerbation.
o
Add clarification that the indicated washout periods are relative to the first 
dose of study drug.


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6/Protocol BP41743, Version 5
o
Add clarification that all antipsychotics are prohibited during Study 
Periods 2 and 3, and the 36-Week Safety Extension Phase.

Appendix 6 Table 3 has been amended to 
o
remove Medical Monitor/Sponsor approval requirement for continuation of 
previous treatment for extrapyramidal symptoms if the patient has been 
on a stable dose for at least 28 days prior to the screening period and the 
Investigator considers it clinically required. 
Additional minor changes have been made to improve clarity and consistency. 
Substantial new information appears in Book Antiqua italics. This amendment represents 
cumulative changes to the original protocol.


RO6889450 —F. Hoffmann-La Roche Ltd
7/Protocol BP41743, Version 5
TABLE OF CONTENTS
PROTOCOL ACCEPTANCE FORM .................................................................... 2
1.
PROTOCOL SUMMARY............................................................................. 15
1.1
Synopsis................................................................................ 15
1.2
Schematic of Study Design.................................................... 29
1.3
Schedule of Activities ............................................................ 29
2.
INTRODUCTION ........................................................................................ 38
2.1
Study Rationale ..................................................................... 38
2.2
Background ........................................................................... 39
2.2.1
Background on Schizophrenia............................................... 39
2.2.2
Background on RO6889450 .................................................. 40
2.3
Benefit/Risk Assessment....................................................... 41
3.
OBJECTIVES AND ENDPOINTS ............................................................... 42
4.
STUDY DESIGN......................................................................................... 46
4.1
Overall Design ....................................................................... 46
4.1.1
Length of the Study ............................................................... 47
4.2
Scientific Rationale for Study Design..................................... 48
4.2.1
Rationale for Study Population and Study 
Duration................................................................................. 48
4.2.2
Rationale for Placebo Control Group..................................... 49
4.2.3
Rationale for Selection of Risperidone as Active 
Control................................................................................... 49
4.2.4
Rationale for Biomarker Assessments................................... 49
4.2.5
Rationale for Digital Biomarker Assessments........................ 50
4.3
Justification for Dose ............................................................. 51
4.4
End of Study Definition .......................................................... 51
5.
STUDY POPULATION................................................................................ 51
5.1
Inclusion Criteria.................................................................... 52
5.2
Exclusion Criteria................................................................... 54
5.3
Confirmation of Eligibility at Baseline..................................... 56
5.4
Lifestyle Considerations......................................................... 56
5.4.1
Alcohol Consumption............................................................. 56


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5.5
Screen Failures ..................................................................... 57
5.6
Recruitment Procedures........................................................ 57
6.
TREATMENTS............................................................................................ 57
6.1
Treatments Administered....................................................... 59
6.2
Preparation/Handling/Storage/Accountability ........................ 60
6.3
Measures to Minimize Bias: Randomization and 
Blinding.................................................................................. 61
6.3.1
Method of Treatment Assignment.......................................... 61
6.3.2
Blinding.................................................................................. 62
6.4
Treatment Compliance .......................................................... 63
6.4.1
Medication Adherence Platform............................................. 63
6.5
Concomitant Therapy ............................................................ 64
6.5.1
Anti-psychotic medication...................................................... 64
6.5.1.1
Rescue anti-psychotic treatment ........................................... 65
6.5.2
Non anti-psychotic concomitant medication........................... 65
6.5.2.1
Permitted Therapy................................................................. 65
6.5.2.2
Prohibited Therapy ................................................................ 65
6.5.2.3
Restricted Therapy ................................................................ 66
6.6
Treatment after the End of the Study..................................... 66
7.
DISCONTINUATION OF STUDY, STUDY TREATMENT, AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL................................. 66
7.1
Discontinuation of Study Treatment....................................... 66
7.2
Participant Discontinuation/Withdrawal from the 
Study ..................................................................................... 68
7.3
Lost to Follow-Up................................................................... 69
8.
STUDY ASSESSMENTS AND PROCEDURES ......................................... 69
8.1
Efficacy Assessments............................................................ 71
8.1.1
Clinical Outcome Assessments ............................................. 71
8.1.1.1
Positive and Negative Syndrome Scale (PANSS) 
and PANSS-Informant Checklist (PANSS-IC) ....................... 71
8.1.1.2
Clinical Global Impression-Improvement (CGI-I) 
and Severity (CGI-S) Scales.................................................. 72
8.1.1.3
Patient Global Impression of Change (PGI-C) 
Scale...................................................................................... 72


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8.1.1.4
Calgary Depression Scale for Schizophrenia 
(CDSS) .................................................................................. 72
8.1.1.5
Fagerström Test for Nicotine Dependence 
(FTND)................................................................................... 72
8.1.1.6
Recovering Quality of Life (ReQoL-20).................................. 73
8.1.1.7
Readiness for Discharge Questionnaire (RDQ)..................... 73
8.1.1.8
Assessment of Sleep, Mood, Well-being and 
Cognitive Functioning and Treatment Expectancy ................ 73
8.1.1.9
Scale to Assess Unawareness of Mental 
Disorder (Short Version) (SUMD-9)....................................... 74
8.1.1.10
Beck Cognitive Insight Scale ................................................. 74
8.1.1.11
VAGUS Insight into Psychosis Scale..................................... 74
8.2
Safety Assessments .............................................................. 75
8.2.1
Physical Examinations........................................................... 75
8.2.2
Vital Signs.............................................................................. 76
8.2.3
Electrocardiograms................................................................ 76
8.2.4
Clinical Safety Laboratory Assessments................................ 77
8.2.5
Columbia-Suicide Severity Rating Scale 
(C-SSRS)............................................................................... 78
8.2.6
Extrapyramidal Symptom Rating Scale-
Abbreviated Version .............................................................. 79
8.2.7
Psychiatric/Medical History and Demographic 
Data....................................................................................... 79
8.3
Adverse Events and Serious Adverse Events ....................... 80
8.3.1
Time Period and Frequency for Collecting 
Adverse Event and Serious Adverse Event 
Information............................................................................. 80
8.3.2
Method of Detecting Adverse Events and Serious 
Adverse Events ..................................................................... 81
8.3.3
Follow-Up of Adverse Events and Serious 
Adverse Events ..................................................................... 81
8.3.3.1
Investigator Follow-Up........................................................... 81
8.3.3.2
Sponsor Follow-Up ................................................................ 81
8.3.4
Regulatory Reporting Requirements for Serious 
Adverse Events ..................................................................... 82
8.3.4.1
Emergency Medical Contacts................................................ 82


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8.3.5
Pregnancy ............................................................................. 82
8.3.6
Non-Serious Adverse Events of Special Interest................... 83
8.4
Treatment of Overdose.......................................................... 83
8.5
Pharmacokinetics .................................................................. 84
8.6
Pharmacodynamics and Biomarkers Analyses...................... 84
8.6.1
Clinical Genotyping................................................................ 85
8.7
Pharmacodynamics and Biomarker Samples........................ 85
8.8
Samples for Research Biosample Repository ....................... 86
8.8.1
Overview of the Research Biosample Repository.................. 86
8.8.2
Sample Collection.................................................................. 86
8.9
Other Assessments ............................................................... 87
8.9.1
Mini International Neuropsychiatric Interview ........................ 87
8.9.2
Wide Range Achievement Test 4 .......................................... 87
8.9.3
Wechsler Abbreviated Scale of Intelligence –
Second Edition ...................................................................... 87
8.9.4
Ecological Momentary Assessment (EMA)............................ 88
8.9.5
Feedback Questions.............................................................. 88
8.9.6
Premorbid Adjustment Scale ................................................. 88
8.10
Timing of Study Assessments ............................................... 89
8.10.1
Screening and Pre-treatment Assessments .......................... 89
8.10.2
Assessments during Treatment............................................. 89
8.10.3
Assessments at Study Completion/Early 
Termination Visit.................................................................... 90
8.10.4
Follow-Up Assessments ........................................................ 90
8.10.5
Assessments at Unscheduled Visits...................................... 91
9.
STATISTICAL CONSIDERATIONS ............................................................ 91
9.1
Statistical Hypotheses ........................................................... 91
9.2
Sample Size Determination ................................................... 91
9.3
Populations for Analyses ....................................................... 92
9.4
Statistical Analyses................................................................ 93
9.4.1
Demographics and Baseline Characteristics ......................... 93
9.4.2
Efficacy Analyses .................................................................. 93
9.4.3
Safety Analyses..................................................................... 95




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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
AE
Adverse event
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase
ANA
Anti-nuclear antibodies
ANCA
Anti-neutrophil cytoplasmic antibodies
anti-dsDNA
Anti-double-stranded DNA
aPTT
Activated partial thromboplastin time
AST
Aspartate aminotransferase
BCIS
Beck Cognitive Insight Scale
BP
Blood pressure
CDSS
Calgary Depression Scale for Schizophrenia
CGI-I
Clinical Global Impression-Improvement
CGI-S
Clinical Global Impression Severity
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
CRP
C-reactive protein
CSR
Clinical study report
C-SSRS
Columbia-Suicide Severity Rating Scale
CTCAE
Common terminology criteria for adverse events
CTM
Clinical Team Manager
CYP
Cytochrome
DNA
Deoxyribonucleic acid
EC
Ethics Committee
ECF
Eligibility Checklist Form
ECG
Electrocardiogram
ECT
Electroconvulsive therapy
eCOA
Electronic clinical outcome assessment
eCRF
Electronic case report form
EDC
Electronic data capture
EMA
Ecological Momentary Assessment
ePIP
Electronic Protocol Inquiry Platform


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Abbreviation
Definition
EPS
Extrapyramidal symptoms
ESR
Erythrocyte sedimentation rate
ESRS-A
Extrapyramidal symptom rating scale, abbreviated
EOT
End of Treatment
ETV
Early Termination Visit
FDA
Food and Drug Administration
FSH
Follicle-stimulating hormone
FTND
Fagerström Test for Nicotine Dependence
GPCR
G protein coupled receptor
HBsAg
Hepatitis B surface antigen
HBcAb
Total hepatitis B core antibody
HCV
Hepatitis C virus
HDL
High-density lipoproteins
HIPAA
Health Insurance Portability and Accountability Act
HIV
Human immunodeficiency virus
IB
Investigator’s Brochure
ICH
International Council for Harmonisation
IEC
Independent Ethics Committee
IMP
Investigational medicinal product
IND
Investigational New Drug (application)
INR
International normalized ratio
IRB
Institutional Review Board
IRT
Interactive response technology
IUD
Intrauterine device
IUS
Intrauterine hormone-releasing system
LDH
Lactate dehydrogenase
LDL
Low-density lipoproteins
LPLV
Last participant, last visit
MAD
Multiple-ascending dose
MTS
Most troubling symptoms
MTD
Maximum tolerated dose
NGS
Next generation sequencing
NSAESI
Non-serious adverse event of special interest
OTC
Over-the-counter
PANSS
Positive and Negative Syndrome Scale
PAS
Premorbid Adjustment Scale
PD
Pharmacodynamic


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Abbreviation
Definition
PK
Pharmacokinetic
PRO
Patient-reported outcome
POT
Postural orthostatic tachycardia
QD
Once daily
QRS
QRS complex
QT
QT interval
QTc
QT corrected for heart rate
QTcF
QT corrected for heart rate using the Fridericia’s 
correction factor
RBC
Red blood cell
RBR
Research biosample repository
RDQ
Readiness for Discharge Questionnaire
RNA
Ribonucleic acid
ROW
Rest of the world
RR
RR interval
SAD
Single ascending dose
SAE
Serious adverse event
SAP
Statistical analysis plan
SoA
Schedule of activities
SOP
Standard operating procedure
SUMD
Scale to Assess Unawareness of Mental Disorder
SUSAR
Suspected unexpected serious adverse reactions
TAAR
Trace amine-associated receptor
TAAR1
Trace amine-associated receptor 1
ULN
Upper limit of normal
US
United States
WASI-II
Wechsler Abbreviated Scale of Intelligence – Second 
Edition
WRAT-4
Wide Range Achievement Test
WBC
White blood cell
WOCBP
Women of childbearing potential
WONCBP
Women of non-childbearing potential


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1.
PROTOCOL SUMMARY
1.1
SYNOPSIS
PROTOCOL TITLE:
A PHASE II, MULTI-CENTER, RANDOMIZED, DOUBLE-BLIND, 
PARALLEL GROUP, PLACEBO-CONTROLLED TRIAL OF THE 
EFFICACY AND THE SAFETY OF RO6889450 (RALMITARONT) 
VS. PLACEBO IN PATIENTS WITH AN ACUTE EXACERBATION 
OF SCHIZOPHRENIA OR SCHIZOAFFECTIVE DISORDER.
SHORT TITLE
EFFECT OF RO6889450 VERSUS PLACEBO IN PATIENTS WITH 
AN ACUTE EXACERBATION OF SCHIZOPHRENIA OR 
SCHIZOAFFECTIVE DISORDER
PROTOCOL NUMBER:
BP41743
VERSION:
5
TEST PRODUCT:
RO6889450 
PHASE:
II
RATIONALE
RO6889450 is a novel compound and a partial agonist of the trace amine-associated receptor 1 
(TAAR1) for the treatment of schizophrenia. RO6889450 is currently in Phase II clinical 
development. 
TAAR1 is a class A G protein coupled receptor (GPCR). It is expressed in the amygdala, 
hypothalamus, subiculum, and rhinal cortices as well as areas of the brain where modulation of 
dopaminergic (ventral tegmental area) and serotonergic (dorsal raphe nucleus) neuronal activity 
occurs. TAAR1 partial agonists have been shown to modulate dopaminergic, serotonergic, and 
glutamatergic neurotransmission, and have demonstrated anti-psychotic, anti-addictive, stress 
response, and glucose-regulating activity in nonclinical models. By targeting overlapping brain 
circuits that are implicated in psychotic and affective symptoms, and reward processing, as well 
as brain and peripheral circuits that regulate energy homeostasis, RO6889450 represents a 
potential novel therapy for the treatment of psychotic and affective disorders, including 
schizophrenia and schizoaffective disorder.
In schizophrenic patients, the F-DOPA signal is increased indicating an abnormal increase in 
presynaptic dopamine synthesis capacity. Elevated dopamine synthesis capacity, as measured 
by [18F]-DOPA, is seen in people with schizophrenia and correlates with the degree of 
psychosis in patients who are treatment responsive. In rodents, the F-DOPA signal was 
significantly decreased by RO6889450, which provides initial evidence that RO6889450 may 
normalize a key abnormality of the dopamine system in patients with schizophrenia. These 
results indicate a potential utility of RO6889450 in the treatment of patients with acute 
exacerbation of schizophrenia. Recently, results of a Phase II trial with the investigational
product SEP-363856, characterized as a TAAR1 and 5HT1a agonist, have shown improvement 
in patients with acute exacerbation of schizophrenia at 4 weeks. A 6-month open-label 
extension period following the 4-week study was associated with continued improvement as 
assessed by the Positive and Negative Syndrome Scale (PANSS) total score and Clinical 
Global Impression Severity (CGI-S) with minimal effects on metabolic parameters and 
extrapyramidal symptoms. In addition, negative symptoms continued to show improvement 
during a 26-week, open-label treatment as assessed by the Brief Negative Symptom Scale total 
score and the Marder PANSS negative symptom factor score.


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This Phase II study will be conducted to further investigate and confirm whether the 
administration of RO6889450 as a monotherapy treatment in patients with an acute 
exacerbation of schizophrenia can improve the symptoms of schizophrenia. The 36-Week 
Safety Extension Phase of this study will aim to evaluate long-term safety, tolerability, and 
selected effectiveness outcomes.
OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary

To compare the effect of 4-week 
treatment with two doses of 
RO6889450 (45 mg and 150 mg) vs. 
placebo in participants with acute 
symptoms of schizophrenia or 
schizoaffective disorder. 

Change from baseline at Week 4 in 
the Positive and Negative Syndrome 
Scale (PANSS) total score.
Secondary

To compare the effect of 4-week 
treatment with two doses of 
RO6889450 (45 mg and 150 mg) 
with placebo on symptoms of 
schizophrenia or schizoaffective 
disorder as assessed with PANSS. 

Proportion of participants with at 
least 20% or 50% improvement from 
baseline on PANSS total score.

Changes from baseline in the 
PANSS factor scores and proportion 
of participants with at least 20% or 
50% improvement from baseline in 
the PANSS factor scores.

To compare the effect of 4-week 
treatment with two doses of 
RO6889450 (45 mg and 150 mg) with 
placebo on: Clinical Global 
Impression Severity (CGI-S) and 
improvement (CGI-I).

Change from baseline (CGI-S and 
CGI-S MTS scores)

CGI-I and CGI-I MTS scores

To compare the effect of 4-week 
treatment with two doses of 
RO6889450 (45 mg and 150 mg) 
with placebo on time-to-readiness for 
discharge from inpatient unit.

Time from first randomized treatment 
intake to readiness for discharge as 
assessed by the Readiness for 
Discharge Questionnaire (RDQ) or 
actual discharge or censoring if the 
participant discontinues the study 
early.


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Objectives
Endpoints

To compare the safety and tolerability 
of 4-week treatment with two doses of 
RO6889450 (45 mg and 150 mg) vs. 
placebo.

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 standing 
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, and urinalysis test results.

Change from baseline in Columbia-
Suicide Severity Rating Scale (C-
SSRS) and Extrapyramidal symptom 
rating scale, abbreviated (ESRS-A).

To observe the effect of treatment of 
two doses of RO6889450 (45 mg and 
150 mg) up to 12 weeks.

Proportion of participants with at least 
20% or 50% improvement from 
baseline on PANSS total score.

Changes from baseline in the PANSS
total and factor scores and proportion 
of participants with at least 20% or 
50% improvement from baseline in 
the PANSS factor scores.

CGI-S and CGI-S MTS.

CGI-I and CGI-I MTS.

To observe the safety and tolerability 
of extended treatment with two doses 
of RO6889450 (45 mg and 150 mg)
up to 12 weeks.

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 standing 
vital signs recordings.

Change from screening in 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, and urinalysis test results.

Change from baseline in C-SSRS and 
ESRS-A. 


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Objectives
Endpoints

To evaluate the pharmacokinetics 
(PK) of RO6889450 and 
RO6889450-derived metabolite(s).

Concentration per time point.

AUCss of RO6889450 and, if feasible,
RO6889450- derived metabolite(s) at 
Week 4.

Cmax of RO6889450 and, if feasible,
RO6889450-derived metabolite(s) at 
Week 4.

Other PK parameters as appropriate.
Exploratory

To evaluate the changes in Sleep, 
Mood, Well-being, Cognitive 
Functioning and Treatment 
Expectancy.

Smartphone App Questionnaire.

To assess the changes in ReQoL.

Change in ReQoL from baseline, 
proportion of patients with 10 points 
improvement or more.

To compare the effect of two doses 
of RO6889450 (45 mg and 150 mg)
with placebo on: Patient Global 
Impression - Change (PGI-C).

PGI-C.

To assess the relationship between 
the levels of inflammatory biomarkers 
and cognitive subtype.

Differences in levels of inflammatory 
biomarkers between subgroups of 
patients defined by pre-morbid and 
current IQ estimate (Wide Range 
Achievement Test [WRAT-4] and 
Wechsler Abbreviated Scale of 
Intelligence – Second Edition [WASI-
II]).

To evaluate the change in the level 
of depression in schizophrenia
measured by Calgary Depression 
Scale for Schizophrenia (CDSS) up 
to 48 weeks.

Calgary Depression Scale for 
Schizophrenia.

To evaluate the changes in the level 
of insight into mental disorder.

Scale to Assess Unawareness of 
Mental Disorder (SUMD).

VAGUS insight into Psychosis Scale.

Beck Cognitive Insight Scale (BCIS).

To explore the changes in nicotine 
addiction measured by Fagerström 
Test for Nicotine Dependence.

Fagerström Test for Nicotine 
Dependence.

To explore the effects of RO6889450 
on levels and patterns of social and 
general activity and psychotic 
symptoms

Ecological Momentary Assessment

To assess patients perception of 
changes relative to their condition 
and relevance and ease of 
understanding of the PRO 
instruments used in the study

Feedback questions

To evaluate relationship between the  
premorbid functioning and treatment 
response

Premorbid Adjustment Scale (PAS)


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Objectives
Endpoints

To observe the effect of treatment 
with two doses of RO6889450 
(45 mg and 150 mg) up to 48 weeks

Changes from baseline in the PANSS 
total and factor scores at Week 48.
Analysis by the following groups: 
risperidone, RO6889450 45 mg, 
RO6889450 150 mg, 
placebo/RO6889450 45 mg, 
placebo/RO6889450 150 mg.

CGI-S

CGI-I 

To observe the safety and tolerability 
of long-term treatment with 
RO6889450 up to 48 weeks

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 standing 
vital signs recordings.

Change from screening in 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, and urinalysis test results.

Change from baseline in C-SSRS and 
ESRS-A.
OVERALL DESIGN
This is a Phase II, multi-center, randomized, double-blind, parallel group, placebo-controlled 
study in participants with an acute exacerbation of schizophrenia or schizoaffective disorder.
Study Design
Participants who are experiencing an exacerbation of their schizophrenia, starting no later than 
8 weeks prior to the screening visit, will be included. 
After eligibility is confirmed during the screening period (Study Period 1), approximately 280 
participants will be randomized outside Japan (United States [US] and rest of the world [ROW]) 
in equal proportions (approximately 70 per group) to one of the following treatments: 150 mg 
QD of RO6889450, 45 mg QD of RO6889450, placebo, or risperidone 4 mg QD (titration period: 
2 mg of risperidone on Day 1, 4 mg of risperidone from Day 2) in a double-blind fashion for 
4 weeks. In addition to these 280 participants, approximately 28 participants will be recruited in 
Japan.
Outside Japan randomization will be based on region (North America, Eastern Europe, and 
Asia), baseline PANSS total (80-95 and 96 and above), duration of the disease (≤ 5 years 
and > 5 years), and sex. In Japan randomization will be stratified according to baseline PANSS 
total (80-95 and 96 and above). Participants must remain as inpatients throughout Study Period
1 and during the 4 weeks of the double-blind treatment period (Study Period 2). 
After completion of the 4-week Study Period 2, the participants may enter a double-blind 
extension period (Study Period 3) if agreed between Investigator and participant based on 
clinical status.  
Participants treated with risperidone, or 150 mg QD of RO6889450, or 45 mg QD of 
RO6889450 during the Study Period 2 will continue with their respective treatments in the Study 
Period 3, while participants assigned to placebo will be randomized to either 150 mg QD or 
45 mg QD of RO6889450 in a blinded fashion. Outside Japan randomization will be based on 


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region (North America, Eastern Europe, and Asia), baseline PANSS total (80-95 and 96 and 
above), duration of the disease (≤ 5 years and > 5 years), and sex. In Japan randomization will 
be stratified according to baseline PANSS total (80-95 and 96 and above). At the beginning of 
the Study Period 3, participants will be discharged from the hospital or may remain inpatient for 
the first week if required according to the clinical judgment of the Investigator. If the participant 
must remain in the hospital beyond the first weeks of Study Period 3 according to the clinical 
judgment of the Investigator, the Investigator will need to obtain approval from the Sponsor. For 
Japan, due to regional differences in health care, Sponsor approval is not required.
After completion of Study Period 3, participants may be offered continuation in the optional 
36-Week Safety Extension Phase if they meet additional inclusion criteria. Participants will 
continue to receive the same treatments as those they received during Study Period 3, in a 
double-blind fashion.
The assessment of the primary endpoint (PANSS) will be performed by trained centralized 
raters independent from the investigational sites. Participants who discontinue study medication 
during Study Period 2 are required to complete the Study Period 2 EOT visit as soon as 
possible after the last dose of study drug (if possible, PANSS assessment should be performed 
before rescue medications are taken). These participants are also required to return to the clinic 
4 weeks after the first dose of study drug (at the end of the 4-week Study Period 2) for Week 4 
early termination visit (ETV). Participants will also be asked to return for the follow-up visit 
(4 weeks after the last dose of study drug).
Treatment Groups and Duration
The investigational medicinal product (IMP) will be one of the following: 150 mg QD of 
RO6889450, 45 mg QD of RO6889450, placebo, or risperidone 4 mg QD (titration period: 2 mg 
of risperidone on Day 1, 4 mg of risperidone from Day 2) in a double-blind fashion for 4 weeks in 
Study Period 2, 8 weeks in Study Period 3, and 36 weeks in the 36-Week Safety Extension
Phase. 
Length of Study
The total duration of the study for each participant will be approximately 17 weeks (or 53 weeks 
if participating in the 36-Week Safety Extension Phase) divided as follows:

Study Period 1: Screening: approximately 3 to 7 days (1 week: inpatient).

Study Period 2: Double-blind treatment period: 28 days (4 weeks: inpatient).

Study Period 3: Double-blind extension treatment period: 56 days (8 weeks). At the 
beginning of the extension period, participants will be discharged from the hospital or 
may remain inpatient for the first weeks if required according to the clinical judgment of 
the Investigator.

36-Week Safety Extension Phase (optional): 36 weeks. Participants, who have 
completed Study Period 3 and in the opinion of the Investigator may benefit from the 
prolonged treatment, may enter 36-Week Safety Extension Phase if they meet 
additional eligibility criteria. Participants with worsening of their psychiatric or medical 
status that would preclude their safe participation in the 36-Week Safety Extension 
Phase or their ability to comply with the required procedures will not be eligible for the
36-Week Safety Extension Phase of this study.

Study Period 4: Safety follow-up/Follow-up Period for 36-Week Safety Extension 
Phase: 28 days (4 weeks). Mandatory follow-up assessments for all participants 
4 weeks after the last dose of study drug.

End of study visit: 1 day
Participants must be observed/treated on an inpatient basis from Day -3 (at the latest) until Day 
28. Participants will be discharged on Day 28 of the Study Period 2 once all planned study 
activities are done. The inpatient period can be extended into the double-blind extension 
treatment period (Study Period 3) if deemed necessary by the Investigator.


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At the Investigator’s discretion and upon Sponsor notification, a day pass may be granted to 
participants that need to temporarily leave the hospital during the inpatient periods. Urine drug 
screen and alcohol test need to be performed on the return of participant to the hospital.
End of Study
The end of the study is defined as the date of the last participant, last visit (LPLV) in the study.
PARTICIPANT POPULATION
The participants in this study will be patients diagnosed with an acute exacerbation of 
schizophrenia or schizoaffective disorder between 18 to 45 years of age, inclusive, who fulfill all 
of the given inclusion criteria.
Inclusion/Exclusion Criteria
Inclusion Criteria
Informed Consent
1.
Able and willing to provide written informed consent and to comply with the study protocol 
according to the International Council for Harmonisation (ICH) and local regulations. 
Alternatively, if applicable, a legally authorized representative must be able to consent for the 
participant according to ICH and local regulations.
Age
2.
Participant must be 18 to 45 years of age inclusive, at the time of signing the informed 
consent.
Type of Participants and Disease Characteristics
3.
Participants with a DSM-5 diagnosis of schizophrenia or schizoaffective disorder as 
confirmed by the Mini International Neuropsychiatric Interview (MINI).
4.
Disease duration 10 years.
5.
Have a current acute exacerbation of schizophrenia (or a psychotic exacerbation of 
schizoaffective disorder) of no more than 8 weeks before screening visit and no current signs 
of apparent lack of treatment response.
6.
At the time of screening, the participant needs to be either hospitalized or requiring inpatient 
psychiatric care according to clinical judgment for the treatment of the acute exacerbation. If 
the participant has been hospitalized for the current exacerbation, the hospitalization has to 
be of a maximum of 1 week prior to screening. In exceptional situations (e.g., delay due to 
the administrative procedures), hospitalization up to a maximum of 10 days prior to 
screening is permitted (prior discussion with the Medical Monitor is recommended).
7.
In previous exacerbations and hospitalizations, the subject has shown a pattern of response
to appropriate antipsychotic treatment.
8.
Medically stable over a period of 3 months (non-psychiatric conditions) prior to screening visit 
and not expected to require hospitalization or change of treatment for non-psychiatric 
conditions for the duration of the study. 
9.
Screening and baseline CGI-S 4 (moderate or worse).
10. Screening and baseline PANSS total score 80. 


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11. Screening and baseline PANSS with scores of 4 (moderate or worse) on 2 or more of the 
following items: delusions, conceptual disorganization, unusual thought content, hallucinatory 
behavior, or suspiciousness/persecution.
Weight
12. Body mass index (BMI) between 18 and 35 kg/m2 inclusive.
Sex
13. Male and female participants:
A female is eligible to participate if she is not pregnant (see Appendix 5, negative serum 
pregnancy test at screening), not breastfeeding, and at least one of the following conditions 
applies:
a) Women of non-childbearing potential (WONCBP), as defined in Appendix 5.
b) Women of childbearing potential (WOCBP), who 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/ligation, male sexual partner who is sterilized, 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 (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.
Inclusion Criteria for the Optional 36-Week Safety Extension Phase
Participants who, according to clinical judgment of the Investigator, may benefit from prolonged 
treatment and meet the following additional inclusion criteria, may be eligible for participation in 
the 36-Week Safety Extension Phase:
A.
Successful completion of the 12-week treatment (Study Periods 2 and 3).
B.
Able and willing to provide written informed consent for the 36-Week Safety Extension 
Phase and to comply with the study protocol according to the ICH and local regulations. 
Alternatively, if applicable, a legally authorized representative must be able to consent for 
the participant according to ICH and local regulations. 
C.
Female participants of childbearing potential must have a negative urine pregnancy test at 
the Week-12 visit and be willing to remain abstinent or continue the use of contraceptive 
methods as described in Inclusion Criterion 13. 
D.
No signs or symptoms of worsening psychiatric or medical status that would preclude the 
patient from the participation in the 36-Week Safety Extension Phase or affect their ability 
to comply with the study requirements.
E.
No history of confirmed or suspected vasculitis and/or no clinically significant 
abnormality in laboratory assessments taken for evaluation of the possible presence of 
vasculitis (i.e., C-reactive protein [CRP], erythrocyte sedimentation rate [ESR], 
anti-neutrophil cytoplasmic antibodies [ANCA], anti-nuclear antibodies [ANA], 
anti-double-stranded DNA [anti-dsDNA] antibodies, and anti-phospholipid antibodies).


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Exclusion Criteria
General exclusions
1.
Has been inpatient for 1 week (or in exceptional situations [e.g., delay due to the 
administrative procedures] 10 days) or had any other hospitalization for acute 
exacerbation of schizophrenia or schizoaffective disorder within the prior 8 weeks or signs of 
lack of response to antipsychotic treatment.
2.
Disease duration longer than 10 years.
3.
Is currently an inpatient on an involuntary basis.
4.
The C-SSRS "Suicidal Ideation" item 4 (active suicidal ideation with some intent to act, 
without specific plan) or item 5 (active suicidal ideation with specific plan and intent) 
answered “Yes” or any “Yes” answers to “Suicidal Behavior” within one month from 
Screening or between Screening and Baseline (i.e., since last visit). In addition, any 
Investigator judgment of significant risk of suicide or harming themselves or others.
5.
Lifetime history of homicidal behavior.
6.
Moderate to severe substance use disorder within six months (excluding nicotine) as defined 
by DSM-5.
7.
Other current DSM-5 diagnosis (e.g., bipolar disorder, major depressive disorder).
Medical conditions
8.
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, or endocrine conditions).
9.
Positive result at screening for hepatitis B surface antigen (HBsAg), hepatitis C virus (HCV), 
or human immunodeficiency virus (HIV)-1 or -2. Participants with positive anti-hepatitis C
antibody who have been successfully treated and test negative for HCV RNA are eligible for 
study entry.
10. Tardive dyskinesia that is moderate to severe or requires treatment.
11. History of neuroleptic malignant syndrome.
12. Clinically significant abnormalities in laboratory safety test results (including hepatic and 
renal panels, complete blood count, chemistry panel and urinalysis), including:
a)
Aspartate aminotransferase (AST), or alanine aminotransferase (ALT) 2 upper limit of 
normal (ULN), or total bilirubin > 1.5 ULN with the exception of known Gilbert 
syndrome.
b)
Serum creatinine > 1.5 ULN.
NOTE: 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.


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13. 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.
Prior/Concomitant Therapy
14. Participants for whom risperidone is contraindicated or who have a documented history of 
lack of response or intolerance to risperidone or paliperidone or participants with known 
hypersensitivity to risperidone, paliperidone, or to any excipients in Risperdal.
15. Participant treated with a long-acting injectable antipsychotic (LAI) or other antipsychotics 
that cannot be washed-out within the allotted screening period (see list of specific 
medications in Section 6.5).
16. History of electroconvulsive therapy (ECT) for any reason.
17. Participant treated with clozapine at any dose in the 12 months preceding the screening visit 
or participants treated with clozapine at > 200 mg/day at any time. Note: low dose 
(200mg/day) use for insomnia or dyskinesia longer than 12 months prior to screening visit 
is permitted.
18. Participant currently receiving a psychotropic or other medication used as a psychotropic, 
which cannot be discontinued during the screening period.
19. Positive urine drug screen for amphetamines, methamphetamines, opiates, buprenorphine, 
methadone, cocaine, and barbiturates. In case of positive urine drug screen for cannabinoids 
(including cannabidiol), the participant may be allowed to enter the study only in case of a 
sporadic use of cannabis. Regular consumption meeting the criteria for cannabis use 
disorder (mild, moderate, or severe) is not permitted.
20. 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.
Prior/Concurrent Clinical Study Experience
21. Participant has previously received RO6889450.
22. Participant received an investigational drug within 28 days or five times the half-life of the 
investigational drug (whichever is longer) prior to the first study drug administration (study 
Day 1).
NUMBER OF PARTICIPANTS
Approximately 280 participants will be randomized (70 per group: RO6889450 150 mg QD; 
RO6889450 45 mg QD; risperidone 4 mg QD; and placebo) outside Japan (US and ROW). In 
addition to these 280 participants, approximately 28 participants will be recruited in Japan.
Outside Japan randomization will be based on region (North America, Eastern Europe, and 
Asia), baseline PANSS total (80-95 and 96 and above), duration of the disease (≤ 5 years 
and > 5 years), and sex. In Japan randomization will be stratified according to baseline PANSS 
total (80-95 and 96 and above). Participants must remain as inpatients at a minimum during the 
screening period and during Study Period 2. 


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CONCOMITANT MEDICATIONS
Any medication (prescription and over-the-counter [OTC]) taken within 28 days of study screening 
and any non-pharmacological interventions (e.g., individual psychotherapy, cognitive behavioral 
therapy, smoking cessation therapy, and rehabilitative therapy) will be recorded on the 
appropriate electronic case report form (eCRF).
The Medical Monitor should be contacted if there are any questions regarding concomitant or 
prior therapy.
Anti-psychotic medication
All anti-psychotics are prohibited in the study during Study Periods 2 and 3, the 36-Week Safety 
Extension Phase, and with a minimum washout period of 72 hours before the initiation of study 
medication, depending on the anti-psychotic medication. Washout periods for a specific anti-
psychotic medication are provided in the table below.
Rescue anti-psychotic treatment
If the clinical state of the participant would require treatment with an anti-psychotic other than 
the study medication, in the judgment of the Investigator, an antipsychotic should be prescribed 
and the participant will be immediately withdrawn from the study drug. Investigators should 
make a reasonable effort to complete a final assessment including efficacy endpoints before 
starting antipsychotic medication. The reasons for use of rescue medication should be 
documented in detail.


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Anti-psychotic and rescue medication
Type of medication
Timelines and instructions
Antipsychotic medication

asenapine

chlorpromazine

fluphenazine

haloperidol

iloperidone

loxapine

molindone

olanzapine

pericyazine

perospirone

perphenazine

prochlorperazine

quetiapine

trifluoperazine

thiothixene

ziprasidone

zuclopenthixol
Permitted as prior medication and during the screening 
period, but prohibited 72 hours prior to the first dose of 
study medication and during Study Periods 2 and 3, and 
the 36-Week Safety Extension Phase (blinded treatment).

risperidone

paliperidone
Permitted as prior medication and during the 
screening period, but prohibited 72 hours prior to the 
first dose of study medication and during Study 
Periods 2 and 3, and the 36-Week Safety Extension 
Phase (blinded treatment). 
Participant excluded if there is a history of lack of 
response or intolerance to risperidone or paliperidone.

aripiprazole. 2 weeks

blonanserin, 3 weeks

brexpiprazole. 3 weeks

cariprazine. 15 weeks

aripiprazole LAI (Abilify 
Maintena). 2 months

aripiprazole lauroxil 
(Aristada). 4 months

fluphenazine deaconate. 
2 months

haloperidol deacanoate. 
2 months

olanzapine LAI. 2 months
Permitted as prior medication if it had been stopped 
before the indicated time periods prior to the first 
dose of study medication. Prohibited during Study 
Periods 2 and 3 and the 36-Week Safety Extension 
Phase (blinded treatment).
Note: Single doses (before reaching steady state) of 
aripiprazole, brexpiprazole, or blonanserin 
administered to control current exacerbation may be 
used (upon discussion with the Medical Monitor) 
but not within 72 hours prior to the first dose of 
study medication upon discussion with the Medical 
Monitor.

paliperidone palmitate 
(Invega Sustenna, Invega 
Trinza). 6 months

risperidone LAI (Risperdal 
Consta). 1 month
Permitted as prior medication if had been stopped 
before the indicated time periods prior to the first 
dose of study medication. Participants excluded if 
there is a history of lack of response or intolerance to 
risperidone or paliperidone. Prohibited during Study 
Periods 2 and 3 and the 36-Week Safety Extension 
Phase (blinded treatment).

clozapine 
Excluded any use in previous 12 months before 
screening, or any lifetime use at doses of 200 mg/day 
or greater.


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Non anti-psychotic concomitant medication
Permitted Therapy
Non-psychoactive medications, including over-the-counter medications, that are required to 
treat pre-existing conditions or adverse events (AEs) that occur during the study may be used at 
the discretion of the Investigator.
All therapy and/or medication administered to manage AEs should be recorded on the AE
eCRF. For further information regarding the management of specific AEs see Appendix 2. 
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.
Agents designed to prevent pregnancy: intrauterine device in place, oral contraceptives, dermal 
contraceptives, and injectable or implantable hormonal agents are permitted from enrollment 
until the end of the treatment period.
Concomitant therapy includes any medication, e.g., prescription drugs, OTC drugs, vaccines 
(including those against COVID-19), approved dietary and herbal supplements, nutritional 
supplements and any non-pharmacological interventions (e.g., individual psychotherapy, group 
therapy, 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. 
Prohibited Therapy
All medications (prescription and OTC) taken within 28 days of study screening and any 
non-pharmacological interventions (e.g., individual psychotherapy, cognitive behavioral therapy, 
smoking cessation therapy, and rehabilitative therapy) will be recorded on the appropriate 
eCRF.
As a general rule, no new concomitant medication or therapies will be permitted, with the 
exception of medications to treat pre-existing conditions or AEs, unless the rationale for 
exception is discussed and clearly documented between the Investigator and the Sponsor.
Specific prohibited medications are provided in the table below.
Prohibited Therapies
Type of medication
Timelines and instructions
Illegal substance use (including legal cannabis) : opiates, 
amphetamine, barbiturate, cocaine, cannabis, 
cannabidiol, or hallucinogens
From enrollment until the end of 
the treatment period
All psychotropic medications including anxiolytic, 
antidepressants, mood stabilizer, hypnotic, sedative 
medication, and St John’s wort except those listed in 
Section 6.5.2.1 permitted therapy and Table 3 restricted 
therapy.
From enrollment until the end of 
the treatment period. Must be 
discontinued during the screening 
period, regardless of the 
indication for which they have 
been prescribed.
Treatment with sedating anti-histamines (such as 
promethazine or diphenhydramine) 
Should not be initiated during the 
treatment period, nor should the 
dose be changed for those 
participants who were already on 
treatment at the time of 
randomization.
Participants receiving treatment for tardive dyskinesia 
(e.g., valbenazine or deutetrabenazine) are excluded.
From enrollment until the end of 
the treatment period.
The following strong CYP3A4 inducers are prohibited: 
carbamazepine, aprepitant, phenytoin.
From enrollment until the end of 
the treatment period.
The following strong P-gp inducers are prohibited: 
verapamil, apalutamide.
From enrollment until the end of 
the treatment period.
Clinically relevant substrates of P-gp, including quinidine 
and loperamide
From enrollment until the end of 
the treatment period.


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Restricted Therapy
The list of restricted therapies is provided in the table below.
Restricted Therapies
Type of medication
Timelines and instructions
Medication for extrapyramidal 
symptoms (EPS)

benztropine: up to 4 mg/day (up 
to 2 mg single dose), 

or biperiden up to 6 mg/day (up 
to 2 mg single dose), 

or trihexyphenidyl up to 6 
mg/day (up to 3 mg single dose)

propranolol (up to 60 mg/day)
Initiation and dose increase of anticholinergic 
medications should only happen to treat emergent 
EPS related AEs. Treatment should be limited to a 
7-day period. A prescription may be renewed if 
necessary after reevaluation. Continuation of previous 
treatment may be allowed if the patient has been on a 
stable dose for at least 28 days prior to the screening 
period and the Investigator considers it clinically 
required.
Lorazepam or equivalent 
benzodiazepine 

Total dose 6 mg/day of 
lorazepam during screening and 
the first week of the trial

Total dose 4 mg/day 
lorazepam from Week 2 until 
the end of the Study Period 3.

Total dose 3 mg/day of 
alprazolam during screening 
and the first week of the trial

Total dose 2 mg/day of 
alprazolam from Week 2 until 
the end of the Study Period 3

Total dose 90 mg/day of 
oxazepam during screening and 
the first week of the trial

Total dose 60 mg/day of 
oxazepam from Week 2 until 
the end of the Study Period 3.
Benzodiazepine use is permitted provided the patient 
has been receiving a stable dose for at least 3 months 
and the total dose for all uses is < 6mg/day of 
lorazepam.
Initiation and/or dose increase of lorazepam or 
equivalent benzodiazepine should only happen to 
treat emergent anxiety, akathisia, agitation, or sleep 
disorders, and only within the maximum dose 
described in the left column.
Lorazepam or equivalent benzodiazepine treatment 
should not be administered within 12 hours prior to 
PANSS assessments.
Hypnotic or sedative medication

zolpidem tartrate up to 10 
mg/day, 

or chloral hydrate up to 2 g/day, 

or zaleplon up to 10 mg/day, 

or zopiclone up to 7.5 mg/day
Hypnotic or sedative medication is preferred treatment 
for sleep disorders rather than lorazepam and 
equivalent benzodiazepines.
Routine use is allowed to treat sleep disorders if the 
patient takes a stable restricted dose for at least 3 
months prior to the screening period, and only within 
the maximum dose described in the left column.
Initiation and/or dose increase of hypnotic should only 
happen to treat emergent sleep disorders, and only 
within the maximum dose described in the left column.
Hypnotic or sedative medications should not be 
administered within 12 hours prior to PANSS 
assessments.


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1.2
SCHEMATIC OF STUDY DESIGN
An overview of the study design is provided in Figure 1.
Figure 1
Overview of Study Design
A. Without 36-Week Safety Extension Phase
B. With Optional 36-Week Safety Extension Phase
1.3
SCHEDULE OF ACTIVITIES
The schedule of the activities (SoA) is provided in Table 1 (without the 36-week safety 
extension phase) and Table 2 (for the 36-week safety extension phase).


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Table 1
Schedule of Activities without 36-Week Safety Extension Phase
Period 1
Period 2
Period 3
Period 4
Double-blind Treatment Period
(4 weeks)
Double-blind Extension Treatment Period
(8 weeks)
Follow-up 
Period
(4 weeks)
Visit Name/Study Week 
Screeninga
Baseline
1
1
2s
3
4 b,s
Period 2 
EOT
4b
ETV
5
6
7
8s
10
12 b,s
Period 3 
EOT
16b,s, ee
Study Day
-7 to -3
1
3
7
14
21
28
28
35
42
49
56
70
84
112
Visit window ( days)x
1
1
1
1
1
1
1
2
2
2
2
3
3
3
Written Informed Consent
X
Inclusion/Exclusion criteria
X
X
Eligibility Checklist Form
X
Randomization
X
(X)r
Demographics
X
FTNDc,v
X
X
X
X
X
X
X
Psychiatric/Medical Historybb
X
Mini International 
Neuropsychiatric Interview 
(MINI)
X
Physical Examd, bb
X
X
X
X
12 lead ECGbb
X
X
X
X
X
X
X
X
Vitals (supine and standing)bb
X
X
X
X
X
X
X
X
X
X
X
X
Weight and waist 
circumferencebb,cc
X
X
X
X
X
X
X
X
X
Previous and Concomitant 
Medicationsbb
X
X
X
X
X
X
X
X
X
X
X
X
X
Alcohol Testbb,y
X
X
X
X
X
X
X
X
Viral serologybb
X
Blood Chemistrye,bb
X
X
X
X
X
X
X
Hematologye,bb
X
X
X
X
X
X
X
Coagulatione,bb
X
X
X
X
X
X
X






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Table 2
Schedule of Activities for the 36-Week Safety Extension Phase (Optional)
36-Week Safety Extension Phase
Follow-up Period for 
36-Week Safety 
Extension Phase b,s
Visit Name
Additional 
Assessments at 
Week 12 
Week 24
Week 36
Week 48 /
(Additional to 
Period 3 EOT)
36-Week Safety 
Extension EOT
Study Week
12
24
36
48
52
Study Day
84
168
252
336
364
Visit window ( days)x
3




Written Informed Consent
Xdd 
Inclusion criteria for extension phase
X
Physical Examd, bb
X
X
X
X
12 lead ECGbb
X
X
X
X
Vitals (supine and standing)bb
X
X
X
X
Weight and waist circumferencebb,cc
X
X
X
X
Previous and Concomitant Medicationsbb
X
X
X
X
Alcohol Testbb,y
X
X
X
X
Blood Chemistrye,bb
X
X
X
X
Hematologye,bb
X
X
X
X
Coagulatione,bb
X
X
X
X
Lipidse,bb
X
X
X
X
Urinalysise,bb
X
X
X
X
Prolactinf, bb
X
X
X
X
Urine drug screenbb
X
X
X
X
Pregnancy Testg bb
X
X
X
PK samplesh,bb
X
X
X




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Footnotes for Schedule of Activities Table 1 and Table 2
a Screening period can be extended up to 10 days upon discussion with the Medical Monitor and only in the case of delay in availability of 
laboratory results.
b EOT, End of Treatment; ETV, Early termination visit.
During Study Period 2: If a participant voluntarily withdraws from the study or is withdrawn by the Investigator, the participant will be asked to 
complete Study Period 2 EOT visit as soon as possible after the last dose of study drug. This may be sooner than Day 28. Participant will also be 
asked to return to the clinic 4 weeks after the first dose of study drug (at the end of the 4-week Study Period 2) for Week 4 ETV to complete 
assessments of the primary and secondary efficacy outcomes. Participants will also be asked to return for the follow-up visit (4 weeks after the 
last dose of study drug). 
During Study Period 3: If a participant voluntarily withdraws from the study or is withdrawn by the Investigator, the participant should return to 
complete Study Period 3 EOT visit as soon as possible after the last dose of study drug. This may be sooner than Day 84. Participant will also be 
asked to return for the follow-up visit assessments (4 weeks after the last dose of study drug). 
During 36-Week Safety Extension Phase: If a participant voluntarily withdraws from the study or is withdrawn by the Investigator, the participant 
should return to complete the 36-Week Safety Extension EOT visit as soon as possible after the last dose of study drug. The participant will also 
be asked to return for the follow-up visit assessments (4 weeks after the last dose of study drug).
For the participants who discontinue study treatment prematurely, if the EOT visit for Study Period 2 and 3, and the 36-Week Safety Extension 
Phase falls into the windows of planned visit, only missing assessments need to be completed (see Section 7.1 and 8.10.3).
c FTND (Fagerström Test for Nicotine Dependence) excludes cigar, snuff, oral, and vaping (e-cigarette) users.
d
Height at screening only.
e All study-required laboratory assessments, with the exception of dipstick urinalysis, urine dipstick alcohol test, drugs of abuse, urine pregnancy 
test, COVID-19 test (when not performed centrally), and erythrocyte sedimentation rate (ESR), will be performed by a central laboratory.
Microscopic urinalysis if deemed necessary to be performed centrally (see Appendix 4).
f
Prolactin results will be kept blinded to participants and Investigators.
g All women of childbearing potential (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.
h Pre-dose at Week 1 and 2; pre-dose, 1, 2 (0.5) and 6 hours (0.5) post-dose at Week 4; one sample pre-dose at Weeks 6, 8, 12, 24, 36, and 
48 visits. PK sampling at Week 4 should be performed within two days before the Day 28 visit. During outpatient period of the study, PK samples 
should be taken (if possible) as the last assessment after all other assessments have been completed. Additional PK samples will be taken at 
the time of treatment discontinuation and in case of overdose.
i
Plasma samples for the exploratory biomarker assessments will be processed centrally.
j
Whole blood samples will be collected for clinical genotyping and will be processed centrally (see Section 8.6.1). Any other time point can be 
used if blood volume limits are exceeded at a particular visit day.


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Footnotes for Schedule of Activities Table 1 and Table 2 (cont.)
k Participants must be observed/treated on an inpatient basis from Day -3 (at the latest) until Day 28. Participants will be discharged on Day 28 of 
Study Period 2 once all planned study activities are done. The inpatient period can be extended into the blinded extension treatment period if 
deemed necessary by the Investigator (see Section 4.1.1).
l
Done by centralized raters.
m IMP dispensing (see Section 6).
n Phone calls by a case manager at the minimum once weekly are mandatory. During the 36-Week Safety Extension Phase, phone calls by a 
case manager once a month are mandatory. More frequent phone calls are encouraged. Follow-up phone calls will be made approximately 7, 
14, and 21 days after the last dose of study drug or after early termination (see Section 8.10.4).
o Study drug two tablets (one each from Bottle A and B) and two capsules (from Bottle C) except for Day 1 when only one capsule should be 
taken is administered once daily, at bedtime, without food and swallowed whole with fluid. Ideally, no food should be consumed for at least 
2.5 hours before and after the dosing.
p The Assessment of Sleep, Mood, Well-being and Cognitive Functioning and Treatment Expectancy is optional but strongly recommended. In 
total up to 28 questionnaires for assessment of Sleep, Mood, Well-being and Cognitive Functioning and Treatment Expectancy will be presented 
on the smartphone as part of AiCure app at selected time points that will appear as random to the participant. During Study Period 2 and for 
Japanese patients during Study Period 3 and Study Period 4 or Study Period 3 and 36-Week Safety Extension Phase, the questions will be 
captured on Medavante Virgil platform. Participants continuing in the 36-Week Safety Extension Phase will have the option to continue using this 
smartphone app for the first 4 weeks (Weeks 13-16).
q This assessment will not be performed in non-English speaking countries without linguistic validated translation. This applies also to patients who 
do not speak English as a first language but are living in an English speaking country. If validated translations become available, they may be 
used. Equivalent scales may be used, if available.
r After completion of the 4-week Study Period 2, the participants may be re-randomized into a double-blind extension period (Study Period 3) if 
agreed between Investigator and participant based on clinical status. Randomization numbers will remain unchanged.
s The study visit can be split over 2 days within visit window.
t
The use of medication adherence platform via a smartphone app in Japan may not be required.
u EMA is optional but strongly recommended. EMA will be performed 3 times throughout the day, 5 days a week (not at the visit day).
Assessments between Day 21 and Day 28 will be for training purpose and less frequent. EMA will not be performed in Japan. Participants
continuing in the 36-Week Safety Extension Phase will have the option to continue using this smartphone app for the first 4 weeks 
(Weeks 13-16).
v If onsite visits subsequent to the Period 2 EOT visit are not possible (due to, e.g., local COVID-19 restrictions or emergency situations), this 
assessment can be performed remotely if approved by the Sponsor. The scope of the assessment remains the same. Source documentation 
should detail if the assessment has been performed remotely.
w Unless performed locally within 2 weeks and available documentation can be provided. 


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Footnotes for Schedule of Activities Table 1 and Table 2 (cont.)
x In exceptional situations (i.e., local COVID-19 restrictions or emergency situations), the visit may be split between two days.
y Alcohol test will be performed using a urine dipstick test.
z Serious Adverse Event (SAE) only.
aa
If onsite visits during study Period 3 and the 36-Week Safety Extension Phase are not possible (due to, e.g., local COVID-19 restrictions or
emergency situations) study drug can be shipped from sites directly to a patient if approved by Sponsor and relevant health authorities, if 
applicable. This must be confirmed and documented in the participant's source file.
bb
If the post Period 2 EOT visit study assessments and procedures cannot be administered because the visit cannot take place (due to, e.g.,
local COVID-19 restrictions or emergency situations), the Home HealthCare System can be used if approved by Sponsor. The Home 
HealthCare System will not be used in Japan. The scope of the assessment remains the same. Source documentation should detail if the 
assessment has been performed remotely.
cc
For anthropometric measurements of weight and waist circumference the use of the same weighing scale and tape measure throughout the 
study is recommended.
dd
Informed consent form for the 36-Week Safety Extension Phase must be signed prior to initiation of any procedures related to the 36-Week 
Safety Extension Phase.
ee
Only for participants who completed Study Period 3 but did not enter the optional 36-Week Safety Extension Phase.
ff Safety blood samples will be taken and may be analyzed if needed, to investigate any new clinical safety signal.
gg
Samples for vasculitis monitoring (i.e., C-reactive protein [CRP] (Note: CRP is analyzed as part of the chemistry panel), erythrocyte
sedimentation rate [ESR], anti-neutrophil cytoplasmic antibodies [ANCA], anti-nuclear antibodies [ANA], anti-double-stranded DNA [anti-
dsDNA] antibodies, anti-phospholipid antibodies) will be taken as indicated and in case of an AE or physical examination finding that is 
assessed as suspected vasculitis (see Section 8.2.1).


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2.
INTRODUCTION
RO6889450 is a novel compound and a partial agonist of the trace amine-associated 
receptor 1 (TAAR1) for the treatment of schizophrenia. RO6889450 is currently in Phase 
II clinical development. 
2.1
STUDY RATIONALE
TAAR1 is a class A G protein coupled receptor (GPCR). It is expressed in the amygdala, 
hypothalamus, subiculum, and rhinal cortices as well as areas of the brain where 
modulation of dopaminergic (ventral tegmental area) and serotonergic (dorsal raphe 
nucleus) neuronal activity occurs. TAAR1 partial agonists have been shown to modulate 
dopaminergic, serotonergic, and glutamatergic neurotransmission, and have 
demonstrated anti-psychotic, anti-addictive, stress response, and glucose-regulating 
activity in nonclinical models. By targeting overlapping brain circuits that are implicated 
in psychotic and affective symptoms, and reward processing, as well as brain and 
peripheral circuits that regulate energy homeostasis, RO6889450 represents a potential 
novel therapy for the treatment of psychotic and affective disorders, including 
schizophrenia and schizoaffective disorder.
In schizophrenic patients, the F-DOPA signal is increased indicating an abnormal 
increase in presynaptic dopamine synthesis capacity. Elevated dopamine synthesis 
capacity, as measured by [18F]-DOPA, is seen in people with schizophrenia and
correlates with the degree of psychosis in patients who are treatment responsive. In 
rodents, the F-DOPA signal was significantly decreased by RO6889450, which provides 
initial evidence that RO6889450 may normalize a key abnormality of the dopamine 
system in patients with schizophrenia. These results indicate a potential utility of 
RO6889450 in the treatment of patients with acute exacerbation of schizophrenia.
Recently, results of a Phase II trial with the investigational product SEP-363856, 
characterized as a TAAR1 and 5HT1a agonist, have shown improvement in patients with 
acute exacerbation of schizophrenia at 4 weeks (Koblan et al 2020). A 6-month,
open-label extension period following the 4-week study was associated with continued 
improvement as assessed by the Positive and Negative Syndrome Scale (PANSS) total 
score and Clinical Global Impression Severity (CGI-S) with minimal effects on metabolic 
parameters and extrapyramidal symptoms. In addition, negative symptoms continued to 
show improvement during a 26-week, open-label treatment as assessed by the Brief 
Negative Symptom Scale total score and the Marder PANSS negative symptom factor 
score (Correll et al 2020).
This Phase II study will be conducted to further investigate and confirm whether the
administration of RO6889450 as a monotherapy treatment in patients with an acute 
exacerbation of schizophrenia can improve the symptoms of schizophrenia. The 
36-Week Safety Extension Phase of this study will aim to evaluate long-term safety, 
tolerability, and selected effectiveness outcomes.


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The rationale for the study design is provided in Section 4.2.
2.2
BACKGROUND
2.2.1
Background on Schizophrenia
Schizophrenia is a major chronic psychiatric disorder with a lifetime prevalence of 1% in 
the general population. It starts in late adolescence and early adulthood and typically 
progresses throughout the life of the patient with a course of exacerbations and 
remissions. Usually, there is functional deterioration after each psychotic exacerbation 
leading to a poor outcome in up to 70% of patients consisting of unemployment, 
homelessness, and poverty and a consequent disintegration of their social network. 
Besides chronic deterioration in their social functioning, patients with schizophrenia have 
several co-morbidities, including severe medical conditions; metabolic syndrome, 
attributable at least partly to side-effects of currently available antipsychotic medications; 
increased suicidal risk; and significant rates of substance abuse (Sadock and Sadock 
2007, Meyer and Stahl 2009, Wobrock and Soyka 2009). Symptoms and signs of 
schizophrenia are clustered into three major domains: positive symptoms 
(e.g., psychotic symptoms like delusions or hallucinations), negative symptoms (e.g.,
blunted affect, amotivation/apathy), and cognitive deficits (e.g., executive dysfunction, 
poor verbal memory), with frequent occurrences of co-morbid depressive symptoms.
Antipsychotic treatment of schizophrenia mainly targets the symptoms found during 
acute exacerbations, including acute positive symptoms.  These drugs act as 
antagonists at the dopaminergic D2 receptor, as well as acting on other receptors such 
as the serotonergic (e.g., 5-HT2A), cholinergic (e.g., muscarinic M1), and histaminergic 
(e.g., H1) receptors (Kim et al 2009). These include first-generation drugs such as 
phenothiazines and butyrophenones, which, despite having great potency as 
antipsychotics, are associated with frequent and severe extrapyramidal symptoms 
(EPS), such as Parkinsonism, acute dystonia and akathisia. Second- generation
(atypical) antipsychotics (SGAs) are currently the mainstay of therapy and include drugs 
such olanzapine, quetiapine, risperidone, and aripiprazole, and in case of treatment 
resistance, clozapine. These latter compounds are associated with less severe EPS, but 
are associated with metabolic syndrome (dyslipidemia, insulin resistance, weight gain, 
elevations in blood pressure [BP]), which can unfavorably alter the benefit-risk ratio 
(Meyer and Stahl 2009; Kim et al 2009; Gründer et al 2009; Thomas et al 2009). 
Metabolic syndrome and obesity are estimated to occur in 33% of patients with particular 
SGAs, such as olanzapine, clozapine, risperidone, and quetiapine. There is an obvious 
need for new therapies that may effectively treat psychotic symptoms with improved 
safety and tolerability profiles compared to current medicines.
Current atypical antipsychotics are efficacious in the treatment of positive symptoms, but 
have minimal effects on the negative and cognitive symptoms. Thus, there is also a
need for treatments of these symptom domains in schizophrenia (Sanger 2004; Stip et al 
2005). 


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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 sub-cortical and cortical circuits. Underlying 
the symptomatic phenomena are disturbances in monoaminergic and glutamatergic 
neurotransmission (e.g., dopamine, serotonin, noradrenaline, and glutamate). These 
pathways are widely present in the central nervous system (CNS) and are potentially 
capable of influencing many areas involved in emotional processing, cognition, and 
behavior (Belmaker and Agam 2008; Racagni and Popoli 2008; Sen and Sanacora 
2008). Until recently, the excess dopamine hypothesis was the major pathophysiological 
theory of psychosis, based largely on the effectiveness of D2 antagonists. Currently, 
dysfunctions in other neurotransmitters, such as glutamate, are known to exist and are 
being explored as new therapeutic targets (Moghaddam and Javitt 2012).
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 endogenous 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, dopaminergic, and glutamatergic synaptic 
transmission. Recently, a family of GPCRs has been identified and named trace amine-
associated receptor (TAAR), 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). Hence, 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 predictive 
of antipsychotic, stress-response modulating, anti-addictive, and glucose-regulating 
activities, indicating therapeutic potential. 
RO6889450 is not an inhibitor or an inducer of the major human cytochrome (CYP)
enzymes, but is a substrate for human CYP3A4, CYP2C19, and flavin-containing 
monooxygenase. 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 (Report 1095250). Results from an ongoing Phase I study (JP40960) showed 
no relevant difference in exposure between different genotypes of CYP2C19. 


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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, and pharmacodynamics of single doses of RO6889450 at 5, 15, 50, 
100, 200, 300, or 450 mg (or placebo) and multiple doses of RO6889450 at 15, 50, 150, 
300, or 450 mg once daily for 2 weeks.
Pharmacokinetics of RO6889450 were well characterized after single and multiple doses 
and support once daily (QD) dosing in the subsequent studies. Steady-state plasma 
concentration was achieved after 5 to 6 days of dosing.
No clinically significant or relevant abnormalities, including dose-related trends were 
observed in electrocardiograms (ECGs), ambulatory BP measurements, and laboratory 
safety parameters (blood chemistry, hematology, urinalysis) for either single or multiple 
dose administrations. Two Dose-Limiting Events (DLE) occurred in the 450 mg multiple 
dose cohort: one event of generalized exanthema resulting in treatment discontinuation 
and one patient experiencing several episodes of postural orthostatic tachycardia (POT; 
increased pulse rate 30 bpm without hypotension). Both subjects had received active 
treatment. There were no serious adverse events (SAEs) or severe adverse events 
(AEs) reported. The most common AE observed was headache. POT was observed in 
most subjects including those receiving placebo; however, there was a trend towards 
higher pulse rates at the highest dose levels (450 mg single dose and multiple doses) 
and this POT was never associated with orthostatic hypotension.
Given its positive metabolic profile, RO6889450 may provide benefits for the general 
medical condition of patients with schizophrenia having metabolic syndrome 
co-morbidities. A detailed description of the chemistry, pharmacology, and safety of 
RO6889450 is provided in the RO6889450 Investigator’s Brochure (IB).
2.3
BENEFIT/RISK ASSESSMENT
RO6889450 has the potential to improve both positive and negative symptoms of 
schizophrenia. In healthy volunteers, RO6889450 was well tolerated when administered 
as a multiple dose up to 300 mg for 14 days. No clinically significant or relevant 
abnormalities, including dose-related trends, were observed in ECGs, ambulatory BP
measurements, or laboratory safety parameters in either single or multiple dose 
administrations up to the maximum tolerated dose (MTD) of 300 mg. In this study, the 
doses tested will be 150 mg QD, i.e., half of the MTD defined in the MAD study 
(BP30134) and 45 mg QD. 
The unmet medical need for effective treatment of both positive and negative symptoms 
in patients with schizophrenia with an improved safety profile is immense. Given the 
potential of RO6889450 to significantly improve symptoms in schizophrenia, the 
observed safety/tolerability profile in healthy volunteers and the measures implemented 


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to ensure the patient’s safety, the overall benefit/risk assessment for clinical trial 
participation is considered favorable.
An assessment was conducted to determine whether there is any impact of the 
coronavirus disease 2019 (COVID-19) pandemic on the benefit/risk assessment of this 
study protocol including, but not limited to, the patient population under study and study 
treatment being evaluated. On the basis of that assessment, no impact is anticipated 
and the existing safety monitoring and management guidelines, and risk mitigation 
measures provided in the study protocol are considered adequate.
At the time of writing, there was no evidence to suggest any interaction between 
RO6889450 and SARS-CoV-2 vaccines. When required, SARS-CoV-2 vaccines may be 
administered at any time during the study. SARS-CoV-2 vaccines should be given in 
accordance with the approved vaccine label. Any vaccine should be documented in the 
electronic case report form (eCRF) as a concomitant medication. 
More detailed information about the known and expected benefits in the context of 
potential risks and reasonably expected AEs of RO6889450 is provided in the 
RO6889450 Investigator’s Brochure.
3.
OBJECTIVES AND ENDPOINTS
The objectives and corresponding endpoints are provided in Table 3.


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Table 3
Objectives and Endpoints
Objectives
Endpoints
Primary

To compare the effect of 4-week 
treatment with two doses of RO6889450 
(45 mg and 150 mg) vs. placebo in 
participants with acute symptoms of 
schizophrenia or schizoaffective 
disorder. 

Change from baseline at Week 4 in the 
Positive and Negative Syndrome Scale 
(PANSS) total score.
Secondary

To compare the effect of 4–week 
treatment with two doses of 
RO6889450 (45 mg and 150 mg) with 
placebo on symptoms of schizophrenia 
or schizoaffective disorder as assessed 
with PANSS.

Proportion of participants with at least 
20% or 50% improvement from baseline 
on PANSS total score.

Changes from baseline in the PANSS 
factor scores and proportion of 
participants with at least 20% or 50% 
improvement from baseline in the 
PANSS factor scores.

To compare the effect of 4–week 
treatment with two doses of 
RO6889450 (45 mg and 150 mg) with 
placebo on: Clinical Global Impression 
Severity (CGI-S) and improvement 
(CGI-I).

Change from baseline (CGI-S and 
CGI-S MTS scores)

CGI-I and CGI-I MTS scores

To compare the effect of 4–week 
treatment with two doses of 
RO6889450 (45 mg and 150 mg) with 
placebo on time-to-readiness for 
discharge from inpatient unit.

Time from first randomized treatment 
intake to readiness for discharge as 
assessed by the Readiness for 
Discharge Questionnaire (RDQ) or 
actual discharge or censoring if the 
participant discontinues the study early.

To compare the safety and tolerability of 
4-week treatment with two doses of 
RO6889450 (45 mg and 150 mg) vs. 
placebo.

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 standing vital 
signs recordings.

Change from screening 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, 
and urinalysis test results.

Change from baseline in Columbia-
Suicide Severity Rating Scale (C-SSRS) 
and Extrapyramidal symptom rating 
scale, abbreviated (ESRS-A).


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Table 3
Objectives and Endpoints (cont.)
Objectives
Endpoints

To observe the effect of treatment 
with two doses of RO6889450 
(45 mg and 150 mg) up to 12 weeks.

Proportion of participants with at least 20% or 
50% improvement from baseline on PANSS 
total score.

Changes from baseline in the PANSS total 
and factor scores and proportion of
participants with at least 20% or 50% 
improvement from baseline in the PANSS 
factor scores.

CGI-S and CGI-S MTS.

CGI-I and CGI-I MTS.

To observe the safety and 
tolerability of extended treatment 
with two doses of RO6889450 
(45 mg and 150 mg) up to 
12 weeks.

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 standing vital signs 
recordings.

Change from baseline in 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, and 
urinalysis test results.

Change from baseline in C-SSRS and ESRS-
A. 

To evaluate the pharmacokinetics 
(PK) of RO6889450 and 
RO6889450-derived metabolite(s).

Concentration per time point.

AUCss of RO6889450 and, if feasible,
RO6889450-derived metabolite(s) at Week 4.

Cmax of RO6889450 and, if feasible,
RO6889450-derived metabolite(s) at Week 4.

Other PK parameters as appropriate.
Exploratory

To evaluate the changes in Sleep, 
Mood, Well-being, Cognitive 
Functioning and Treatment 
Expectancy.

Smartphone App Questionnaire.

To assess the changes in ReQoL.

Change in ReQoL from baseline, proportion of 
patients with 10 points improvement or more.

To compare the effect of two doses 
of RO6889450 (45 mg and 150 mg)
with placebo on: Patient Global 
Impression - Change (PGI-C).

PGI-C.

To assess the relationship between 
the levels of inflammatory 
biomarkers and cognitive subtype.

Differences in levels of inflammatory 
biomarkers between subgroups of patients 
defined by pre-morbid and current IQ estimate 
(Wide Range Achievement Test [WRAT-4] 
and Wechsler Abbreviated Scale of 
Intelligence – Second Edition [WASI-II]).


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Table 3
Objectives and Endpoints (cont.)
Objectives
Endpoints

To evaluate the change in the level 
of depression in schizophrenia
measured by Calgary Depression 
Scale for Schizophrenia (CDSS) up 
to 48 weeks.

Calgary Depression Scale for Schizophrenia.

To evaluate the changes in the level 
of insight into mental disorder.

Scale to Assess Unawareness of Mental 
Disorder (SUMD).

VAGUS insight into Psychosis Scale

Beck Cognitive Insight Scale (BCIS).

To explore the changes in nicotine 
addiction measured by Fagerström 
Test for Nicotine Dependence.

Fagerström Test for Nicotine Dependence.

To explore the effects of RO6889450 
on levels and patterns of social and 
general activity and psychotic 
symptoms

Ecological Momentary Assessment

To assess patients perception of 
changes relative to their condition 
and relevance and ease of 
understanding of the PRO 
instruments used in the study

Feedback questions

To evaluate relationship between the  
premorbid functioning and treatment 
response

Premorbid Adjustment Scale (PAS)

To observe the effect of treatment 
with two doses of RO6889450 
(45 mg and 150 mg) up to 48 weeks

Changes from baseline in the PANSS total 
and factor scores at Week 48. Analysis by the 
following groups: risperidone, RO6889450 
45 mg, RO6889450 150 mg, placebo/ 
RO6889450 45 mg, placebo/RO6889450 
150 mg

CGI-S

CGI-I

To observe the safety and tolerability 
of long-term treatment with 
RO6889450 up to 48 weeks

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 standing vital signs 
recordings

Change from screening in 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, and 
urinalysis test results

Change from baseline in C-SSRS and 
ESRS-A


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4.
STUDY DESIGN
4.1
OVERALL DESIGN
This is a Phase II, multi-center, randomized, double-blind, parallel group, placebo-
controlled study in participants with an acute exacerbation of schizophrenia or 
schizoaffective disorder. An overview of the study design is provided in Section 1.2.
After eligibility is confirmed during the screening period (Study Period 1), approximately 
280 participants will be randomized outside Japan (United States [US] and rest of the 
world [ROW]) in equal proportions (approximately 70 per group) to one of the following 
treatments: 150 mg QD of RO6889450, 45 mg QD of RO6889450, placebo, or 
risperidone 4 mg QD (titration period: 2 mg of risperidone on Day 1, 4 mg of risperidone 
from Day 2) in a double-blind fashion for 4 weeks. In addition to these 280 participants, 
approximately 28 participants will be recruited in Japan.
Outside Japan randomization will be based on region (North America, Eastern Europe, 
and Asia), baseline PANSS total (80-95 and 96 and above), duration of the disease 
(5 years and 5 years), and sex. In Japan randomization will be stratified according to 
baseline PANSS total (80-95 and 96 and above). Participants must remain as inpatients 
throughout Study Period 1 and during the 4 weeks of the double-blind treatment period
(Study Period 2). 
After completion of the 4-week Study Period 2, the participants may enter a double-blind 
extension period (Study Period 3) if agreed between Investigator and participant based 
on clinical status. 
Participants treated with risperidone, or 150 mg QD of RO6889450, or 45 mg QD of 
RO6889450 during the Study Period 2 will continue with their respective treatments in 
the Study Period 3, while participants assigned to placebo will be randomized to either 
150 mg QD or 45 mg QD of RO6889450 in a blinded fashion. Outside Japan 
randomization will be based on region (North America, Eastern Europe, and Asia), 
baseline PANSS total (80-95 and 96 and above), duration of the disease (5 years and 
5 years), and sex. In Japan randomization will be stratified according to baseline 
PANSS total (80-95 and 96 and above). At the beginning of the Study Period 3, 
participants will be discharged from the hospital or may remain inpatient for the first 
week if required according to the clinical judgment of the Investigator. If the participant 
must remain in the hospital beyond the first week of Study Period 3 according to the 
clinical judgment of the Investigator, the Investigator will need to obtain approval from 
the Sponsor. For Japan, due to regional differences in health care, Sponsor approval is 
not required.
After completion of Study Period 3, participants may be offered continuation in the
optional 36-Week Safety Extension Phase if they meet additional inclusion criteria. 
Participants will continue to receive the same treatments as those they received during 
Study Period 3, in a double-blind fashion. 


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The assessment of the primary endpoint (PANSS) will be performed by trained 
centralized raters independent from the investigational sites. Participants who 
discontinue study medication during Study Period 2 are required to complete the Study 
Period 2 EOT visit as soon as possible after the last dose of study drug (if possible,
PANSS assessment should be performed before rescue medications are taken). These 
participants are also required to return to the clinic 4 weeks after the first dose of study
drug (at the end of the 4-week Study Period 2) for Week 4 early termination visit (ETV).
Participants will also be asked to return for the follow-up visit (4 weeks after the last dose 
of study drug).
4.1.1
Length of the Study
The total duration of the study for each participant will be approximately 17 weeks (or 
53 weeks if participating in the 36-Week Safety Extension Phase) divided as follows:

Study Period 1: Screening: approximately 3 to 7 days (1 week: inpatient).

Study Period 2: Double-blind treatment period: 28 days (4 weeks: inpatient)

Study Period 3: Double-blind extension treatment period: 56 days (8 weeks). At the 
beginning of the extension period, participants will be discharged from the hospital 
or may remain inpatient for the first weeks if required according to the clinical 
judgment of the Investigator (If the participant must remain in the hospital beyond 
the first week of Study Period 3 according to the clinical judgment of the 
Investigator, the Investigator will need to obtain approval from the Sponsor. For Asia 
region, Sponsor approval is not required).

36-Week Safety Extension Phase (optional): 36 weeks. Participants, who have
completed Study Period 3 and in the opinion of the Investigator may benefit from the 
prolonged treatment, may enter 36-Week Safety Extension Phase if they meet 
additional eligibility criteria. Participants with worsening of their psychiatric or 
medical status that would preclude their safe participation in the 36-Week Safety 
Extension Phase or their ability to comply with the required procedures will not be 
eligible for the 36-Week Safety Extension Phase of this study.

Study Period 4: Safety follow-up/Follow-up Period for 36-Week Safety Extension
Phase: 28 days (4 weeks). Mandatory follow-up assessments for all participants
4 weeks after the last dose of study drug.

End of study visit: 1 day
Participants must be observed/treated on an inpatient basis from Day -3 (at the latest) 
until Day 28. Participants will be discharged on Day 28 of Study Period 2 once all 
planned study activities are done. The inpatient period can be extended into the double-
blind extension treatment period (Study Period 3) if deemed necessary by the 
Investigator.


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At the Investigator’s discretion and upon Sponsor notification, a day pass may be 
granted to participants that need to temporarily leave the hospital during the inpatient 
periods. Urine drug screen and alcohol test need to be performed on the return of 
participant to the hospital.
4.2
SCIENTIFIC RATIONALE FOR STUDY DESIGN
The study rationale is provided in Section 2.1.
4.2.1
Rationale for Study Population and Study Duration
The primary objective of the study is to test the efficacy of RO6889450 for the treatment 
of acute exacerbation of schizophrenia or schizoaffective disorder; therefore participants 
in this study will be patients diagnosed with schizophrenia or schizoaffective disorder 
who are experiencing an acute exacerbation as determined by their clinical history, 
current clinical assessment, and confirmed by a minimum severity of symptoms 
measured through the PANSS total score, specific positive symptom items of the 
PANSS and the CGI-S scale.
In a recent large meta-analysis of 167 placebo-controlled clinical trials conducted in 
schizophrenia (Leucht et al 2019), mean patient age was negatively correlated with 
placebo-drug differences in the primary endpoint, suggesting that trials in an older
population with schizophrenia and more chronic may have a lower potential for signal 
detection. For that reason, this Phase II trial will include participants between 18 to 45 
years of age.
Clinical investigations of the treatment of acute exacerbations of schizophrenia have
occurred in studies of durations varying from 4 to 8 weeks (Beasley et al 1997; Marder 
et al 1994; Citrome 2010). Older literature, suggested a delayed onset of response to
antipsychotic treatment resulting in a need for prolonged exposure of a subset of 
patients to placebo. However several meta-analyses have demonstrated that the biggest 
improvement in controlled trials occurs within the first 2 weeks (Agid et al 2003;Leucht 
et al 2005) In a re-analysis of data from placebo-controlled registry trials of olanzapine
and risperidone, most of the reduction in symptoms occurred by the fourth week in the
study (McMahon et al 2008). In addition, drop-out rates in the placebo groups reached 
up to 60% in 6-week studies making statistical inferences less reliable. In the recent 
large meta-analysis, study duration was not associated with drug-placebo differences. 
As this is the first study of RO6889450 in patients with an acute exacerbation of 
schizophrenia, a duration of 4 weeks was selected for the assessment of the primary 
efficacy endpoint, while reducing patient burden and addressing ethical concerns of 
prolonged placebo treatment as well as potential bias due to high dropout rates in longer 
clinical trials.
Patients who complete the Study Period 2 will have the option to continue into a 
double-blind 8-week extension period (Study Period 3), in treatment with RO6889450 
150 mg or 45 mg, or with risperidone 4 mg. This period is intended to further assess the 


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safety and efficacy of RO6889450 over a longer period. Participants who complete 
Study Period 3 will have the option to enter a 36-Week Safety Extension Phase, 
continuing with their allocated treatment. This 36-Week Safety Extension Phase is 
intended to further assess long-term safety and drug effect of RO6889450.
4.2.2
Rationale for Placebo Control Group 
Currently, superiority over placebo is considered the gold standard method to 
demonstrate safety and efficacy of new medications, including antipsychotic agents 
(Kemmler et al 2005). Despite advances in clinical trial methodology, alternative trial 
designs offer more challenges to interpretation of results. Without a placebo comparator 
within the same study, it is difficult to estimate whether improvements in symptoms 
correspond to nonspecific treatment effects or the natural course of the disease. 
Additionally, in non-placebo-controlled designs, it is difficult to assess whether the 
apparent non-significant difference is related to the investigational agent being equally 
effective or ineffective to the active comparator or study deficiencies (Streiner et al 
2008). Thus for methodological reasons, this study will employ four treatment groups: 
RO6889450 (150 mg or 45 mg), risperidone 4 mg, or placebo.
While placebo-controlled trials may be necessary, it is imperative to minimize the 
duration of exposure to ineffective treatment and provide required safety measures to 
protect the well-being of study patients. For this reason, patients are required to remain 
in an inpatient setting for the entire duration of the 4-week double-blind period and will 
be allowed certain concomitant medications (see Section 6.5).
4.2.3
Rationale for Selection of Risperidone as Active Control
Antipsychotic treatment has become the mainstay in the management of patients with
acute exacerbations of schizophrenia. In a recent meta-analysis of 32 oral antipsychotics 
risperidone was confirmed as one of the most widely studied antipsychotic medications 
and also confirmed to be one of the most efficacious treatments for the treatment of 
acute exacerbation of schizophrenia, particularly for positive symptoms (Huhn et al 
2019). Given observations that placebo responses have increased in recent years (Agid 
et al 2013) the risk of a falsely negative study is addressed by including a risperidone 
treatment group for assay sensitivity. The 4 mg/day dose of risperidone has been
selected based on the recommendations of approved labeling for the treatment of adults 
with schizophrenia. Risperidone at a dose of 4 mg/day has been used frequently in 
recent years as an active control arm in placebo-controlled trials to evaluate other new 
treatments for schizophrenia (Durgama et al 2014, Downing et al 2014).
4.2.4
Rationale for Biomarker Assessments
Increased understanding of interactions between the immune system and the brain in 
several chronic neurological and psychiatric disorders stimulated recent interest in the 
investigation of immune system alterations in schizophrenia. Advances in genetics have 
led to the identification of associations between genes involved in the regulation of the 


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immune system and increased risk of schizophrenia. A considerable body of evidence 
supports the immune hypothesis of schizophrenia, i.e., the notion that patients with 
schizophrenia have immunological alterations in the blood. The particular evidence 
includes immune cell numbers, inflammatory markers, oxidative stress, and antibody 
titers. Further, potential predictive values of baseline blood levels of these markers to 
therapeutic agents have been studied and confirmed by several independent studies 
(Miller and Goldsmith 2017). A dedicated exploratory biomarker assessment (see 
Section 8.6) will be performed in order to investigate the role of the immune system in 
the study population and assess the potential predictive value of these markers to the 
RO6889450 response.
Furthermore, more than 100 loci in the human genome contain single nucleotide 
polymorphism haplotypes that associate with risk of schizophrenia. The strongest 
evidence thus far is schizophrenia’s association with genetic markers across the major 
histocompatibility complex locus also best known for its role in immunity (Sekar et al 
2016; Ripke et al 2014). This study will therefore also collect blood for genotyping
analyses to explore the potential of genetic markers for stratification, i.e., to identify a 
subset of patients with a specific genetic profile that may be more likely to respond to 
RO6889450.
4.2.5
Rationale for Digital Biomarker Assessments
Ecological Momentary Assessment (EMA) involves participants being prompted by 
notifications several times a day to complete a series of questions via a mobile device 
such as a smartphone (Shiffman et al 2008). Data collected reflects an individual's 
momentary experiences at a given time point in the context of their daily life, improving 
ecological validity of assessment data and overcoming memory deficits and recall and 
potential expectation biases of both participant and examiner (Shiffman et al 2008). 
Studies have demonstrated the feasibility and validity of digital EMA methods in 
schizophrenia (Granholm et al 2008; Granholm et al 2013; Granholm et al 2020) and the 
ability of EMAs to capture information on symptoms and functioning in schizophrenia
such as autonomic regulation and auditory hallucinations (Kimhy et al 2017), self-stigma
(Ben-Zeev 2012), suicidal ideation (Depp et al 2018), paranoia and positive symptoms
(Ben-Zeev et al 2012, So et al 2014) and motivational negative symptoms (Moran et al 
2017). 
The digital biomarker approach EMA 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 8.9.4 for more details). 


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4.3
JUSTIFICATION FOR DOSE
Doses of 45 mg QD and 150 mg QD have been selected based on both preclinical and 
clinical observations with RO6889450. Improvements were observed in reward-related 
behavioral tasks in Study BP30134. In the reinforcement learning working memory 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 50 mg and 150 mg of RO6889450 when compared to placebo. The
effort-choice benefit 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 150 mg 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. For these reasons, a dose of 
150 mg QD of RO6889450 is considered adequate to demonstrate potential effects on 
key deficits in schizophrenia. The dose of 45 mg QD of RO6889450 is expected to have 
a pharmacological effect based on pre-clinical and clinical observations and will provide 
a clear blood exposure difference with 150 mg. 
Further details are provided in the RO6889450 Investigator’s Brochure.
4.4
END OF STUDY DEFINITION
A participant is considered to have completed the study if he/she has completed all 
phases of the study including the last study visit.
The end of the study is defined as the date of the last participant, last visit (LPLV) in the 
study.
5.
STUDY POPULATION
The study population rationale is provided in Section 4.2.1.
The participants in this study will be patients diagnosed with an acute exacerbation of 
schizophrenia or schizoaffective disorder, between 18 to 45 years of age, inclusive, who 
fulfill all of the given inclusion criteria and none of the exclusion criteria.
Prospective approval of protocol deviations from recruitment and enrollment criteria 
(e.g., protocol waivers or exemptions) is not permitted.


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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 and to comply with the study 
protocol according to the International Council for Harmonisation (ICH) and local 
regulations. Alternatively, if applicable, a legally authorized representative must be 
able to consent for the participant according to ICH and local regulations.
Age
2. Participant must be 18 to 45 years of age inclusive, at the time of signing the
informed consent.
Type of Participants and Disease Characteristics
3. Participants with a DSM-5 diagnosis of schizophrenia or schizoaffective disorder as 
confirmed by the Mini International Neuropsychiatric Interview (MINI).
4. Disease duration10 years.
5. Have a current acute exacerbation of schizophrenia (or a psychotic exacerbation of 
schizoaffective disorder) of no more than 8 weeks before screening visit and no 
current signs of apparent lack of treatment response.
6. At the time of screening, the participant needs to be either hospitalized or requiring 
inpatient psychiatric care according to clinical judgment for the treatment of the acute 
exacerbation. If the participant has been hospitalized for the current exacerbation, 
the hospitalization has to be of a maximum of 1 week prior to screening. In 
exceptional situations (e.g., delay due to the administrative procedures),
hospitalization up to a maximum of 10 days prior to screening is permitted (prior 
discussion with the Medical Monitor is recommended).
7. In previous exacerbations and hospitalizations, the subject has shown a pattern of 
response to appropriate antipsychotic treatment.
8. Medically stable over a period of 3 months (non-psychiatric conditions) prior to 
screening visit and not expected to require hospitalization or change of treatment for 
non-psychiatric conditions for the duration of the study. 
9. Screening and baseline CGI-S4 (moderate or worse).
10. Screening and baseline PANSS total score80.


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11. Screening and baseline PANSS with scores of 4 (moderate or worse) on 2 or more 
of the following items: delusions, conceptual disorganization, unusual thought 
content, hallucinatory behavior, or suspiciousness/persecution.
Weight
12. Body mass index (BMI) between 18 and 35 kg/m2 inclusive.
Sex
13. Male and female participants:
A female is eligible to participate if she is not pregnant (see Appendix 5,
negative serum pregnancy test at screening), not breastfeeding, and at least one 
of the following conditions applies:
a) Women of non-childbearing potential (WONCBP), as defined in 
Appendix 5.
b) Women of childbearing potential (WOCBP), who 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/ligation, male sexual partner who is sterilized, 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 (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.
Inclusion Criteria for the Optional 36-Week Safety Extension Phase
Participants who, according to clinical judgment of the Investigator, may benefit from 
prolonged treatment and meet the following additional inclusion criteria, may be eligible 
for participation in the 36-Week Safety Extension Phase: 
A.
Successful completion of the 12-week treatment (Study Periods 2 and 3).


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B.
Able and willing to provide written informed consent for the 36-Week Safety 
Extension Phase and to comply with the study protocol according to the ICH and 
local regulations. Alternatively, if applicable, a legally authorized representative must 
be able to consent for the participant according to ICH and local regulations. 
C.
Female participants of childbearing potential must have a negative urine pregnancy 
test at the Week-12 visit and be willing to remain abstinent or continue the use of 
contraceptive methods as described in Section 5.1, Inclusion Criterion 13. 
D.
No signs or symptoms of worsening psychiatric or medical status that would 
preclude the patient from the participation in the 36-Week Safety Extension Phase 
or affect their ability to comply with the study requirements.
E.
No history of confirmed or suspected vasculitis and/or no clinically significant 
abnormality in laboratory assessments taken for evaluation of the possible presence 
of vasculitis (i.e., C-reactive protein [CRP], erythrocyte sedimentation rate [ESR], 
anti-neutrophil cytoplasmic antibodies [ANCA], anti-nuclear antibodies [ANA], 
anti-double-stranded DNA [anti-dsDNA] antibodies, and anti-phospholipid 
antibodies).
5.2
EXCLUSION CRITERIA
Participants are excluded from the study if any of the following criteria apply:
General Exclusions
1. Has been inpatient for 1 week (or in exceptional situations [e.g., delay due to the 
administrative procedures] 10 days) or had any other hospitalization for acute 
exacerbation of schizophrenia or schizoaffective disorder within the prior 8 weeks or 
signs of lack of response to antipsychotic treatment.
2. Disease duration longer than 10 years.
3. Is currently an inpatient on an involuntary basis.
4. The C-SSRS "Suicidal Ideation" item 4 (active suicidal ideation with some intent to 
act, without specific plan) or item 5 (active suicidal ideation with specific plan and 
intent) answered “Yes” or any “Yes” answers to “Suicidal Behavior” within one 
month from Screening or between Screening and Baseline (i.e., since last visit). In 
addition, any Investigator judgment of significant risk of suicide or harming 
themselves or others.
5. Lifetime history of homicidal behavior.


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6. Moderate to severe substance use disorder within six months (excluding nicotine) as 
defined by DSM-5.
7. Other current DSM-5 diagnosis (e.g., bipolar disorder, major depressive disorder).
Medical Conditions
8. 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, or endocrine conditions).
9. Positive result at screening for hepatitis B surface antigen (HBsAg), hepatitis C virus
(HCV), or human immunodeficiency virus (HIV-1 or -2). Participants with positive 
anti-hepatitis C antibody who have been successfully treated and test negative for 
HCV RNA are eligible for study entry.
10. Tardive dyskinesia that is moderate to severe or requires treatment.
11. History of neuroleptic malignant syndrome.
12. Clinically significant abnormalities in laboratory safety test results (including hepatic 
and renal panels, complete blood count, chemistry panel and urinalysis), including:
a)
Aspartate aminotransferase (AST), or alanine aminotransferase (ALT) 2upper
limit of normal (ULN), or total bilirubin > 1.5 ULN with the exception of known 
Gilbert syndrome.
b)
Serum creatinine 1.5 ULN.
NOTE: 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.
13. 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.
Prior/Concomitant Therapy
14. Participant for whom risperidone is contraindicated or who have a documented 
history of lack of response or intolerance to risperidone or paliperidone or 
participants with known hypersensitivity to risperidone, paliperidone, or to any 
excipients in Risperdal.


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15. Participant treated with a long-acting injectable antipsychotic (LAI) or other 
antipsychotics that cannot be washed-out within the allotted screening period (see 
list of specific medications in Section 6.5).
16. History of electroconvulsive therapy (ECT) for any reason.
17. Participant treated with clozapine at any dose in the 12 months preceding the
screening visit or participants treated with clozapine at ≥200 mg/day at any time. 
Note: low dose (200mg/day) use for insomnia or dyskinesia longer than 12 months 
prior to screening visit is permitted (Appendix 6).
18. Participants currently receiving a psychotropic or other medication used as a 
psychotropic, which cannot be discontinued during the screening period.
19. Positive urine drug screen for amphetamines, methamphetamines, opiates, 
buprenorphine, methadone, cocaine, and barbiturates (see Section 8.2.4). In case of 
positive urine drug screen for cannabinoids (including cannabidiol), the participant 
may be allowed to enter the study only in case of a sporadic use of cannabis. 
Regular consumption meeting the criteria for cannabis use disorder (mild, 
moderate, or severe) is not permitted. 
20. 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.
Prior/Concurrent Clinical Study Experience
21. Participant has previously received RO6889450.
22. Participant received an investigational drug within 28 days or five times the half-life of 
the investigational drug (whichever is longer) prior to the first study drug 
administration (study Day 1).
5.3
CONFIRMATION OF ELIGIBILITY AT BASELINE
1. Participant will be excluded if unable to taper off an antipsychotic at least 72 hours 
prior to baseline (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 participating in the study.


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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 treatment. Screen failures may be tracked 
separately.
The Investigator will maintain a screening log to record details of all participants 
screened and to confirm eligibility or record reasons for screening failure.
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. Individuals who screen fail 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 Medical Monitor or delegate. Re-screening 
of participants who were screen failures for safety reasons is not allowed.
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 
discussion with Sponsor/Medical Monitor. Re-screened participants should be 
assigned a new participant number.
In order to re-screen such a participant, all inclusion and exclusion criteria should be re-
evaluated and all applicable screening assessments repeated.
5.6
RECRUITMENT PROCEDURES
This is a global competitive study without a target number of participants to be enrolled 
at any site outside Japan. 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 treatment is defined as any investigational treatment(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant 
according to the study protocol.
For Study BP41743, there are four formulations that are being administered:

active RO6889450 film-coated tablets (45 mg and 150 mg)

placebo film-coated tablets (to match 45 mg and 150 mg active RO6889450)

active comparator (risperidone) over-encapsulated tablets in hard gelatin capsules 
(2 mg)

placebo hard gelatin capsules (to match 2 mg comparator).


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For the RO6889450 film-coated tablets, the active tablet core consists of RO6889450 
drug substance and the inactive ingredients:  microcrystalline cellulose, lactose 
monohydrate, croscarmellose sodium, sodium stearyl fumarate, and colloidal silicon 
dioxide. The film-coat is composed of the following ingredient: Opadry II white 
32F280008. All the ingredients used in the film-coated tablet formulation are of 
compendial grade (USP/NF and/or Ph. Eur). For clinical studies, film-coated tablets are 
available containing 45 mg and 150 mg of RO6889450 (amounts given as RO6889450 
free base).
A placebo matching the RO6889450 film-coated tablets, in terms of size, shape and 
color, has also been developed for clinical usage. Placebo film-coated tablets have been 
manufactured containing: Isomalt, microcrystalline cellulose, lactose monohydrate, 
croscarmellose sodium, sodium stearyl fumarate, and colloidal silicon dioxide and no 
active substance. The film-coat is composed of the following ingredient: Opadry II white 
32F280008. All the ingredients used in the film-coated tablet formulation are of 
compendial grade (USP/NF and/or Ph. Eur).
For the blinded active risperidone comparator, the risperidone tablet 2 mg is over-
encapsulated with the following ingredients: lactose agglomerated and magnesium 
stearate. The capsule shell is composed of the following ingredients: gelatin, red iron 
oxide, yellow iron oxide, and titanium dioxide. All the ingredients used in the capsule 
shell formulation are of compendial grade (USP/NF and/or Ph. Eur).
For the blinded placebo for 2 mg risperidone comparator, the capsule fill only contains 
microcrystalline cellulose and no active substance. The capsule shell is composed of the 
following ingredients: gelatin, red iron oxide, yellow iron oxide, and titanium dioxide. All 
the ingredients used in the capsule shell formulation are of compendial grade (USP/NF 
and/or Ph. Eur).
All investigational medicinal products (IMPs) required for completion of this study 
(RO6889450 and matching placebo and risperidone 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. During Study Period 2, all study drug 
administration will be at the study center under supervision of site staff. During Study 
Period 3, study drug will be dispensed to patients as detailed in SoA (Section 1.3).
Cases of overdose, medication error, drug abuse, or drug misuse, along with any 
associated AEs, should be reported as described in Appendix 2, Section 5.2.


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6.1
TREATMENTS ADMINISTERED
Study drug should be taken at bedtime, without food, and swallowed whole with fluid. 
Ideally, no food should be consumed for at least 2.5 hours before and after dosing. If the 
interval between the meals cannot be respected, an interval as long as possible should 
be reached and documented.
Table 4 summarizes the treatments administered.
Table 4
Summary of Treatments Administered
Study Treatment 
Name:
RO6889450
RO6889450 
Placebo
Risperidone
Risperidone-
Placebo
IMP and NIMP
IMP
IMP
IMP
IMP
Dose Formulation:
Film-coated 
tablets
Film-coated 
tablets
Hard capsules
Hard capsules
Unit Dose 
Strength(s)/Dosage 
Level(s):
150 mg
45 mg
Matching active 
film-coated 
tablet, one per 
strength
2 mg
Matching active 
hard capsule
Dose:
150 mg
45 mg
NA
4 mg
NA
Route of 
Administration:
Oral
Oral
Oral
Oral
Sourcing:
Provided 
centrally by the 
Sponsor
Provided 
centrally by the 
Sponsor
Provided 
centrally by the 
Sponsor
Provided 
centrally by the 
Sponsor
Packaging and 
Labeling:
Study treatment 
will be provided 
in HDPE 
bottles. Each 
HDPE bottle 
will be labeled 
as required per 
country 
requirement.
Study treatment 
will be provided 
in HDPE 
bottles. Each 
HDPE bottle 
will be labeled 
as required per 
country 
requirement.
Study treatment 
will be provided 
in HDPE 
bottles.
Each HDPE 
bottle will be 
labeled as 
required per 
country 
requirement.
Study treatment 
will be provided 
in HDPE 
bottles.  
Each HDPE 
bottle will be 
labeled as 
required per 
country 
requirement.
Each participant will receive bottles with three study treatments:

one HDPE bottle (Bottle A) with 45 mg dose of RO6889450 or corresponding 
placebo, 

one HDPE bottle (Bottle B) with 150 mg dose of RO6889450 or corresponding 
placebo,

one HDPE bottle (Bottle C) with risperidone or risperidone placebo. 


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Each participant will take the study treatments from all three bottles daily as detailed 
below:

one 45 mg tablet of RO6889450 or corresponding placebo tablet from Bottle A, 

one 150 mg tablet of RO6889450 or corresponding placebo tablet from Bottle B,

two risperidone 2 mg or corresponding placebo capsules from Bottle C (except 
for Day 1, when only one risperidone 2 mg or corresponding placebo capsule 
should be taken).
Guidelines for treatment interruption or discontinuation are provided in Section 7.
Please see the IB(s) for more details. 
For risperidone, see the local prescribing information for more details.
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 study medication will be in accordance with Roche 
standards 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, integrity of seals and temperature conditions.

Report any deviations or product complaints to the Study Monitor upon discovery.
Each double-blind bottle will be labeled with a unique medication number (MEDNO). The 
qualified individual responsible for dispensing the study drug will dispense the correct 
containers of IMP to the participant at each dispensing visit by matching the MEDNOs 
allocated by the Interactive response technology (IRT) for that visit with the MEDNOs 
printed on the IMP labels. If the IMP dispensing visit cannot take place in the clinic (e.g.,
due to travel restrictions due to an outbreak of COVID-19) and alternative methods of 
delivery are not feasible, the IMP dispensing may be done with direct site to patient
shipment (with prior approval from relevant health authority if applicable).
The Investigator or delegate must confirm that appropriate temperature conditions have 
been maintained during transit for all study treatment received and any discrepancies 
are reported and resolved before use of the study treatment. Please refer to IMP Label 
for storage conditions.


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Only participants enrolled in the study may receive study treatment and only authorized 
site staff may supply or administer study treatment. All study treatments 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.
The Investigator is responsible for study treatment 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 (SOP) 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 
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
Approximately 280 participants will be randomized outside Japan (US and ROW) in the 
study. In addition to these 280 participants, approximately 28 participants will be 
recruited in Japan. After being screened, those participants who meet all eligibility 
criteria will be randomly assigned in equal proportions to one of the four treatment 
groups: RO6889450 150 mg QD; RO6889450 45 mg QD; risperidone 4 mg QD; or
placebo. Outside Japan randomization will be based on region (North America, Eastern 
Europe, and Asia), baseline PANSS total (80-95 and 96 and above), duration of the 
disease (≤ 5 years and > 5 years), and sex. In Japan randomization will be stratified 
according to baseline PANSS total (80-95 and 96 and above).
Participants completing Study Period 2 will be eligible to enter the Study Period 3. 
Participants treated with risperidone, with 150 mg QD of RO6889450 or with 45 mg QD 
of RO6889450 during Study Period 2 will continue with their respective blinded 
treatments. Participants assigned to placebo will be randomized to either 150 mg QD or 
45 mg QD of RO6889450, in a ratio of 1:1 using their baseline values for stratification. 
Participants who enter the 36-Week Safety Extension Phase will continue with their 
respective blinded treatments.
A participant randomization list will be created for the initial randomization and the 
randomization of the placebo participants into the Study Period 3.
All participants will be centrally assigned to randomized study treatment using an IRT. 
Before the study is initiated, the log in information and directions for the IRT will be 
provided to each site.


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Study treatment will be dispensed at the study visits summarized in SoA.
Returned study treatment should not be re-dispensed to the participants.
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 investigational site and the 
Sponsor Study Management Team (SMT) will be blinded to the study treatment 
(randomized and actually given).
Treatment codes should not be broken except in an emergency. If unblinding is 
necessary for participant management (e.g., in case the knowledge is needed for 
treatment of an SAE), the Investigator will be able to break the treatment code using 
IRT. The Sponsor must be notified before the blind is broken unless identification of the 
study treatment is required for a medical emergency in which the knowledge of the 
specific blinded study treatment will affect the immediate management of the 
participant’s condition. In this case, the Sponsor must be notified within 24 hours after 
breaking the blind. The date and reason that the blind was broken must be recorded in 
the source documentation and CRF, as applicable. 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. 
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.
The randomization list will be made available to the individuals responsible for PK 
sample bioanalysis and to statisticians or statistical programmers at Roche. Unblinding 
of any Roche individual will be according to the relevant Roche SOPs.
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.
The primary analysis of the study will be performed and interpreted when Week 4 data 
are available for all randomized patients. The Sponsor will be unblinded for analysis and
interpretation, while patients and Investigators will remain blinded for the extension 
phase of the study.
The Sponsor may choose to conduct up to two interim efficacy analyses for internal 
decision making. The interim analysis will be performed and interpreted by members of 
the Sponsor’s study team and appropriate senior management personnel, who will be 
unblinded at the treatment group level. 


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Access to treatment assignment information will follow the Sponsor’s standard 
procedures.
6.4
TREATMENT COMPLIANCE
During the Study Period 2, qualified site personnel will dispense the correct dose 
according to the randomization schedule. This individual will write the date dispensed 
and participant number on the study treatment bottle labels and the Drug Accountability
Record. This individual will also record in the participant’s records the medication 
numbers that are printed on the bottles each participant receives during the study.
During Study Period 3 (extension phase), qualified site personnel will dispense the 
correct dose according to the randomization schedule, will write the date dispensed and 
participant number on the study treatment bottle labels and will also record in the 
participant’s records the medication numbers that are printed on the bottles each 
participant receives. If the IMP dispensing visit cannot take place in the clinic (e.g., due 
to travel restrictions due to an outbreak of COVID-19) and alternative methods of 
delivery are not feasible, the IMP dispensing may be done with the direct site to patient 
shipment upon Sponsor/Medical Monitor approval (with prior approval from relevant 
health authority if applicable).
During Study Period 3 (extension phase) only, treatment compliance verification will be 
done using the medication adherence platform via a smartphone app (see 
Section 6.4.1). At each visit day, participant should bring the study treatment containers 
and drug accountability will be checked by the site. The use of the medication adherence 
platform via a smartphone app in Japan may not be required. 
During the 36-Week Safety Extension Phase, treatment compliance will be verified 
through phone calls once a month with the participant or participant’s caregiver who will 
be asked to keep a weekly account of the participant’s compliance. At each visit, the 
participant should bring the study treatment containers, and drug accountability will also 
be checked by the site. The medication compliance platform via a smartphone app will 
not be used during the 36-Week Safety Extension Phase.
If the compliance of participant is insufficient (80%) on a weekly basis, it has to be 
discussed with the Sponsor.
6.4.1
Medication Adherence Platform
This trial will employ a medication adherence monitoring platform via a smartphone 
AiCure app (“Platform”) during Study Period 3 in all countries except Japan, where the 
use of medication adherence platform may not be required. The Platform may either be 
provided to a participant preloaded on a smartphone, or the participant may download 
the Platform onto their own smartphone. Platform workflow is as follows: 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 


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webcam of the smartphone to confirm participant identity and medication to be taken. In 
addition, built-in reminders and a communication system allow 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 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 who are 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 do not take their medication regularly will be contacted by study staff 
for retraining and motivational interventions.
6.5
CONCOMITANT THERAPY
Any medication (prescription and over-the-counter [OTC]) taken within 28 days of study 
screening and any non-pharmacological interventions (e.g., individual psychotherapy, 
cognitive behavioral therapy, smoking cessation therapy, and rehabilitative therapy) will
be recorded on the appropriate eCRF.
All medication administered to manage adverse events should be recorded on the 
Adverse Event eCRF.
The Medical Monitor should be contacted if there are any questions regarding 
concomitant or prior therapy.
6.5.1
Anti-psychotic medication
All anti-psychotics are prohibited in the study during Study Periods 2 and 3, the 36-Week 
Safety Extension Phase, and with a minimum washout period of 72 hours before the 
initiation of study medication, depending on the anti-psychotic medication. Washout
periods for a specific anti-psychotic medication are provided in Appendix 6, Table 1.


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6.5.1.1
Rescue anti-psychotic treatment
If the clinical state of the participant would require treatment with an anti-psychotic other 
than the study medication, in the judgment of the Investigator, an antipsychotic should 
be prescribed and the participant will be immediately withdrawn from the study drug. The 
reasons for use of rescue medication should be documented in detail.
Investigators should make a reasonable effort to complete a final assessment including 
efficacy endpoints before starting antipsychotic medication (see Section 1.3, Section 7.1
and Appendix 6, Table 1). Patients should be followed up as specified in Sections 7, 
8.10.3 and 8.10.4.
6.5.2
Non anti-psychotic concomitant medication
6.5.2.1
Permitted Therapy
Non-psychoactive medications, including OTC medications, that are required to treat
pre-existing conditions or AEs that occur during the study may be used at the discretion 
of the Investigator.
All therapy and/or medication administered to manage AEs should be recorded on the 
AE eCRF. For further information regarding the management of specific AEs see 
Appendix 2. 
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.
Agents designed to prevent pregnancy: intrauterine device in place, oral contraceptives, 
dermal contraceptives, and injectable or implantable hormonal agents are permitted from 
enrollment until the end of the treatment period.
Concomitant therapy includes any medication, e.g., prescription drugs, OTC drugs, 
vaccines (including those against COVID-19), approved dietary and herbal supplements, 
nutritional supplements and any non-pharmacological 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. 
6.5.2.2
Prohibited Therapy
All medications (prescription and OTC) and any non-pharmacological interventions (e.g., 
individual psychotherapy, cognitive behavioral therapy, smoking cessation therapy, and 
rehabilitative therapy) taken within 28 days of study screening will be recorded on the 
appropriate eCRF.


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As a general rule, no new concomitant medication or therapies including
non-pharmacological interventions (e.g., individual psychotherapy, cognitive behavioral 
therapy, smoking cessation therapy, and rehabilitative therapy) will be permitted, with 
the exception of medications to treat pre-existing conditions or AEs, unless the rationale 
for exception is discussed and clearly documented between the Investigator and the 
Sponsor.
Specific prohibited medications are provided in Appendix 6, Table 2.
6.5.2.3
Restricted Therapy
The list of restricted therapies is provided in Appendix 6, Table 3.
6.6
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 early participant withdrawal. 
Participants should consult with their physician on available treatment options, such as 
antipsychotics, to begin after the last dose of study drug. Participants should be followed 
up as specified in Sections 7, 8.10.3 and 8.10.4.
7.
DISCONTINUATION OF STUDY, STUDY TREATMENT, AND
PARTICIPANT DISCONTINUATION/WITHDRAWAL
An excessive rate of withdrawals (either participants discontinuing study treatment 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. Temporary study drug interruption is an acceptable method to manage adverse 
events if deemed appropriate by the Investigator.
Details on study and site closures are provided in Appendix 1 Regulatory, Ethical, and 
Study Oversight Considerations.
7.1
DISCONTINUATION OF STUDY TREATMENT
Participants must discontinue study drug if they have withdrawn consent or experience 
any of the following:

Pregnancy

Participant is 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.


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
Participant must be discontinued from the study treatment in the case of suicidal
behavior or active suicidal ideation with specific plan and intent, or violent or 
aggressive behavior resulting in any type of injury or property damage.  

If the participant has worsening of psychotic symptoms that require treatment with 
anti-psychotic medication in addition to the study treatment, in the opinion of the 
Investigator, the participant should be discontinued from the study treatment and 
appropriate anti-psychotic medication should be initiated.

After the participant is discharged after the mandatory hospitalization, but the 
participant has worsening of psychotic symptoms that requires new hospitalization, 
the participant should be discontinued from the study treatment.

Symptomatic patients with moderate or severe COVID-19 infection (as per WHO 
guidelines) with signs of pneumonia or hypoxia must be withdrawn from the study 
treatment.

Participants entering the 36-Week Safety Extension Phase: if the participant has
confirmed vasculitis. In addition, the participant may be discontinued if vasculitis 
is suspected on the basis of (1) any clinically significant abnormality on the 
laboratory assessments for vasculitis monitoring or (2) a relevant AE (i.e., rash, 
myalgia, arthritis, and fever) or (3) a clinically significant physical examination 
finding that indicates the possible presence of vasculitis. Cases of suspected 
vasculitis are to be discussed with the Medical Monitor, and action taken with 
study treatment will be determined accordingly.
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.
Every effort should be made to obtain information on participants who withdraw from the 
study treatment but have not withdrawn consent. Participants who discontinue study 
treatment prematurely will be asked to return to the clinic for a study completion/early 
termination visit (ETV; see Section 8.10.3) and should be asked to return for follow‑up 
assessments (see Section 8.10.4), unless the participant withdrew consent.
If a participant voluntarily withdraws from the study or is withdrawn by the Investigator
during Study Period 2, the participant will be asked to complete Study Period 2 end of 
treatment (EOT) visit as soon as possible after the last dose of study drug. Participant 
will also be asked to return to the clinic 4 weeks after the first dose of study drug (at the 
end of the 4-week Study Period 2) for Week 4 early termination visit (ETV) to complete
assessments of the primary and secondary efficacy outcomes (PANSS, CGI-S, CGI-S 
MTS, CGI-I and CGI-I MTS), regardless of their adherence to treatment. Participants will 
also be asked to return for the follow-up visit (4 weeks after the last dose). If a participant
voluntarily withdraws from the study or is withdrawn by the Investigator during Study 
Period 3, the participant should return to complete Study Period 3 EOT visit as soon as 
possible after the last dose of study drug. Participant will be asked to return for the 
follow-up visit assessments (4 weeks after the last dose). If a participant voluntarily 
withdraws from the study or is withdrawn by the Investigator during the 36-Week Safety 


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Extension Phase, the participant should return to complete the 36-Week Safety 
Extension Phase EOT visit as soon as possible after the last dose of study drug. The 
participant will be asked to return for the follow-up visit assessments (4 weeks after the 
last dose). For the participants who discontinue study treatment prematurely, if the EOT 
visit for Study Periods 2 and 3, and the 36-Week Safety Extension Phase falls into the 
windows of planned visit, only missing assessments need to be completed (see 
Section 8.10.3). The primary reason for premature study treatment discontinuation 
should be documented on the appropriate eCRF. Participants who discontinue study 
treatment prematurely will not be replaced.
Discontinuation of study intervention for abnormal liver function should be considered by 
the Investigator when a participant meets one of the conditions outlined in Appendix 3 or 
if the Investigator believes it is in the 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 screening 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.
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 conditions that the Investigator or Sponsor determines may jeopardize the 
participant’s safety if he/she continues in the study.
Every effort should be made to obtain information on participants who withdraw from the
study. 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 be used as part of the overall research data. A participant's 
withdrawal from this study does not, by itself, constitute withdrawal of samples donated 
to the Research Biosample Repository (RBR).


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Participants who withdraw from the study will not be replaced. 
See 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.
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 Schedules of Activities 
(SoA; Section 1.3). Protocol waivers or exemptions are not allowed. If the post Study 
Period 2 EOT visit study assessments and procedures cannot be administered because 
the visit cannot take place (due to, e.g., local COVID-19 restrictions or emergency 
situations), the Home HealthCare System can be used (e.g., ECG, Labs, PK sampling, 
physical examinations etc.) if approved by the Sponsor. The Home HealthCare System 
will not be used in Japan.
Post Period 2 EOT visit safety and efficacy assessments can be performed remotely due 
to local restrictions (due to, e.g., local COVID-19 restrictions or emergency situations), if
approved by the Sponsor as detailed in Section 1.3.
Immediate safety concerns should be discussed with the Sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
study treatment.
Training, guidance on rater qualifications and procedures are described separately in the 
Ratings Manual.




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8.1
EFFICACY ASSESSMENTS
Scale administration will be performed according to Table 5.
8.1.1
Clinical Outcome Assessments
8.1.1.1
Positive and Negative Syndrome Scale (PANSS) and PANSS-
Informant Checklist (PANSS-IC)
The PANSS is a 30-item rating scale that evaluates positive, negative, and other 
symptoms in patients with schizophrenia (Kay et al 1987). The Positive sub-scale
assesses the features exhibited in schizophrenia that are not present in those with a 
normal mental state. The Negative sub-scale (7 items) assesses features that are 
absent in schizophrenia but that would be present in those with a normal mental state. 
The General sub-scale assesses the overall severity of the disorder and the risk of 
aggression. Each item is rated on a 7-point scale (1 absent, 7 extreme). A total 
score as well as subscale and factor scores will be derived. It takes approximately 40 
minutes to administer. The PANSS assessment will be performed by an approved 
remote centralized rater. Remote independent raters will administer assessments live via 
secure videoconference. In exceptional situations, PANSS assessment by an approved 
remote centralized rater can be accessed via phone link if the video link is not available. 
The independent 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.
The PANSS-Informant Checklist (PANSS-IC) is an informant questionnaire designed to 
supplement the PANSS by collecting information about the participant’s symptoms and 
behaviors during the past seven days from the informant. The information is meant to be 
gathered from an informant such as a caregiver or from a treating clinician or site 
personnel during the inpatient stay who has had significant contact with the participant 
during the reference period. During the interview, the informant will be asked for their 
observations about the participant’s symptoms and behaviors, this information may be 
used to inform ratings of fourteen PANSS items (i.e., Positive = P1, P3, P4, P5, P6, P7; 
Negative = N2, N4 and General = G5-G6, G7, G8, G14, G16). For each item, it will be 
assessed if the symptom is present or not, subsequent questions will then assess the 
frequency, severity or interference of the symptom. 
Collecting informant data is particularly helpful for subjects who are unwilling or unable 
to accurately report their symptoms during the interview. The checklist does not provide 
any direct study data but is simply used to assist the independent rater in rating the 
PANSS.
During the outpatient period of the study, if participants do not have a designated 
caregiver, the independent raters may, as an exception, rate the PANSS based on 
information collected from an Informant, i.e., study personnel.


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8.1.1.2
Clinical Global Impression-Improvement (CGI-I) and Severity 
(CGI-S) Scales
The CGI (Guy 1976) is one of the most commonly used outcome measures in 
psychopharmacology clinical trials. The CGI is the general name for two scales: the 
CGI- Severity scale (CGI-S) that measures global severity of illness at a given point in 
time and the CGI-improvement scale (CGI-I) that measures change from the baseline 
state at following visits. The CGI rating scale permits a global evaluation by the clinician 
of the subject’s improvement over time. The CGI-S is a 7-point scale ranging from 1 (no 
symptoms) to 7 (very severe). The CGI-I is a 7-point scale, ranging from 1 (very much 
improved) to 7 (very much worse).
At screening, clinicians will gather information from the patient’s past psychiatric history, 
caregiver feedback, and clinical judgement to determine one to two most troubling 
symptoms (MTS). 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. 
Duration of the scales will be approximately 15 to 20 minutes to complete all CGI-I and 
CGI-S scales.
8.1.1.3
Patient Global Impression of Change (PGI-C) Scale
The generic Global Impression is a measure commonly used in clinical trials to provide 
concise information on overall health state (Guy 1976). The change component is 
intended as a measure of change in health state and can be adapted for participant self-
assessment (PGI-C). A 7-point participant-based (PGI-C) global impression of change 
will be employed.
PGI-C: 1 = Very much improved; 2 = Much improved; 3 = Somewhat improved; 4 = No
change; 5 = Somewhat worse; 6 = Much worse; 7 = Very much worse
8.1.1.4
Calgary Depression Scale for Schizophrenia (CDSS) 
The CDSS (Addington et al 1990) is a scale used to assess the level of depression in 
schizophrenia (assess depressive symptoms separate from positive, negative and 
extrapyramidal symptoms). The instrument has nine items with a 4-point Likert scale 
(ranging from 0 = absent, 1 = mild, 2 = moderate, 3 = severe). The duration of the CDSS 
assessment will be approximately 15 to 20 minutes to complete.
8.1.1.5
Fagerström Test for Nicotine Dependence (FTND)
The FTND (Heatherton et al 1991) will be used to assess nicotine consumption during 
the course of the study. The FTND 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. It contains six items that evaluate the 
quantity of cigarette consumption, the compulsion to use, and dependence. Yes/No 


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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. The FTND excludes cigar, snuff, oral, and 
vaping (e-cigarette) users.
8.1.1.6
Recovering Quality of Life (ReQoL-20)
Recovering Quality of Life (ReQoL; Keetharuth et al 2018) is a new instrument that
measures mental health service users’ own perspectives of ‘recovery’ and quality of life. 
It was developed from the outcomes that service users identified as being central to 
them, as well as from the literature (Connell et al 2014; Connell et al 2018; Keethaurt et 
al 2018). The stages of measurement development include the identification of themes 
and items (Stage 1), the face and content validity with service users (Stage 2), and the 
psychometric testing by collecting data on the draft questionnaires (Stage 3) before 
finalizing the measures. The scoring options of the items are: None of the time, Only 
occasionally, Sometimes, Often, and Most or all of the time. The measure is suitable for 
self-completion and for use across a wide spectrum of mental health conditions (both 
psychotic and non-psychotic) and for different levels of severity, for individuals aged 16 
or over. The duration of the scale will take approximately 5 minutes to complete.
The assessment will not be performed in non-English speaking countries without 
linguistic validated translation. This applies also to patients who do not speak English as 
a first language but are living in an English speaking country. If validated translations 
become available, they may be used. Equivalent scales may be used, if available.
8.1.1.7
Readiness for Discharge Questionnaire (RDQ)
The RDQ is a tool used to assess inpatients with schizophrenia on their readiness for 
discharge, independent of socio-economic factors (Potkin et al 2005). The RDQ consists 
of five items using a 4-level Likert scale to assess suicidality/homicidality, control of 
aggression/impulsivity, activities of daily living, medication-taking, and 
delusions/hallucinations interfering with functioning and global status. The sixth item 
examines the overall clinical state of the patient using the CGI-S as an anchor. A final 
question assesses readiness for discharge. The RDQ has been shown to be significantly 
correlated with PANSS total and factor scores as well as actual discharge. The duration 
of the scale will take approximately 5 minutes to complete.
8.1.1.8
Assessment of Sleep, Mood, Well-being and Cognitive 
Functioning and Treatment Expectancy
Three Likert scales assessing sleep quality, mood / well-being, and cognitive functioning 
and treatment expectancy is optional but strongly recommended. The scales will be 
administered via the smartphone or the Medavante Virgil Platform (Appendix 7). 
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 Period 2: “Do you think you were taking 


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placebo or drug?” The scales will be completed up to 28 times by the participant at pre-
defined time points appearing random to patients.
8.1.1.9
Scale to Assess Unawareness of Mental Disorder (Short 
Version) (SUMD-9)
The Scale to Assess Unawareness of Mental Disorder (SUMD) short form (Amador et al, 
1994) is a 9-item clinician-reported outcome designed to measure current awareness of 
mental illness. The instrument is a shortening of the 74-item Scale to Assess 
Unawareness of Mental Disorder (Amador et al 1994), consists of three general items 
and six symptom items. Each item is scored on a 3-point Likert scale, with following 
response options (Michel et al 2013): “not applicable” (0), “aware” (1), 
“somewhat/unaware” (2) and “severely unaware” (3), hence higher scores indicating 
poorer awareness. Each item is examined separately without calculation of subscale 
scores. The assessment is likely to take 5 to 10 minutes to complete.
8.1.1.10
Beck Cognitive Insight Scale
The Beck Cognitive Insight Scale (BCIS) (Beck et al 2004) is a 15-item patient-reported 
outcome. The instrument was developed to evaluate patients’ self-reflectiveness and 
their overconfidence in their interpretations of their experiences. It encompasses two sub 
scales covering self-reflectiveness (9 items) and self-certainty (6 items). Each item 
utilizes a 4-point scale ranging from “do not agree at all” (0) to “agree completely” (3). 
Items 1, 3, 4, 5, 6, 8, 12, 14, and 15 are summed to form the self-reflectiveness score, 
whereas items 2, 7, 9, 10, 11, and 13 are summed to form the self-certainty score. A 
composite index of the BCIS reflecting cognitive insight was calculated by subtracting 
the score for the self-certainty scale from that of the self-reflectiveness scale. The 
duration of this assessment is likely to take less than 15 minutes to complete.
8.1.1.11
VAGUS Insight into Psychosis Scale
The VAGUS is the insight into psychosis scale with both self-report and clinician-rated 
versions. 
The assessment will not be performed in non-English speaking countries without 
linguistic validated translation. This applies also to patients who do not speak English as 
a first language but are living in an English speaking country. If validated translations 
become available, they may be used. Equivalent scales may be used, if available.
8.1.1.11.1
VAGUS Self-report. 
The VAGUS self-reported (VAGUS-SR) (Gerretsen et al 2014) is a 10-item patient-
reported outcome measure designed to measure clinical insight into psychosis. Each 
item utilizes a 10-point Likert scale ranging from “strongly disagree” (0) to “strongly 
agree” (10). Four sub scores, Illness Awareness (2 items), Symptom Attribution (4 
items), Awareness of Need for Treatment (3 items) and Awareness of Negative 
Consequences (1 item) are generated form this instrument. Items 2, 3, 7 and 8 are 
reverse scored, hence 10 minus the actual score. Each sub score is summed and then 


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divided by the number of responses. The total score is the sum of scores divided by 4. 
The assessment will take less than 5 minutes to complete.
8.1.1.11.2
VAGUS Clinician-reported
The VAGUS clinician-reported (VAGUS-CR) (Gerretsen et al 2014) is a 5-item clinician-
reported outcome measure designed to measure clinical insight into psychosis. Each 
item utilizes a 10-point Likert scale ranging from “strongly disagree” (0) to “strongly 
agree” (10). Four sub scores, Illness Awareness (1 item), Symptom Attribution (2 items), 
Awareness of Need for Treatment (1 items) and Awareness of Negative Consequences 
(1 item) are generated by this instrument. Item 4 is reverse scored, hence 10 minus the 
actual score. Each sub score is summed and then divided by the number of responses. 
The total score is the sum of scores divided by 4. The assessment is expected to take 
less than 5 minutes to complete.
8.2
SAFETY ASSESSMENTS
Planned time-points for all safety assessments are provided in the SoA (Section 1.3).
Safety assessments will consist of monitoring and recording AE, including SAEs and 
non-serious AEs of special interest; 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.
Scales administration will be performed according to Table 5.
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. 
Height will also be measured and recorded at screening only. 
Body mass index (BMI) will be calculated with the measure of weight and height 
according to SoA (Section 1.3).
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.
Investigators should pay special attention to clinical signs of rash, myalgia, arthritis,
and fever, and report these as AEs. These AEs should be evaluated for the possible 
presence of vasculitis and discussed with the Medical Monitor.
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Any abnormality identified at baseline should be recorded on the General Medical 
History and Baseline Conditions 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 Adverse Event eCRF.
8.2.2
Vital Signs
Vital signs will include participant’s temperature, systolic and diastolic BP 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, BP and pulse 
measurements will be taken again after two minutes in a standing position (standing vital 
signs) at the time point specified in Section 1.3.
BP 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 BP measurements.
8.2.3
Electrocardiograms
Sites will be provided with ECG equipment by the central ECG analysis vendor. 
Twelve-lead ECG will be obtained as outlined in the SoA (see Section 1.3) with the 
following parameters: heart rate, PQ (PR), QRS, QT, RR, and QTcF intervals, 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 mealtime 
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. 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 screening visit conditions; this includes but 
is not limited to food intake, activity level, stressors, and room temperature. In case of an 
absolute QTc of > 500 msec and/or an increase from screening visit QTc > 60 msec, 
another ECG triplicate must be recorded within the next 5 minutes. It may be appropriate 
to repeat abnormal ECGs to rule out improper lead placement potentially contributing to 


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the ECG abnormality. Refer to Section 7.1 for QTc withdrawal criteria and additional QTc 
readings that may be necessary.
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). 
Changes in T‑wave and U‑wave morphology and overall ECG interpretation will be 
documented. T-wave information will be captured as normal or abnormal, U-wave 
information will be captured in two categories: absent/normal or abnormal.
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 with the exception of dipstick urinalysis, urine dipstick alcohol 
test, drugs of abuse, urine pregnancy test, COVID-19 test (when not performed 
centrally), and ESR (see Appendix 4). 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 must be supplied 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 CRF. 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.


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Results of clinical laboratory testing will be recorded on the eCRF or be received as 
electronically produced laboratory reports submitted directly from the local or 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 at screening 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, 
benzodiazepines or opiates, the test could be repeated to confirm wash out.
Based on continuous analysis of the data in this study and other studies, any sample 
type not considered critical for safety may be stopped at any time if the data from the 
samples collected does not produce useful information.
8.2.5
Columbia-Suicide Severity Rating Scale (C-SSRS)
RO6889450 is a CNS-active study treatment. There has been concern that some 
CNS-active study treatments may be associated with an increased risk of suicidal 
ideation or behavior. Although this study treatment 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 OR people with schizophrenia, the Sponsor 
considers it important to monitor for such events before or during this clinical study.
Participants 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 treatment in participants who experience signs of suicidal ideation or 
behavior.
Families and informants of participants 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 Columbia-Suicide 
Severity Rating Scale (C-SSRS).
The C-SSRS is a tool used to assess the lifetime suicidality of a patient (C-SSRS
baseline) as well as any new instances of suicidality (C-SSRS since last visit). The 


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C-SSRS incorporates a structured interview to prompt recollection of suicidal ideation, 
including the intensity of the ideation, behavior, and attempts at actual/potential lethality 
(Posner et al 2011). The “baseline” 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 to 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
specifically to 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
Psychiatric/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) and any non-pharmacological 
interventions (e.g., individual psychotherapy, cognitive behavioral therapy, smoking 
cessation therapy, and rehabilitative therapy) used by the participant within 28 days prior 
to the screening visit.
A detailed psychiatric history will be taken during the screening period (including Mini 
International Neuropsychiatric Interview [MINI]). This will include information regarding 
specific symptoms, number of hospitalizations, and treatment history (including 
treatment response, detailed description of current episode, type / reason for 
exacerbation, e.g., compliance problem or breakthrough relapse). Sources for this 
information may include reliable caregivers or treating psychiatrists or medical records. 
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. This will 
include the information mentioned above along with other pertinent information as 
specified on the ECF. The completed ECF will be forwarded as soon as all requested 
information is available during screening to the Clinical Team Manager (CTM) or local 
Site 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.


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8.3
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS
The definitions of an AE or SAE can be found in Appendix 2. The non-serious AEs of 
special interest and disease-related events and/or disease-related outcomes not 
qualifying as AEs or SAEs are discussed in Section 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 Adverse Event 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:

Other AEs

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 the condition being studied

Hospitalization or prolonged hospitalization

Patient-reported outcome data
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 adverse events at each participant’s contact. All 
adverse events, whether reported by the participant or noted by study personnel, will be 
recorded in the participant’s medical record and the Adverse Event eCRF as follows:
After informed consent has been obtained but prior to initiation of study treatment, 
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 treatment, all adverse events, regardless of relationship to 
study treatment, will be reported until 28 days after the final dose of study treatment. 


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Post-study adverse events and serious adverse events: The Investigator is not 
required to actively monitor participants for adverse events after the end of the adverse 
event reporting period of 28 days.
However, if the Investigator learns of any SAE (including a death) or other adverse 
events of concern that the Investigator considers the event to be related to study 
treatment or study participation at any time after a participant has been discharged from 
the study, 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 is the preferred method to inquire 
about AE occurrence.
A consistent methodology of non-directive questioning should be adopted for eliciting 
adverse event 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 adverse event 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 serious adverse events 
considered to be related to study treatment or trial-related procedures until a final 
outcome can be reported.
During the study period, resolution of adverse events (with dates) should be documented 
on the Adverse Event 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 Adverse Event eCRF.
All pregnancies reported during the study should be followed until pregnancy outcome 
and reported according to the instructions provided in Appendix 5.
8.3.3.2
Sponsor Follow-Up
For serious adverse events, non-serious adverse events 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.


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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 treatment 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 treatment under clinical 
investigation. The Sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, Institutional Review Boards 
(IRB)/Independent Ethics Committees (IEC), and Investigators. 
Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSAR) 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 IB 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 7 days a week. 
The Medical Monitor’s contact details will be available on a separate list generated by 
the study management team.
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 final 
dose of study treatment.
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).


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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 treatment, as defined 
below:
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 patient exposed to a medicinal product. This term applies only when a 
contamination of the study treatment is suspected.
8.4
TREATMENT OF OVERDOSE
The MTD of RO6889450 has been defined as 300 mg QD (based on tolerability 
demonstrated when administered as a single dose up to 450 mg [Phase I SAD study] 
and the occurrence of two dose-limiting events [DLEs] in the 450 mg cohort in a 14- day 
Phase I MAD study in healthy volunteers). For this study, treatment overdose is 
considered as the accidental or intentional use of a drug in a quantity that is two times 
higher in a day than the assigned dose at any group within a 24-hour time period.
An overdose or incorrect administration of study drug is not an AE unless it results in 
untoward medical effects (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. 
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.
Obtain a blood sample for PK analysis within 1 day from the date of the final dose of 
study treatment, if requested by the Medical Monitor (determined on a case-by-case 
basis).


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4.
Document the quantity of the excess dose, as well as the duration of the overdose, 
in the eCRF.
8.5
PHARMACOKINETICS
Mandatory blood samples will be collected from all participants, independent of study 
group assignment at the time points specified in Section 1.3. Additional PK samples will 
be taken at the time of treatment discontinuation. The exact time of dose administration 
on the day of PK collection at Week 4, and the exact time of last dose administration 
preceding the PK collection at Week 1 and 2 or treatment discontinuation should also be 
recorded in the eCRF. Plasma concentrations of RO6889450 and derived metabolite(s),
as applicable, will be measured by a specific and validated LC-MS/MS method. 
Population PK analyses using nonlinear mixed effects modelling will be performed to 
analyze the sparse dose-plasma concentration-time data of RO6889450. If deemed 
necessary, data may be pooled with data from other studies with RO6889450 (and 
derived metabolite[s] if available and applicable) in order to improve the parameter 
estimates of the model. PK/PD or dose exposure response analyses may be conducted 
as appropriate. 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 AND BIOMARKERS ANALYSES
Blood samples for the analysis of exploratory biomarkers will be collected according to 
the SoA (Section 1.3). The analysis may include but is not limited to biomarkers 
measured in plasma samples related to the immune/inflammation hypothesis of 
schizophrenia or associated pathways: e.g., cytokines (IL-1β, IL-6, TGF- β, IL-12, IFN-γ, 
TNF-α, sIL-2 R, sCD25).
The specimens may also be used for research purposes to identify biomarkers useful for 
predicting and monitoring response to RO6889450, identifying biomarkers useful for 
predicting and monitoring RO6889450 safety, assessing pharmacodynamic effects of 
RO6889450, and investigating mechanism of therapy resistance. Additional markers 
may be measured in the case that a strong scientific rationale develops.
For eligible participants entering the 36-Week Safety Extension Phase of the study,
additional samples will be collected according to the SoA (Section 1.3, Table 2) for 
further investigation of any clinical safety signal that may emerge during the study.
Details on samples are specified in Section 8.7. 


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8.6.1
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]), transferases, 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).
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 8.8) otherwise, specimens will be destroyed after 
successful analysis.
Blood samples will be destroyed within five years after the date of the final CSR. Details 
on processes for collection and shipment of these samples can be found in the Sample 
Handling Manual.
8.7
PHARMACODYNAMICS AND BIOMARKER SAMPLES
Mandatory plasma samples will be collected for the analysis of exploratory biomarkers 
related to the immune/inflammation hypothesis of schizophrenia or associated pathways 
as described in Section 8.6.
Additional mandatory serum and plasma samples will be collected during the 36-Week 
Safety Extension Phase that will be analyzed in the event of any clinical safety signal 
that may emerge during the study. Mandatory blood samples will also be taken for the 
assessment of possible vasculitis, i.e., CRP (collected in the blood chemistry panel), 
ESR, ANCA, ANA, anti-dsDNA antibodies, and anti-phospholipid antibodies.
Mandatory whole-blood samples will be collected to isolate DNA for clinical genotyping 
and may also be used for RNA isolation for gene expression analyses as described in
Section 8.6. Samples should be collected as specified in the SoA. Based on continuous 
analysis of the data in this study and other studies, any sample type and/or analysis not 
considered critical for safety may be stopped at any time if the data from the samples 
collected does not produce useful information. 


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Unless otherwise specified below, samples will be destroyed no later than 5 years after 
the date of final CSR. For participants who consent to RBR, leftover samples will be 
transferred to RBR (see Section 8.8).
Any remaining samples after the specified analyses may also be used for additional 
(assay) validation experiments. Samples may be used for research to develop methods, 
assays, prognostics, and/or companion diagnostics related to pathways associated with 
schizophrenia, and/or mechanism of action of RO6889450.
Details on processes for collection and shipment of these samples can be found in 
separate sample documentation.
8.8
SAMPLES FOR RESEARCH BIOSAMPLE REPOSITORY
8.8.1
Overview of the Research Biosample Repository
The Roche Research Biosample Repository (RBR) is a centrally administered group of 
facilities for the long-term storage of human biologic samples, including body fluids, solid 
tissues, and derivatives thereof (e.g., DNA, RNA, proteins, peptides). The collection, 
storage, and analysis of the RBR samples will facilitate the rational design of new 
pharmaceutical agents and the development of diagnostic tests that may allow for 
individualized drug therapy for patients in the future.
For the RBR, leftover blood samples from participants who give specific consent to 
participate in this RBR will be stored. RBR samples 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.
8.8.2
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 ten 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). 


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The repository specimens will be subject to the confidentiality standards (as described 
under Confidentiality and Appendix 1). 
8.9
OTHER ASSESSMENTS
8.9.1
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 
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.
8.9.2
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, 
as part of Day 14 assessments. The age-corrected standard score obtained will be used 
as pre-morbid IQ estimate.
The assessment will not be performed in non-English speaking countries without 
linguistic validated translation. This applies also to patients who do not speak English as 
a first language but are living in an English speaking country. If validated translations 
become available, they may be used. Equivalent scales may be used, if available. In 
Japan, the Japanese Adult Reading Test (JART) will be used as an equivalent scale.
8.9.3
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 WASI-II (or an equivalent test in non-English speaking countries, if available) 
will be administered according to standard instructions, as part of Day 14 assessments. 
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.
The assessment will not be performed in non-English speaking countries without 
linguistic validated translation. This applies also to patients who do not speak English as 
a first language but are living in an English speaking country. If validated translations 
become available, they may be used. In Japan, the Wechsler Adult Intelligence Scale -
Fourth edition (WAIS-IV) will be used as an equivalent scale.


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8.9.4
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. 
In the present study, EMA will be used to assess the participants’ functioning associated 
to positive and 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 
Wi-Fi or if cellular data is available. If no Wi-Fi network is available and cellular data is 
unavailable, the sensor data will be transferred during site visits.
The assessment is optional but strongly recommended. 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.
EMA assessment will not be performed in Japan.
8.9.5
Feedback Questions
Patients will be asked two sets of questions at the end of hospitalization (Week 4 visit). 
In the first set, patients are asked if they have experienced changes in relation to their 
condition. If they respond yes, they will be asked to further describe this change. 
Responses will be captured as free text and closed questions. 
In the second set of questions, patients are asked to provide their feedback on the 
following PRO instruments (ReQoL-20, BCIS, VAGUS, SUMD-9) from an ease of 
understanding and relevance (ReQoL-20) perspective. These question uses a 5-point 
Likert scale ranging from “strongly agree” to “strongly disagree” plus a “no opinion” 
option. The assessment should take approximately 5-10 minutes to administer.
The assessment will not be performed in non-English speaking countries without 
linguistic validated translation. This applies also to patients who do not speak English as 
a first language but are living in an English speaking country. If validated translations 
become available, they may be used. Equivalent scales may be used, if available.
8.9.6
Premorbid Adjustment Scale
Premorbid Adjustment Scale (PAS) (Cannon-Spoor et al 1982, Rabinowitz et al 2007) 
assesses functioning across four developmental stages: childhood (up to 11 years), 
early adolescence (12–15 years), late adolescence (16–18 years) and adulthood (19 
years and beyond); and across five domains: sociability/ withdrawal, peer relationships, 
scholastic performance, adaptation to school and socio-sexual functioning (socio-sexual 


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functioning is not assessed during childhood), in addition 9 items general scale that 
assesses, the level of best functioning achieved by the individual, as well as items 
related to characteristics of illness onset, energy level, education and independence.
PAS is administered by raters on the basis of all available sources of information, 
including interviews with patients and their family members, mainly parents (a close 
relationship with the patient during his childhood and adolescence is necessary) as well 
as medical and school records. PAS assesses life periods up to 1 year before the onset 
of psychotic illness and consists of up to 17 items (depending on disease onset), and 
each item is assessed on a 0-6 Likert scale, where lower numbers indicate normal, 
healthy functioning and higher numbers suggest pathologic development. The PAS 
should take approximately 30 minutes to administer.
8.10
TIMING OF STUDY ASSESSMENTS
8.10.1
Screening and Pre-treatment Assessments
Written informed consent for participation in the study must be obtained before 
performing any study-specific screening tests or evaluations. Informed Consent Forms 
(ICFs) for enrolled participants and for participants who are not subsequently enrolled 
will be maintained at the study site.
All screening and all pre-treatment assessments (related to entry criteria) 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 pre-treatment assessments will be performed within 7 days prior to 
Day 1, unless otherwise specified. The screening period may be extended after 
discussion with the Sponsor (Medical Monitor/designee). 
During screening, the ECF will be completed. This will include all pertinent 
information as specified on the ECF. The completed ECF will be forwarded as soon as
all requested information is available during screening to the CTM or local Site 
Monitor via the CRO ePIP system for documentation and monitoring purposes. The 
Investigator will act as final decision maker regarding exclusion or inclusion of 
participants in the study.
8.10.2
Assessments during Treatment
Under no circumstances will participants who enroll in this study and who 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 must be performed on the day of the specified visit, unless a time window 
is specified in the SoA (see Section 1.3). Assessments scheduled on the day of study 
treatment administration must be performed prior to administration of study treatment, 


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unless otherwise noted in the schedule of assessments. 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 and Table 5). If the latter cannot be followed, every effort should be made to 
conduct ECG and vital signs assessments prior to the blood draws (see Section 8.2.2
and Section 8.2.3), and blood draws should be conducted at least 2 hours prior to PRO
and COA. In exceptional situations, visits may be split over two consecutive days (as 
per SoA, see Section 1.3). In case the Baseline visit is split over two consecutive days, 
study treatment administration must be performed after all assessments have been 
performed.
Participants must be observed/treated on an inpatient basis from Day -3 (at the latest)
until Day 28. Participants will be discharged on Day 28 of the Study Period 2 once all 
planned study activities are done. The inpatient period can be extended into the Study 
Period 3 if deemed necessary by the Investigator. Mandatory phone calls, at a minimum 
once weekly during Study Period 3 and once monthly during the 36-Week Safety 
Extension Phase will be made by a case manager to follow up with the participants (AE, 
concomitant treatment and treatment compliance will be assessed).
8.10.3
Assessments at Study Completion/Early Termination Visit
If a participant voluntarily withdraws from the study or is withdrawn by the Investigator 
during Study Period 2, the participant will be asked to complete Study Period 2 EOT visit 
as soon as possible after the last dose of study drug. Participant will also be asked to 
return to the clinic 4 weeks after the first dose of study drug (at the end of the 4-week 
Study Period 2) for Week 4 ETV to complete assessments of the primary and secondary 
efficacy outcomes (PANSS, CGI-S, CGI-S MTS, CGI-I and CGI-I MTS), regardless of 
their adherence to treatment. Participants will also be asked to return for the follow-up 
visit (4 weeks after the last dose). If a participant voluntarily withdraws from the study or 
is withdrawn by the Investigator during Study Period 3 or the 36-Week Safety Extension
Phase, the participant should return to complete Study Period 3 EOT visit or 36-Week 
Safety Extension EOT visit, respectively, as soon as possible after the last dose of study 
drug. Participant will be asked to return for the follow-up visit assessments (4 weeks 
after the last dose). For the participants who discontinue study treatment prematurely if 
the EOT visit for Study Period 2 and 3, and the 36-Week Safety Extension Phase falls 
into the windows of planned visit, only missing assessments need to be completed. The 
primary reason for premature study treatment discontinuation should be documented on 
the appropriate eCRF. Participants who discontinue study treatment prematurely will not 
be replaced.
8.10.4
Follow-Up Assessments
Follow-up phone calls will be made approximately 7, 14 and 21 days after the last dose 
of study drug or after early termination. An on-site follow-up visit will be performed 4 
weeks after the last dose of study drug or after early termination.


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After the study completion/ETV, adverse events should be followed as outlined in 
Sections 8.3.1 and 8.3.3.
8.10.5
Assessments at Unscheduled Visits
Assessments at unscheduled visits are based on the medical need of the patient.
Assessments that are conducted at regular scheduled visits can be conducted at
unscheduled visits at the discretion of the Investigator.
9.
STATISTICAL CONSIDERATIONS
9.1
STATISTICAL HYPOTHESES 
The primary objective of the study is to demonstrate that at least one RO6889450 dose 
is significantly different from placebo at Week 4 for the primary endpoint.  
A higher PANSS total score indicates a greater pathology. The change from baseline of 
PANSS total score at Week 4 will be calculated as the total score at Week 4 minus the 
total score at baseline. A negative change from baseline in PANSS total score indicates 
improvement.
The following null (H0) and alternative (H1) hypotheses will be tested at a one-sided 
0.05 level between each RO6889450 dose and placebo to assess efficacy of each 
RO6889450 dose.

H0: MEANtreat ≥MEANplacebo  versus

H1: MEANtreat < MEANplacebo
where MEANtreat and MEANplacebo refer to the mean change from baseline for 
RO6889450, risperidone and placebo, respectively. 
The risperidone comparison against placebo is mainly to assess validity of the study 
(assay sensitivity).
9.2
SAMPLE SIZE DETERMINATION
Assuming a true difference of approximately 8.23 between two groups in mean PANSS 
reduction at Week 4 and a standard deviation of 16.5, approximately 50 participants per 
group will provide 80% power to see an effect with a two-sided type I error of 0.1. 
Allowing for about 25% of the participants randomized not completing 4 weeks of 
treatment approximately 70 participants per treatment group will be randomized to the 
study outside Japan (US and ROW). Approximately 28 participants will be recruited in 
Japan. In case of an unexpectedly high proportion of participants not completing the
initial 4 weeks of treatment (i.e., more than 25%), the number of randomized 
participants may be increased to achieve 200 participants completing the initial 4 weeks 
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The primary analysis will be based on all participants recruited outside Japan (US and 
ROW) and in Japan, and will be performed when all randomized patients complete the 
study.
With an anticipated sample size of 50 participants per group any observed reductions 
(versus placebo) by approximately 5.5 or more points is expected to be statistically 
significant.
9.3
POPULATIONS FOR ANALYSES
For purposes of analysis, the following populations are defined in Table 6.
Table 6
Analysis Populations
Population
Description
Efficacy (modified intent-to-treat 
[ITT])
All randomized participants who received at least one dose of 
randomized study medication and have the primary efficacy 
assessments at both baseline and at least one post-baseline. 
Participants who received study medication different from that 
to which they were randomized will be included in the group to 
which they were randomized. The efficacy analysis population 
will be the primary analysis population for all efficacy data 
analyses.
Per protocol (PP)
The per-protocol (PP) analysis population will be defined as a
subset of the ITT population, excluding those who have major 
protocol violations affecting efficacy assessment. Efficacy 
variables will be analyzed for this population based on the 
initial actual treatment received.
PP analysis will only be performed if it contains less than 90% 
of the ITT patients.
Safety
The safety analysis population will consist of all participants 
who have received at least one dose of study medication, 
regardless of whether they withdrew prematurely or not. All 
safety parameters will be summarized by the initial study 
medication actually taken for the safety population.
Pharmacokinetic
All participants who have received at least one dose of study 
treatment 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 which 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.


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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 analysis of the study will be performed and interpreted when all randomized 
patients have completed Period 2 or withdrawn from the study earlier and Period 2 data 
from all patients have been verified and locked. The primary and secondary efficacy 
analyses will be based on the Efficacy population defined in Table 7.
The efficacy parameters of continuous variables will be analyzed using a mixed effects 
model for repeated measures (MMRM) to utilize all the data collected over time with 
consideration of the variance-covariance matrix of the repeated measures. The model 
will include independent variables of fixed categorical effects of treatment (4 levels:
45 mg dose of RO6889450, 150 mg dose of RO6889450, risperidone, placebo), 
assessment weeks (Week 1, Week 2, Week 3, Week 4) and treatment-by-time 
interaction and a covariate of the baseline value. Factors used for stratification at the 
time of randomization will be added to the model. 
A treatment-by-time interaction contrast will be constructed to estimate the difference 
between active treatment and placebo in mean change from baseline to Week 4.
Least squares means per treatment group 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 group
and placebo will be estimated and also reported with 2-sided 90% confidence intervals.
As a supportive analysis, the primary efficacy variable will also be analyzed for the 
Week 4 assessments by analysis of covariance (ANCOVA) adjusting for baseline 
values. The model will include the baseline measure and stratification factors as 
covariate and treatment as the main effect.


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Table 7
Efficacy Statistical Analysis Methods
Endpoint
Statistical Analysis Methods
Primary:
Change from baseline in PANSS total score at
Week 4
Repeated Measures Model as described in
Section 9.4.2.
Secondary:
–
Change from baseline in PANSS factor 
scores
–
CGI-I and CGI-I MTS
–
CGI-S and CGI-S MTS
Similar models as described in Section 9.4.2 will 
be used for change from baseline endpoints of 
approximately continuous variables
–
Proportion of participants with at least 
20% or 50% improvement from baseline 
on PANSS total and factor scores
Binary data will be evaluated by generalized 
estimating equation (GEE) method accounting 
for correlation among repeated measures from 
the same participant. The GEE model will 
include terms of treatment, time, and treatment-
by-time interaction.
–
Time from first randomized treatment 
intake to readiness for discharge as 
assessed by RDQ
The time-to-readiness for discharge will be 
analyzed using an unstratified log rank test. In 
addition, a stratified log rank test of treatment 
difference will be performed if the cell sizes are 
reasonable.
–
PANSS total score up to Week 12
–
PANSS factor scores up to Week 12
–
CGI-S and CGI-S MTS up to Week 12
–
CGI-I and CGI-I MTS up to Week 12
Efficacy assessments performed during the 
Study Period 3 will be analyzed descriptively 
only.
Exploratory:
–
SUMD
–
VAGUS
–
BCIS
–
CDSS
–
Assessment of Sleep, Mood, Well-being 
and Cognitive Functioning and Treatment 
Expectancy
–
WRAT-4
–
WASI-II
–
PGI-C
–
ReQoL
–
FTND
–
EMA
–
Feedback questions
–
PAS
–
PANSS total score up to Week 48
–
PANSS factor scores up to Week 48
–
CGI-S up to Week 48
–
CGI-I up to Week 48
Analysis of exploratory endpoints will be 
descriptive only.


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Adjustment for Multiple Testing
The primary objective of the study is to demonstrate that at least one RO6889450 dose 
is significantly (overall type I error rate of 0.1, 2-sided) different from placebo. Difference 
between risperidone and placebo will be tested independently to check internal validity 
of the study. 
To maintain overall type I error rate for multiple testing of the RO6889450 groups, the 
following two hypotheses will be tested applying the Hochberg’s method for adjustment 
of multiple testing.
a. The larger p-value will be tested at the 0.05 (one-sided) level. When the larger p-
value is0.05, both null hypotheses are rejected.
b. When the larger p-value is > 0.05 (one-sided), the smaller p-value will be tested at 
the 0.025 level (one-sided). When it is 0.025 the null hypothesis is rejected.
Missing Data Handling
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, if not specified otherwise in 
the user manuals.
The main analysis of the primary and secondary continuous efficacy variables will be 
done using a mixed effects model for repeated measures; no imputation for missing data 
will be applied. 
To understand the pattern of missing data observed during the study and thus the 
missing data mechanism, the following data will be reviewed:
•
Timing of discontinuations by treatment group
•
Reasons for discontinuation by treatment group and time
•
Mean of the primary efficacy variable of those who dropped out vs. those who
remained at each scheduled assessment week
9.4.3
Safety Analyses
All safety analyses will be based on the safety analysis population grouped according to 
the treatment assigned at randomization.


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Table 8
Safety Statistical Analysis Methods
Endpoint
Statistical Analysis Methods
Adverse events
The original terms recorded on the eCRF by the Investigator for adverse 
events will be coded by the Sponsor.
Adverse events will be summarized by mapped term and appropriate 
thesaurus level.
Columbia-Suicide
Severity Rating 
Scale (C-SSRS)
The items of the C-SSRS will be summarized and presented by individual 
listings. The number and percentage of participants will be summarized for 
each suicidality ideation or behavior (i.e., those marked “yes”) by study 
treatment and scheduled assessment week.
All ratings will be presented by individual listings. 
Extrapyramidal 
symptom rating 
scale, abbreviated 
(ESRS-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 CGI-S score by treatment group using 
descriptive statistics at each scheduled assessment visit.
Change from baseline to week 4 score will be summarized using descriptive 
statistics including the safety population. In addition, participants (n, %) with 
clinically relevant severity in each of the four symptoms will be summarized
All ratings will be presented by individual listings. 
Clinical laboratory 
tests
All clinical laboratory data will be stored on the database in the units in 
which they were reported. Laboratory test values will be presented in 
International System of Units (SI units; Système International d’Unités) by 
individual listings with flagging of abnormal results. In addition, tabular 
summaries will be used
Vital signs
Vital signs data will be presented by individual listings with flagging of 
values outside the normal ranges and flagging of abnormalities. In addition, 
tabular summaries will be used.
ECG data analysis ECG data will be presented by individual listings. In addition, tabular 
descriptive summaries for the change from baseline in ECG intervals: HR, 
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 utilizing 
a mapped term and appropriate drug dictionary level.
Concomitant medications will be presented in summary tables and listings.
9.4.4
Pharmacokinetic Analyses
Population PK analyses using nonlinear mixed effects modelling will be performed as
described in Section 8.5. The results of the analysis will be reported separately from the 
CSR. Additional PK, PK-PD, or dose/exposure-response analyses will be conducted as 
appropriate.
9.4.5
Pharmacodynamic Analyses
All pharmacodynamic (PD) parameters will be presented by listings and descriptive 
summary statistics separately by group or cohorts. The PD analysis will be presented 
separately from the main CSR.


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9.4.6
Other Analyses
Biomarker exploratory analyses will be specified before database lock. 
For ReQoL, all ratings will be presented by individual listings. In addition, tabular 
summaries will be used.
9.5
INTERIM ANALYSES
Given the hypothesis-generating nature of this study, the Sponsor may choose to 
conduct up to two interim efficacy analyses for internal decision making. 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. Any interim 
analysis will be performed and interpreted by members of the Sponsor project team (not 
in contact with study sites) 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.
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 treatment 
and the study will be reported.


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10.
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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) 
and Appendix 3 (Procedures of recording), Appendix 4 (Clinical laboratory tests), 
Appendix 5 (Contraceptive guidance and collection of pregnancy information), 
Appendix 6 (List of Anti-psychotic, Prohibited, and Restricted Medications), and 
Appendix 7 Assessment of Sleep, Mood, Well-being and Cognitive Functioning and 
Treatment Expectancy. 


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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 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/EC 
before the study is initiated. In addition, any participant recruitment materials must be 
approved by the IRB/EC.
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, including the consent form for the 
36-Week Safety Extension Phase (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 that 


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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. 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.
If the Consent Forms are revised (through an amendment or an addendum) while a 
participant is participating in the study, the participant or a legally authorized 
representative may be re-consented by signing the most current version of the Consent 
Forms or the addendum, in accordance with applicable laws and IRB/EC policy. 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. The study team will provide guidance for which patients need 
to re-consent in the event of an update to the Consent form.
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 may be required to sign a new ICF.
Consent to Participate in the Research Biosample Repository
The Informed Consent Form will contain a separate section that addresses participation 
in the RBR. The Investigator or authorized designee will explain to each participant the 
objectives, methods, and potential hazards of participation in the RBR. Participants will 


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be told that they are free to refuse to participate and may withdraw their samples 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 RBR samples. 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 subject who is participating in the 
Research, the participant's samples 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
Collection, storage, and analysis of RBR samples 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 samples for the RBR have the right to withdraw 
their samples at any time for any reason. If a participant wishes to withdraw consent to 
the testing of his or her samples, 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 BP41743
does not, by itself, constitute withdrawal of samples from the RBR. Likewise, a 
participant’s withdrawal from the RBR does not constitute withdrawal from Study 
BP41743. Data already generated before time of withdrawal of consent to RBR will still 
be used.
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


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names or any information which 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.
Study data may be submitted to government or other health research databases or 
shared with researchers, government agencies, companies, or other groups that are not 
participating in this study. These data may be combined with or linked to other data and 
used for research purposes, to advance science and public health, or for analysis, 
development, and commercialization of products to treat and diagnose disease. In 
addition, redacted clinical study reports and other summary reports will be provided upon 
request.
Confidentiality for Research Biosample Repository
Data generated from RBR samples 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 samples 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 sample 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 


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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 sample data will become and remain the exclusive and unburdened 
property of Roche, except where agreed otherwise.
Monitoring and Oversight Research Biosample Repository
Samples 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 samples 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., 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 CRF.
The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
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.


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Study monitors will perform ongoing source data verification to confirm that data entered 
into the CRF 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.
2.1.2.
Clinical Outcome Assessment Data
The study will use both electronic and paper, 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). The data will be transmitted via 
electronically to a centralized database at the eCOA vendor. The data may be reviewed 
by site staff via secure access to a web. 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. FDA regulations for electronic records (21 CFR Part 
11). 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 will use paper booklets to capture COA data All item-level, score data will be 
entered into electronic data capture (EDC). All original forms on which participants 
records 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 
and complete, microfiche, photographic negatives, microfilm or magnetic media, X-rays, 


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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 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 or 
discontinuation of the study, or for the length of time required by relevant national or 
local health authorities, whichever is longer. After that period of time, the documents 
may be destroyed, subject to local regulations. 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.
Roche will retain study data for 25 years after the final study results have been reported 
or for the length of time required by relevant national or local health authorities.
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. 


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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 and https://eudract.ema.europa.eu.


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2.3.4.
Management of Study Quality
The Sponsor will implement a system to manage the quality of the study, focusing on 
processes and data that are essential to ensuring patient safety and data integrity.  Prior
to study initiation, the Sponsor will identify potential risks associated with critical trial 
processes and data and will implement plans for evaluating and controlling these risks.  
Risk evaluation and control will include the selection of risk-based parameters 
(e.g., adverse event rate, protocol deviation rate) and the establishment of quality 
tolerance limits for these parameters prior to study initiation.  Detection of deviations 
from quality tolerance limits will trigger an evaluation to determine if action is needed.  
Details on the establishment and monitoring of quality tolerance limits will be provided in 
a Quality Tolerance Limit Management Plan.
2.3.5.
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.
4.
STUDY AND SITE CLOSURE
The Sponsor (or designee) has the right to close the study site or terminate this study at 
any time. Reasons for terminating the study 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 treatment development.


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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:

Deterioration in a laboratory value (hematology, clinical chemistry, or urinalysis) or 
other clinical test (e.g., ECG, X-ray) that is associated with symptoms or leads to a 
change in study treatment or concomitant treatment or discontinuation from study 
treatment (see Appendix 3, Section 4).

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 treatment 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 treatment (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 unless the progression is unexpectedly accelerated and not in 
line with the natural history of the disease. If the “Lack of efficacy” would not require 
safety reporting 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 which 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.


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
Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is an AE.

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.


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
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 
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 CRF.
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 terms “severe” and “serious” are not synonymous. Severity refers to the intensity of 
an adverse event (rated as mild, moderate, or severe) 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.
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.


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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 
treatment, indicating "yes" or "no" accordingly. The following guidance should be taken 
into consideration:

Temporal relationship of event onset to the initiation of study treatment.

Course of the event, considering especially the effects of dose-reduction, 
discontinuation of study treatment.

Known association of the event with the study treatment 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 AES AND SAES
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.
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.


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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 treatment:

Serious adverse events

Non-serious adverse events of special interest (NSAESI)

Pregnancies (see Section 8.3.5)
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 Treatment Initiation
After informed consent has been obtained but prior to initiation of study treatment, 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 immediately (i.e., no more than 24 hours after learning of the event).


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Events that Occur after Study Treatment 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 treatment (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 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 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, if the event is believed to be related to prior study 
treatment 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 a quantity that is two 
times higher in a day than the assigned dose at any arm.

Intentional overdose:  intentional administration of a drug in a quantity that is two 
times higher in a day than the assigned dose at any arm.

Medication error:  accidental deviation in the administration of a drug 
In some cases, a medication error may be intercepted prior to administration of 
the drug.

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.
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.


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Special situations are not in themselves adverse events, but may result in adverse 
events. 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). For RO6889450 or matching 
placebo or Risperidone, 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.
In addition, all special situations associated with RO6889450 or matching placebo or 
Risperidone, 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.


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
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.
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 through use of the reference safety 
information in the documents listed below:
Drug
Document
RO6889450
RO6889450 Investigator’s Brochure
Risperidone
US Product Information (USPI)
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.


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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 3 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.


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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 
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 treatment (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 [ALP] and bilirubin 5 times the upper limit of normal [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”.


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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.
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 treatment (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 BP), 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.


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The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see Section 8.3) 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 (see Section 8.3).
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 
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”).


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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

Planned hospitalization required by the protocol (e.g., for wash out of previous 
medication, study treatment administration)

Hospitalization for a preexisting condition, provided that all of the following criteria 
are met:
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.
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:

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."


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Appendix 4
Clinical Laboratory Tests
The tests detailed in Table 1, with the exception of urinalysis, urine dipstick alcohol test, 
drugs of abuse, urine pregnancy test, COVID-19 test (when not performed centrally),
and erythrocyte sedimentation rate (ESR), will be performed by the central laboratory. If
the local laboratory results are used, the results must be captured in source 
documentation and entered into the eCRF.
Local laboratory results may be utilized in the event that the central laboratory results 
are not available in time for either study treatment 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 be 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, urine pregnancy test, COVID-19 test (when not performed 
centrally), and ESR, 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.


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Laboratory Assessments
Parameters
Hematology

Leucocytes, erythrocytes, hemoglobin, hematocrit, 
platelets, differential count (neutrophils, 
eosinophils, basophils, monocytes, lymphocytes.
Clinical Chemistry

Sodium, potassium, chloride, bicarbonate, glucose 
fasting, glycated hemoglobin, urea, creatinine, 
protein, albumin, phosphate, calcium, total and 
direct bilirubin, ALP, ALT, AST, urate, lactate 
dehydrogenase (LDH), C-reactive protein (CRP)

Prolactin (all patients), follicle stimulating hormone 
(FSH, post-menopausal females, as applicable).
Coagulation

International normalized ratio (INR), activated 
partial thromboplastin time (aPTT), PT.
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), 
hepatitis B surface antigen (HBsAg), total hepatitis 
B core antibody (HBcAb), hepatitis C virus (HCV) 
antibody. In cases where HCV was successfully 
treated, a positive HCV serology result can be 
followed by HCV RNA testing
Lipids

Fasting: Cholesterol, low-density lipoproteins (LDL) 
cholesterol, high-density lipoproteins (HDL) 
cholesterol, triglycerides.
Pregnancy Test

All women of childbearing potential (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, 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, white blood cells (WBCs), 
casts, crystals, epithelial cells, and bacteria.
Other Screening Tests

Drugs of abuse will be measured in urine: 
cannabinoids (including cannabidiol), 
amphetamines, methamphetamines, opiates, 
buprenorphine, methadone, cocaine, 
benzodiazepines, and barbiturates.
Alcohol levels will be tested using a urine 
dipstick test.


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Laboratory Assessments
Parameters
Vasculitis Monitoring Tests

C-reactive protein (CRP) (part of the chemistry 
panel), erythrocyte sedimentation rate (ESR), 
anti-neutrophil cytoplasmic antibodies (ANCA), 
anti-nuclear antibodies (ANA), 
anti-double-stranded DNA (anti-dsDNA)
antibodies, anti-phospholipid antibodies
Investigators must document their review of each laboratory safety report.
Prolactin levels that could unblind the study will not be reported to investigative sites or 
other blinded personnel until the study has been unblinded.
Additional Statistical Considerations for Clinical Laboratory Data

Standard Reference Ranges and Transformation of Data
Potential analysis considerations for analyzing Laboratory data includes the use of 
Standard Reference Ranges and potential transformation of data for specific lab tests. 
In this scenario, Roche standard reference ranges, rather than the reference ranges of 
the Investigator, can be used for specific parameters. For these 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 ALP 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 in this analysis, 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 these laboratory parameters. 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 
abnormalities. Marked laboratory abnormalities will be labeled in the participant listings 
as “HH” for very high or “LL” for very low.


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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. The definition of childbearing potential may be adapted for 
alignment with local guidelines or requirements.

Women in the following categories are considered to be Woman of Non-
Childbearing Potential (WONCBP)
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., 


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calendar, ovulation, symptothermal, or post ovulation methods) and withdrawal are not 
acceptable methods of contraception. 
Female participants of childbearing potential are eligible to participate if they agree to 
use highly effective method of contraception consistently and correctly as described in 
Table 1 below.
Per ICH M3(R2), highly effective methods of birth control are defined as those, alone or 
in combination, that result in a low failure rate (i.e., less than 1% per year) when used 
consistently and correctly as described in Table 1 below.


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Table 1
Highly Effective 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:
o
Oral
o
Intravaginal
o
Transdermal

Progestogen-only hormonal contraception associated with inhibition of ovulation:
o
Oral
o
Injectable
Highly Effective Methods That Are User-Independent
(Failure rate of 1% per year)

Implantable progestogen-only hormonal contraception associated with inhibition of 
ovulationa

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.
Sexual abstinence
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study treatment. 
The reliability of sexual abstinence needs to be evaluated in relation to the duration of the study 
and the preferred and usual lifestyle of the participant.
Acceptable Birth Control Methods Which May Not Be Considered As Highly Effective
(Failure rate of 1% per year when used consistently and correctly)

Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the
Primary mode of action

Male or female condom with or without spermicide b

Cap, diaphragm or sponge with spermicide b
a)
Hormonal contraception may be susceptible to interaction with the IMP, which may reduce 
the efficacy of the contraception method.
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.
b)
A combination of male condom with either cap, diaphragm or sponge with spermicide 
(double barrier methods) are also considered acceptable, but not highly effective, birth 
control methods. i.e., when the risk of teratogenicity and genotoxicity is unlikely.


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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.
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 
treatment 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).


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Elective or therapeutic abortion not associated with an underlying maternal or embryo-
fetal 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.
6
CONGENITAL ANOMALIES/BIRTH DEFECTS
Any congenital anomaly/birth defect in a child born to a female participant exposed to 
study treatment 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).


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Appendix 6
List of Anti-psychotic/Rescue, Prohibited, and Restricted
Medications
Table 1
Anti-psychotic/rescue medications
Type of medication
Timelines and instructions
Antipsychotic medication

asenapine

chlorpromazine

fluphenazine

haloperidol

iloperidone

loxapine

molindone

olanzapine

pericyazine

perospirone

perphenazine

prochlorperazine

quetiapine

trifluoperazine

thiothixene

ziprasidone

zuclopenthixol
Permitted as prior medication and during the screening 
period, but prohibited 72 hours prior to the first dose of 
study medication and during Study Periods 2 and 3, and the 
36-Week Safety Extension Phase (blinded treatment).

risperidone

paliperidone
Permitted as prior medication and during the screening 
period, but prohibited 72 hours prior to the first dose of 
study medication and during Study Periods 2 and 3, and the 
36-Week Safety Extension Phase (blinded treatment). 
Participant excluded if there is a history of lack of response 
or intolerance to risperidone or paliperidone.

aripiprazole. 2 weeks

blonanserin, 3 weeks

brexpiprazole. 3 weeks

cariprazine. 15 weeks

aripiprazole LAI (Abilify 
Maintena). 2 months

aripiprazole lauroxil 
(Aristada). 4 months

fluphenazine deaconate. 
2 months

haloperidol decanoate. 
2 months

olanzapine LAI. 2 months
Permitted as prior medication if it had been stopped before 
the indicated time periods prior to the first dose of study 
medication. Prohibited during Study Periods 2 and 3 and 
the 36-Week Safety Extension Phase (blinded treatment).
Note: Single doses (before reaching steady state) of 
aripiprazole, brexpiprazole, or blonanserin administered to
control current exacerbation may be used (upon discussion 
with the Medical Monitor) but not within 72 hours prior 
to the first dose of study medication upon discussion with 
the Medical Monitor.

paliperidone palmitate (Invega 
Sustenna, Invega Trinza). 
6 months

risperidone LAI (Risperdal 
Consta). 1 month
Permitted as prior medication if had been stopped before 
the indicated time periods prior to the first dose of study 
medication. Participants excluded if there is a history of lack 
of response or intolerance to risperidone or paliperidone.
Prohibited during Study Periods 2 and 3 and the 36-Week 
Safety Extension Phase (blinded treatment).

clozapine 
Excluded any use in previous 12 months before screening, 
or any lifetime use at doses of 200 mg/day or greater.


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Table 2
Prohibited Therapies
Type of medication
Timelines and instructions
Illegal substance use (including legal cannabis) : opiates, 
amphetamine, barbiturate, cocaine, cannabis, 
cannabidiol, or hallucinogens 
From enrollment until the end of 
the treatment period
All psychotropic medications including anxiolytic, 
antidepressants, mood stabilizer, hypnotic, sedative 
medication, and St John’s wort except those listed in 
Section 6.5.2.1 permitted therapy and Table 3 restricted 
therapy.
From enrollment until the end of 
the treatment period. Must be 
discontinued during the screening 
period, regardless of the 
indication for which they have 
been prescribed.
Treatment with sedating anti-histamines (such as 
promethazine or diphenhydramine) 
Should not be initiated during the 
treatment period, nor should the 
dose be changed for those 
participants who were already on 
treatment at the time of 
randomization.
Participants receiving treatment for tardive dyskinesia 
(e.g., valbenazine or deutetrabenazine) are excluded.
From enrollment until the end of 
the treatment period
The following strong CYP3A4 inducers are prohibited: 
carbamazepine, aprepitant, phenytoin.
From enrollment until the end of 
the treatment period.
The following strong P-gp inducers are prohibited: 
verapamil, apalutamide.
From enrollment until the end of 
the treatment period.
Clinically relevant substrates of P-gp, including quinidine 
and loperamide
From enrollment until the end of 
the treatment period.


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Table 3
Restricted Therapies
Type of medication
Timelines and instructions
Medication for extrapyramidal 
symptoms (EPS)

benztropine: up to 4 mg/day (up 
to 2 mg single dose), 

or biperiden up to 6 mg/day (up 
to 2 mg single dose), 

or trihexyphenidyl up to 6 
mg/day (up to 3 mg single dose)

propranolol (up to 60 mg/day)
Initiation and dose increase of anticholinergic 
medications should only happen to treat emergent 
EPS related AEs. Treatment should be limited to a 7-
day period. A prescription may be renewed if 
necessary after reevaluation. Continuation of previous 
treatment may be allowed if the patient has been on a 
stable dose for at least 28 days prior to the screening 
period and the Investigator considers it clinically 
required.
Lorazepam or equivalent 
benzodiazepine

Total dose 6 mg/day of 
lorazepam during screening and 
the first week of the trial

Total dose 4 mg/day 
lorazepam from week 2 until the 
end of the Study Period 3.

Total dose 3 mg/day of 
alprazolam during screening 
and the first week of the trial

Total dose 2 mg/day of 
alprazolam from Week 2 until 
the end of the Study Period 3

Total dose 90 mg/day of 
oxazepam during screening and 
the first week of the trial

Total dose 60 mg/day of 
oxazepam from Week 2 until 
the end of the Study Period 3.
Benzodiazepine use is permitted provided the patient 
has been receiving a stable dose for at least 3 months 
and the total dose for all uses is < 6mg/day of 
lorazepam.
Initiation and/or dose increase of lorazepam or 
equivalent benzodiazepine should only happen to 
treat emergent anxiety, akathisia, agitation, or sleep 
disorders, and only within the maximum dose 
described in the left column.
Lorazepam or equivalent benzodiazepine treatment 
should not be administered within 12 hours prior to 
PANSS assessments.
Hypnotic or sedative medication

zolpidem tartrate up to 10 
mg/day, 

or chloral hydrate up to 2 g/day, 

or zaleplon up to 10 mg/day, 

or zopiclone up to 7.5 mg/day
Hypnotic or sedative medication is preferred treatment 
for sleep disorders rather than lorazepam and 
equivalent benzodiazepines.
Routine use is allowed to treat sleep disorders if the 
patient takes a stable restricted dose for at least 3 
months prior to the screening period, and only within 
the maximum dose described in the left column.
Initiation and/or dose increase of hypnotic should only 
happen to treat emergent sleep disorders, and only 
within the maximum dose described in the left column.
Hypnotic or sedative medications should not be 
administered within 12 hours prior to PANSS 
assessments.


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Appendix 7
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 28 ±1)
“Do you think you were taking placebo or study drug?”
Placebo 
☐
Study drug
☐

SAP_001.pdf: 
 
Official Title: 
 
A Phase II, Multi-Center, Randomized, Double-Blind, Parallel Group, 
Placebo-Controlled Trial of The Efficacy and The Safety of 
RO6889450 (Ralmitaront) vs. Placebo in Patients With an Acute 
Exacerbation of Schizophrenia Or Schizoaffective Disorder 
NCT Number: NCT04512066 
Document Date: SAP Version 1: 25-Mar-2022 
 
 


CONFIDENTIAL 
 
This is an F. Hoffmann-La Roche Ltd document that contains confidential information.  Nothing 
herein is to be disclosed without written consent from F. Hoffmann-La Roche Ltd. 
 
RO6889450—F. Hoffmann-La Roche Ltd 
Technical Document for Statistical Analysis BP41743 Interim Analysis 
 
TECHNICAL DOCUMENT FOR STATISTICAL ANALYSIS 
Interim Analysis 
 
TITLE: 
A PHASE II, MULTI-CENTER, RANDOMIZED, DOUBLE-
BLIND, PARALLEL GROUP, PLACEBOCONTROLLED 
TRIAL OF THE EFFICACY AND THE SAFETY OF 
RO6889450 (RALMITARONT) VS. PLACEBO IN PATIENTS 
WITH AN ACUTE EXACERBATION OF SCHIZOPHRENIA OR 
SCHIZOAFFECTIVE DISORDER 
 
PROTOCOL NUMBER: 
BP41743 
STUDY DRUG: 
RO6889450 
VERSION NUMBER: 
1.0 
IND NUMBER: 
 
EUDRACT NUMBER: 
2019-003788-23 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
PLAN PREPARED BY: 
DATE FINAL: 
25 Mar 2022 
 
 
 
Signatures 
 
______________________________ 
Date,
 Statistician 
 
 




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TABLE OF CONTENTS 
1. 
BACKGROUND ............................................................................................ 7 
2. 
STUDY DESIGN ........................................................................................... 7 
2.1 
Protocol Synopsis .................................................................. 10 
2.2 
Objectives and Endpoints ...................................................... 10 
2.3 
Determination of Sample Size ............................................... 13 
2.4 
Analysis Timing and Unblinding ............................................. 14 
2.4.1 
Interim Analysis (IA) .............................................................. 14 
2.4.2 
Primary Analysis .................................................................... 14 
2.4.3 
Final Analysis ........................................................................ 14 
3. 
STUDY CONDUCT ..................................................................................... 14 
3.1 
Randomization ....................................................................... 14 
3.2 
Independent Review Facility .................................................. 15 
3.3 
Data Monitoring ..................................................................... 15 
3.3.1 
Independent Data Monitoring Committee (iDMC) .................. 15 
4. 
STATISTICAL METHODS .......................................................................... 16 
4.1 
Analysis Populations ............................................................. 16 
4.2 
Analysis of Study Conduct ..................................................... 18 
4.2.1 
Disposition of Participants ..................................................... 18 
4.2.2 
Protocol Violations ................................................................. 18 
4.2.3 
Overview of Analysis Population ........................................... 18 
4.3 
Analysis of Treatment Group Comparability .......................... 18 
4.3.1 
Demographic and Baseline Characteristics ........................... 18 
4.3.2 
History of Schizophrenia or Schizoaffective 
Disorder 
19 
4.3.3 
Previous and Current Diseases at Baseline .......................... 19 
4.3.4 
Previous and Concomitant Treatments (Other 
than Study Medication) ............................................................................ 19 
4.4 
Definition of Baseline ............................................................. 20 
4.5 
Efficacy Analysis .................................................................... 20 
4.5.1 
Definition of Time Windows ................................................... 20 
4.5.2 
Primary Efficacy Endpoint ...................................................... 24 


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4.5.2.1 PANSS Total Scores ............................................................ 24 
4.5.2.2 Statistical Hypotheses .......................................................... 25 
4.5.2.3 Primary Estimand ................................................................. 25 
4.5.2.4 Missing Data Assumptions ................................................... 26 
4.5.2.5 Statistical Analysis ................................................................ 26 
4.5.2.6 Sensitivity Analysis ............................................................... 28 
4.5.2.7 Supplementary Analyses ...................................................... 28 
4.5.2.8 Adjustment for Multiple Testing ............................................ 29 
4.5.3 
Secondary Efficacy Endpoints ............................................... 29 
4.5.3.1 PANSS Total Scores at Week 12 ......................................... 30 
4.5.3.2 PANSS Symptom Factor Scores .......................................... 31 
4.5.3.3 PANSS Total and Symptom Factor Score 
Responder .......................................................................................... 33 
4.5.3.4 CGI-S and CGI-I ................................................................... 34 
4.5.3.5 CGI-S MTS and CGI-I MTS .................................................. 35 
4.5.3.6 Readiness for Discharge from Hospital ................................ 36 
4.5.4 
Exploratory Endpoints............................................................ 37 
4.5.4.1 Sleep, Mood, Well-being, Cognitive Functioning 
and Treatment Expectancy ................................................................. 37 
4.5.4.2 Recovering Quality of Life (ReQoL-20) ................................ 39 
4.5.4.3 Patient Global Impression-Change (PGI-C) ......................... 40 
4.5.4.4 Inflammatory Biomarkers and Cognitive Subtype ................ 41 
4.5.4.5 Calgary Depression Scale for Schizophrenia 
(CDSS) 41 
4.5.4.6 Scale to Assess Unawareness of Mental 
Disorder (SUMD-9) ............................................................................. 42 
4.5.4.7 VAGUS insight into Psychosis Scale .................................... 42 
4.5.4.8 Beck Cognitive Insight Scale (BCIS) .................................... 43 
4.5.4.9 Smoking Dependence .......................................................... 44 
4.5.4.10 Ecological Momentary Assessment (EMA) ........................ 44 
4.5.4.11 Feedback questions ........................................................... 45 
4.5.4.12 Premorbid Adjustment Scale (PAS) ................................... 46 
4.5.4.13 PANSS, CGI-S and CGI-I at Week 48 ................................ 47 
4.5.5 
Additional Analyses ............................................................... 47 


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4.5.5.1 Local vs Central PANSS Assessment .................................. 47 
4.5.5.2 WASI-II/WAIS-IV .................................................................. 47 
4.5.5.3 WRAT4/JART ....................................................................... 48 
4.5.5.4 PANSS IC ............................................................................ 48 
4.6 
Pharmacokinetic and Exposure-Response 
Analyses ................................................................................ 49 
4.6.1 
Pharmacodynamic Analyses ................................................. 49 
4.7 
Safety Analyses ..................................................................... 50 
4.7.1 
Definition of Time Windows ................................................... 51 
4.7.2 
Exposure of Study Medication ............................................... 53 
4.7.3 
Adverse Events ..................................................................... 54 
4.7.4 
Clinical Laboratory Tests ....................................................... 56 
4.7.5 
Electrocardiograms (ECG) data analysis ............................... 58 
4.7.6 
Concomitant Medications ...................................................... 59 
4.7.7 
Vital Signs, Body Weight and BMI ......................................... 59 
4.7.8 
Columbia-Suicide Severity Rating Scale (C-
SSRS) 
60 
4.7.9 
Extrapyramidal Symptom Rating Scale, 
Abbreviated Version (ESRS-A) ................................................................ 61 
4.8 
Missing Data Handling ........................................................... 62 
4.9 
Patient Data Listings .............................................................. 62 
5. 
REFERENCES ........................................................................................... 62 
APPENDIX 1 
PROTOCOL SYNOPSIS ....................................................... 64 
APPENDIX 2 
SCHEDULE OF ACTIVITIES STUDY BP41743 .................... 79 
APPENDIX 3 
PANSS SYMPTOM FACTORS ............................................. 87 
APPENDIX 4 
 UNCORRELATED PANSS SCORE MATRIX 
(UPSM) FOR GENERATING TRANSFORMED PANSS 
FACTOR SCORES ..................................................................................... 88 
APPENDIX 5 
CGI-S AND CGI-I QUESTIONS ............................................ 89 
APPENDIX 6 
FAGERSTÖM TEST OF NICOTINE 
DEPENDENCE SCORING ......................................................................... 91 
APPENDIX 7 
ADVERSE EVENT TEMPLATES .......................................... 92 


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APPENDIX 8 
ABUSE LIABILITY MEDDRA TERMS ................................... 96 
APPENDIX 9 
PATIENTS WITH SUICIDAL IDEATION, 
SUICIDAL BEHAVIOR, AND SELF-INJURIOUS BEHAVIOR 
WITHOUT SUICIDAL INTENT BASED ON THE C-SSRS 
DURING TREATMENT ............................................................................... 97 
APPENDIX 10 
ASSESSMENT OF SLEEP, MOOD, WELL-
BEING AND COGNITIVE FUNCTIONING, AND ASSUMED 
TREATMENT ASSIGNMENT ..................................................................... 99 
APPENDIX 11 
PREMORBID ADJUSTMENT SCALE (PAS) ....................... 100 
APPENDIX 12 
CALGARY DEPRESSION SCALE FOR 
SCHIZOPHRENIA (CDSS) ....................................................................... 105 
APPENDIX 13 
THE ABBREVIATED VERSION OF THE SCALE 
TO ASSESS UNAWARENESS IN MENTAL DISORDER IN 
SCHIZOPHRENIA (SUMD-9) ................................................................... 106 
APPENDIX 14 
VAGUS SELF-REPORT VERSION (VAGUS-SR) ............... 107 
APPENDIX 15 
VAGUS-SR SCORING SHEET ........................................... 110 
APPENDIX 16 
VAGUS CLINICIAN RATED VERSION (VAGUS-
CR) 
111 
APPENDIX 17 
VAGUS-CR SCORING SHEET ........................................... 113 
APPENDIX 18 
BECK COGNITIVE INSIGHT SCALE (BCIS) ...................... 114 
APPENDIX 19 
EMA ..................................................................................... 116 
APPENDIX 20 
PANSS IC NEGATIVE QUESTIONS SCORING ................. 122 
 
 
 
 
 
 


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LIST OF TABLES 
Table 1 
Interim Analysis Populations ....................................................... 17 
Table 2 
Analysis Time Windows for Double Blind Treatment Period 2 .... 20 
Table 3 
Analysis Time Windows for Double Blind Extension Period 3 ..... 22 
Table 4 
PANSS Total Score .................................................................... 24 
Table 6 
PANSS Factor Scores ................................................................ 31 
Table 10 
EMA Time Windows .................................................................... 45 
Table 11 
Analysis Time Windows for Double Blind Treatment Period 2 .... 51 
Table 12 
Analysis Time Windows for Double Blind Extension Period 3 ..... 52 
Table 13 
Analysis Time Windows for Long-Term Safety Extension ........... 53 
Table 11 
Adverse Event Time Windows .................................................... 55 
 
LIST OF FIGURES 
Figure 1 Overview of Study Design ...................................................................... 9 
 


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1. 
BACKGROUND 
This Technical Document for Statistical Analysis (TDSA) in an internal document that 
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 (first) interim analysis (IA) results from study BP41743. 
This IA will serve as main efficacy analysis for internal decision making will be performed 
when all non-Japanese patients are randomized and compled the Week 12 visit or 
dropped out from the study earlier. The IA will include all patients randomized until 25-
Nov-2021, i.e all patinets from USA, Russia and Ukraine and those patients from Japan 
who had been randomized up to 25-Nov-2021.  
2. 
STUDY DESIGN 
Study Design 
This is a Phase II, multi-center, randomized, double-blind, parallel group, placebo-
controlled study in participants with an acute exacerbation of schizophrenia or 
schizoaffective disorder. Participants who are experiencing an exacerbation of their 
schizophrenia, starting within 8 weeks prior to the screening visit, will be included. 
After eligibility is confirmed during the screening period (Study Period 1), approximately 
280 participants will be randomized outside Japan (United States [US] and rest of the 
world [ROW]) in equal proportions (approximately 70 per group) to one of the following 
treatments: 150 mg QD of RO6889450, 45 mg QD of RO6889450, placebo, or 
risperidone 4 mg QD (titration period: 2 mg of risperidone on Day 1, 4 mg of risperidone 
from Day 2) in a double-blind fashion for 4 weeks. In addition to these 280 participants, 
approximately 28 participants will be recruited in Japan. 
After completion of the 4-week Study Period 2, the participants may enter a double-blind 
8-week extension period (Study Period 3) if agreed between Investigator and participant 
based on clinical status. Participants treated with risperidone, or 150 mg QD of 
RO6889450, or 45 mg QD of RO6889450 during the Study Period 2 will continue with 
their respective treatments in the Study Period 3, while participants assigned to placebo 
will be randomized to either 150 mg QD or 45 mg QD of RO6889450 in a blinded 
fashion.  
At the beginning of the Study Period 3, participants will be discharged from the hospital 
or may remain inpatient for the first weeks if required according to the clinical judgment 
of the Investigator.  
After completion of Study Period 3, participants may be offered continuation in the 
optional 36-Week Safety Extension Phase if they meet additional inclusion criteria. 
Participants will continue to receive the same treatments as those they received during 
Study Period 3, in a double-blind fashion. 


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The assessment of the primary endpoint (PANSS) will be performed by trained 
centralized raters independent from the investigational sites. Participants who 
discontinue study medication during Study Period 2 are required to complete the Study 
Period 2 EOT visit as soon as possible after the last dose of study drug (if possible, 
PANSS assessment should be performed before rescue medications are taken). These 
participants are also required to return to the clinic 4 weeks after the first dose of study 
drug (at the end of the 4-week Study Period 2) for Week 4 early termination visit (ETV). 
Participants will also be asked to return for the follow up visit (4 weeks after the last dose 
of study drug). 
Anti-psychotic medication 
All anti-psychotics are prohibited in the study during Study Periods 2 and 3 and with a 
minimum washout period of 72 hours before the initiation of study medication. 
Rescue anti-psychotic treatment 
If the clinical state of the participant would require treatment with an anti-psychotic other 
than the study medication, in the judgment of the Investigator, an antipsychotic should 
be prescribed, and the participant will be immediately withdrawn from the study drug. 
Investigators should make a reasonable effort to complete a final assessment including 
efficacy endpoints before starting antipsychotic medication. The reasons for use of 
rescue medication should be documented in detail. 
Length of Study 
The total duration of the study for each participant will be approximately 17 weeks 
divided as follows: 
- 
Study Period 1: Screening: approximately 3 to 7 days (1 week: inpatient). 
- 
Study Period 2: Double-blind treatment period: 28 days (4 weeks: inpatient). 
- 
Study Period 3: Double-blind extension treatment period: 56 days (8 weeks). At 
the beginning of the extension period, participants will be discharged from the 
hospital or may remain inpatient for the first weeks if required according to the 
clinical judgment of the Investigator 
- 
36-Week Safety Extension Phase (optional): 36 weeks. Participants, who have 
completed Study Period 3 and in the opinion of the Investigator may benefit from 
the prolonged treatment, may enter 36-Week Safety Extension Phase if they 
meet additional eligibility criteria. Participants with worsening of their psychiatric 
or medical status that would preclude their safe participation in the 36-Week 


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Safety Extension Phase or their ability to comply with the required procedures 
will not be eligible for the 36-Week Safety Extension Phase of this study. 
- 
Study Period 4: Safety follow-up/Follow-up Period for 36-Week Safety Extension 
Phase: 28 days (4 weeks). Mandatory follow-up assessments for all participants 
4 weeks after the last dose of study drug. 
- 
End of study visit: 1 day  
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. 
Figure 1 Overview of Study Design 
A. Without 36-Week Safety Extension Phase 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
  
 
 
  
  
 
 
 
 
  
 
 
 
 
 
 
 


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B. With Optional 36-Week Safety Extension Phase 
 
 
2.1 
PROTOCOL SYNOPSIS 
The Protocol Synopsis is in Appendix 1 
 
 
  
 
  
 
 
  
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix 1. For additional details, see the Schedule of Assessments of Part A in 
Appendix 2. 
2.2 
OBJECTIVES AND ENDPOINTS 
Objectives 
Endpoints 
Primary 
• 
To compare the effect of 4-week 
treatment with two doses of RO6889450 
(45 mg and 150 mg) vs. placebo in 
participants with acute symptoms of 
schizophrenia or schizoaffective 
disorder.  
• 
Change from baseline at Week 4 in the 
Positive and Negative Syndrome Scale 
(PANSS) total score. 
Secondary 
• 
To compare the effect of 4–week 
treatment with two doses of RO6889450 
(45 mg and 150 mg) with placebo on 
symptoms of schizophrenia or 
schizoaffective disorder as assessed 
with PANSS.  
• 
Proportion of participants with at least 
20% or 50% improvement from baseline 
on PANSS total score. 
• 
Changes from baseline in the PANSS 
factor scores and proportion of 
participants with at least 20% or 50% 
improvement from baseline in the 
PANSS factor scores. 
• 
To compare the effect of 4–week 
treatment with two doses of RO6889450 
(45 mg and 150 mg) with placebo on: 
Clinical Global Impression Severity 
(CGI-S) and improvement (CGI-I).  
• 
Change from baseline (CGI-S and CGI-
S MTS scores) 
• 
CGI-I and CGI-I MTS scores 
• 
To compare the effect of 4–week 
treatment with two doses of RO6889450 
(45 mg and 150 mg) with placebo on 
time-to-readiness for discharge from 
inpatient unit. 
• 
Time from first randomized treatment 
intake to readiness for discharge as 
assessed by the Readiness for 
Discharge Questionnaire (RDQ) or 
actual discharge or censoring if the 
participant discontinues the study early. 


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Objectives 
Endpoints 
• 
To compare the safety and tolerability of 
4-week treatment with two doses of 
RO6889450 (45 mg and 150 mg) vs. 
placebo. 
• 
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 standing vital 
signs recordings. 
• 
Change from screening 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, 
and urinalysis test results. 
• 
Change from baseline in Columbia-
Suicide Severity Rating Scale (C-SSRS) 
and Extrapyramidal symptom rating 
scale, abbreviated (ESRS-A). 
• 
To observe the effect of treatment with 
two doses of RO6889450 (45 mg and 
150 mg) up to 12 weeks. 
• 
Proportion of participants with at least 
20% or 50% improvement from baseline 
on PANSS total score. 
• 
Changes from baseline in the PANSS 
total and factor scores and proportion of 
participants with at least 20% or 50% 
improvement from baseline in the 
PANSS factor scores. 
• 
CGI-S and CGI-S MTS. 
• 
CGI-I and CGI-I MTS. 
• 
To observe the safety and tolerability of 
extended treatment with two doses of 
RO6889450 (45 mg and 150 mg) up to 
12 weeks. 
• 
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 standing vital 
signs recordings. 
• 
Change from baseline in 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, 
and urinalysis test results. 
• 
Change from baseline in C-SSRS and 
ESRS-A.  


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Objectives 
Endpoints 
• 
To evaluate the pharmacokinetics (PK) 
of RO6889450 and RO6889450-derived 
metabolite(s). 
• 
Concentration per time point. 
• 
AUCss of RO6889450 and, if feasible, 
RO6889450-derived metabolite(s) at 
Week 4. 
• 
Cmax of RO6889450 and, if feasible, 
RO6889450-derived metabolite(s) at 
Week 4. 
• 
Other PK parameters as appropriate. 
Exploratory 
• 
To evaluate the changes in Sleep, Mood, 
Well-being, Cognitive Functioning and 
Treatment Expectancy. 
• 
Smartphone App Questionnaire. 
• 
To assess the changes in ReQoL. 
• 
Change in ReQoL from baseline, 
proportion of patients with 10 points 
improvement or more. 
• 
To compare the effect of two doses of 
RO6889450 (45 mg and 150 mg) with 
placebo on: Patient Global Impression - 
Change (PGI-C). 
• 
PGI-C. 
• 
To assess the relationship between the 
levels of inflammatory biomarkers and 
cognitive subtype. 
• 
Differences in levels of inflammatory 
biomarkers between subgroups of 
patients defined by pre-morbid and 
current IQ estimate (Wide Range 
Achievement Test [WRAT-4] and 
Wechsler Abbreviated Scale of 
Intelligence – Second Edition [WASI-II]). 
• 
To evaluate the change in the level of 
depression in schizophrenia measured 
by Calgary Depression Scale for 
Schizophrenia (CDSS) up to 48 weeks. 
• 
Calgary Depression Scale for 
Schizophrenia. 
• 
To evaluate the changes in the level of 
insight into mental disorder. 
• 
Scale to Assess Unawareness of Mental 
Disorder (SUMD). 
• 
VAGUS insight into Psychosis Scale 
• 
Beck Cognitive Insight Scale (BCIS). 
• 
To explore the changes in nicotine 
addiction measured by Fagerström Test 
for Nicotine Dependence. 
• 
Fagerström Test for Nicotine 
Dependence. 
• 
To explore the effects of RO6889450 on 
levels and patterns of social and general 
activity and psychotic symptoms 
• 
Ecological Momentary Assessment 
• 
To assess patients perception of 
changes relative to their condition and 
relevance and ease of understanding of 
the PRO instruments used in the study 
• 
Feedback questions 
• 
To evaluate relationship between the  
premorbid functioning and treatment 
response 
• 
Premorbid Adjustment Scale (PAS) 


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Objectives 
Endpoints 
• 
To observe the effect of treatment with 
two doses of RO6889450 (45 mg and 
150 mg) up to 48 weeks 
• 
Changes from baseline in the PANSS 
total and factor scores at Week 48. 
Analysis by the following groups: 
risperidone, RO6889450 45 mg, 
RO6889450 150 mg, placebo/ 
RO6889450 45 mg, 
placebo/RO6889450 150 mg 
• 
CGI-S 
• 
CGI-I 
• 
To observe the safety and tolerability of 
long-term treatment with RO6889450 up 
to 48 weeks 
• 
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 standing vital 
signs recordings 
• 
Change from screening in 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, 
and urinalysis test results 
• 
Change from baseline in C-SSRS and 
ESRS-A  
 
2.3 
DETERMINATION OF SAMPLE SIZE 
Assuming a true difference of approximately 8.23 between two groups in mean PANSS 
reduction at Week 4 and a standard deviation of 16.5, approximately 50 participants per 
group will provide 80% power to see an effect with a two-sided type I error of 0.1. 
Allowing for about 25% of the participants randomized not completing 4 weeks of 
treatment approximately 70 participants per treatment group will be randomized to the 
study outside Japan (US and ROW). Approximately 28 participants will be recruited in 
Japan. 
The primary analysis will be based on all participants recruited outside Japan (US and 
ROW) and in Japan and will be performed when all randomized patients complete the 
study. 
With an anticipated sample size of 50 participants per group any observed reductions 
(versus placebo) by approximately 5.5 or more points is expected to be statistically 
significant. 


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2.4 
ANALYSIS TIMING AND UNBLINDING 
2.4.1 
Interim Analysis (IA) 
Given the hypothesis-generating nature of this study, the Sponsor may choose to 
conduct up to two efficacy IAs for internal decision making. The decision to conduct an 
optional efficacy IA and the timing of the analysis will be documented in the Sponsor’s 
trial master file prior to the conduct of the IA. Any IA will be performed and interpreted by 
members of the Sponsor project team (not in contact with study sites) 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. 
This IA will serve as main efficacy analysis for internal decision making and will be 
performed when all non-Japanese patients are randomized and compled the Week 12 
visit or dropped out from the study earlier.  
2.4.2 
Primary Analysis 
The primary analysis of the study as per protocol will be performed and interpreted when 
all randomized patients have completed Period 2 (Week 4) or withdrawn from the study 
earlier and Period 2 data from all patients have been verified and locked. This includes 
all participants recruited outside Japan (US and ROW) and in Japan if the participants 
completed Period 2 at the time of the clinical cut-off. The cinical cut-off date is 21-Feb-
2022. 
2.4.3 
Final Analysis 
The final analysis of data from the trial will be performed when all patients of the study, 
including patients from Japan, have either completed the study, or discontinued early 
from the study. 
3. 
STUDY CONDUCT 
3.1 
RANDOMIZATION  
Study Period 2: 
An Interactive Voice/Web Response System (IxRS) is used to randomize participants 
in equal proportion (approximately 70 per group) to one of the following treatments:  
- 
150 mg QD of RO6889450,  
- 
45 mg QD of RO6889450,  
- 
placebo, or  
- 
risperidone 4 mg QD  
Outside Japan randomization will be stratified according to the following factors: 
- 
region (North America, Eastern Europe, and Asia),  


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- 
baseline PANSS total score (80-95 and 96 and above),  
- 
duration of the disease (≤ 5 years and > 5 years),  
- 
and sex.  
In Japan randomization will be stratified according to the following factor: 
- 
baseline PANSS total score (80-95 and 96 and above).  
Study Period 3: 
After completion of the 4-week Study Period 2, the participants may enter a double-
blind extension period (Study Period 3).  Participants treated with risperidone, or 
150 mg QD of RO6889450, or 45 mg QD of RO6889450 during the Study Period 2 
will continue with their respective treatments in the Study Period 3, while participants 
assigned to placebo will be randomized to either 150 mg QD or 45 mg QD of 
RO6889450 in a blinded fashion.  
Outside Japan randomization will be stratified according to the following factors: 
- 
region (North America, Eastern Europe, and Asia),  
- 
baseline PANSS total (80-95 and 96 and above),  
- 
duration of the disease (≤ 5 years and > 5 years),  
- 
and sex.  
In Japan randomization will be stratified according to the following factor: 
- 
baseline PANSS total (80-95 and 96 and above).  
3.2 
INDEPENDENT REVIEW FACILITY 
The primary endpoint PANSS will be assessed live via secure videoconference by 
trained remote centralized raters. If a remote administration session cannot occur for an 
unforeseen reason, it will be rescheduled. 
The assessment of the primary endpoint (PANSS) will be performed by trained 
centralized raters independent from the investigational sites. Remote independent raters 
will administer assessments live via secure videoconference. In exceptional situations, 
PANSS assessment by an approved remote centralized rater can be accessed via 
phone link if the video link is not available. The independent 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. 
3.3 
DATA MONITORING 
3.3.1 
Independent Data Monitoring Committee (iDMC) 
No iDMC is utilized for this study. 


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4. 
STATISTICAL METHODS 
4.1 
ANALYSIS POPULATIONS 
For purposes of analysis, the following populations are defined in Table 1. 
Note: Patients randomized to RO6889450 whom RO6889450 and RO6889450-derived 
metabolite RO7208008 concentrations are below quantification limit (BQL) over the 
whole treatment Period 2 will be regarded as having not received their randomized study 
medication and will be excluded from all analysis populations. PK samples collected at 
Day 28 (or the last sample collected before Day 28 for those patients who discontinued 
earlier) from patients randomized to placebo or risperidone will be analyzed for 
RO6889450 and RO7208008 concentrations. Those patients with positive 
concentrations will be regarded as having not received their randomized study 
medication and will be excluded from all analysis populations. 


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Table 1 
Interim Analysis Populations 
Population 
Description 
 
 
Population Evaluable for 
Efficacy Analysis [EAP] 
All randomized participants who received at least one dose of 
randomized study medication regardless of whether they 
withdrew prematurely or not. Participants who received study 
medication different from that to which they were randomized 
will be included in the group to which they were randomized. 
Population Evaluable for 
Efficacy Analysis [EAPP3] 
Participants who received at least one dose of randomized 
study medication in Period 3 (8 week out-patient period) of the 
study. 
Per Protocol [PP] 
The per-protocol (PP) analysis population will be defined as a 
subset of the EAPpopulation, excluding those who have major 
protocol violations affecting efficacy assessment. Efficacy 
variables will be analyzed for this population based on the 
initial actual treatment received.  
PP analysis will only be performed if it contains less than 90% 
of the EAPpatients. 
Safety [SE] 
The safety analysis population will consist of all participants 
who received at least one dose of randomized study 
medication, regardless of whether they withdrew prematurely 
or not. Participants will be analyzed according to the treatment 
group to which they were randomized. 
Pharmacokinetic [PK] 
All participants who have received at least one dose of study 
treatment 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 which 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. 
 
Major protocol violations leading to exclusion from PP analysis population are: 
– 
Concomitant use of prohibited medications (not related to treatment of an AE) or 
therapy. 
– 
Improper use of non-benzodiazepines hypnotics or benzodiazepines, including 
max doses. 
– 
PANSS missed at any scheduled clinic or phone visit 
– 
Repeat misuse of study drug or repeated under dosing or over soding <80% 
or >120% of doses (weekly). 
– 
Subject repeatedly failing to attend study visit in which safety & efficacy 
assessments are done. 


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– 
Violation of any exclusion criteria discovered after randomization. 
– 
Violation of any inclusion criteria discovered after randomization. 
 
4.2 
ANALYSIS OF STUDY CONDUCT 
4.2.1 
Disposition of Participants 
For all patients in the EAP analysis population, withdrawal of study drug and reason for 
withdrawal will be summarized per treatment arm to which participants are randomized.  
4.2.2 
Protocol Violations 
The major protocol violations will be identified before database snaphot. 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.   
4.2.3 
Overview of Analysis Population 
The number (percentage) of participants excluded from the analysis populations will be 
summarized by reason for exclusion per treatment arm.  
4.3 
ANALYSIS OF TREATMENT GROUP COMPARABILITY 
The evaluation of treatment arm comparability between the two treatment arms will 
include summaries of demographics and baseline characteristics. 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.  
4.3.1 
Demographic and Baseline Characteristics 
Summary tables of demographics and baseline characteristics will be produced for the 
EAP analysis populations by treatment arm to which participants were randomized. The 
following variables will be summarized: 
Categorical variables: 
• 
Sex (Male vs. Female)  
• 
Age (continuous) at baseline 
• 
Race (Black or African American vs. White vs. Asian) 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 


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and others if appropriate.  
Baseline data for efficacy scales will be included in the respective efficacy outputs.  
4.3.2 
History of Schizophrenia or Schizoaffective Disorder 
Summary statistics will be generated for the EAP analysis populations by treatment 
group and will include each patient’s history of schizophrenia or schizoaffective disorder. 
The key variables from the electronic Case Report Form (eCRF) listed in the psychiatric 
history page will be summarized.  
• 
Diagnosis (schizophrenia, schizoaffective disorder depressed subtype, 
schizoaffective disorder bipolar subtype) 
• 
Duration of disease (years), calculated relative to the year of randomization (year of 
randomization – year of diagnosis) 
• 
Number of hospitalizations for worsening of schizophrenia/schizoaffective disorder in 
the past year 
• 
Duration (in months) since the most recent hospitalization for worsening of 
schizophrenia, calculated relative to the randomization date. 
 
4.3.3 
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. 
The number and percentage of patients with previous (resolved) diseases will be 
summarized by treatment group in the EAP. 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. 
4.3.4 
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. 


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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 defined as the last non-missing value 
recorded prior to or on the first day of randomized double-blind study drug 
administration. 
4.5 
EFFICACY ANALYSIS 
4.5.1 
Definition of Time Windows 
Table 2 
Analysis Time Windows for Double Blind Treatment Period 2 
Applicable to all patients 
 
Analysis Window Label  
Baseline 
Day 7 
Day 14 
Day 21 
Day 28 
Planned Study Day 
1 
7 
14 
21 
28 
PANSS, CGI-S, CGI-S MTS, CGI-I(4), CGI-I MTS(4) 
Study Day 
 
≤ 1(1)  
2 to 10(2) 
11 to 17 
18 to 24 
≥ 25(3) 
RDQ, PGI-C 
Study Day 
 
NA 
2 to 10(2) 
11 to 17 
18 to 24 
≥ 25(3) 
ReQoL, FTND 
Study Day 
 
≤ 1(1)  
NA 
2 to 21 
NA 
≥ 22(3) 
CDSS, SUM-D, VAGUS, BCIS 
Study Day 
 
≤ 1(1) 
NA 
NA 
NA 
≥ 2(3) 
(1) Latest assessment prior to intake of first study medication. Use date and time, if available. 
(2) May include assessments on day 1 if AFTER time of first study medication. 
(3) Includes any assessments on that study day or later but prior to the date of first dose in the 
double-blind extension treatment period (Period 3). 
(4) No baseline for CGI-I and CGI-I MTS. 
• 
For analysis and reporting: all patients entering Period 2 will be included as per the 
population definitions in the section 4.1.  
• 
Summaries will use the time windows as above and analysis flags as defined below 
and only include the time windows shown in the table.  Hence summaries will not 
include “screening” or “follow-up”.  
• 
Listings will include the analysis window label as above as well as the label which 
was assigned in the database.  All values, also duplicates per window, will be 
included in listings.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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• 
All analyses will have 4 treatment arms, as per randomization in Period 2. 
• 
The analysis dataset will contain all assessment results. Analysis flags will be 
created to indicate the values that will enter the respective stats analysis and 
associated summary tables:  
– ANAFLAG = ‘Y’ if the assessment (1) is in time window AND (2) the assessment 
is within 4 days after the last dose of study drug. If more than one assessment is 
in the same time window after applying (1) and (2) the assessment that is closest 
to planned study day (see above) will be selected. 
– ANAFLAG1 =’Y’, for the “Hypothetical Estimand”, if the assessment (1) is in time 
window AND (2) the assessment is within 4 days after the last dose of study drug 
AND (3) the assessment is prior to ICE3 as defined in section 4.5.2.3 or within 4 
days of ICE2. If more than one assessment is in the same time window after 
applying (1), (2) and (3) the assessment that is closest to planned study day (see 
above) will be selected. 
– ANAFLAG2 =’Y’, for the “Treatment Policy Estimand”, if the assessment (1) is in 
time window AND (2) the assessment is closest to planned study day (see 
above) if more than one assessment is in same window. 
 


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Table 3 
Analysis Time Windows for Double Blind Extension Period 3 
Applicable to all patients randomized to Period 3 
Analysis 
Window 
Label  
Period 3 
Baseline 
Day 35 
Day 42 
Day 
49 
Day 56 
Day 
70 
Day 84 
Week 
24 
Week 
36 
Week 
48 
PANSS, ReQoL, FTND 
Study 
Day 
Last assessment 
before first dose 
in Period 3(1)  
NA 
NA 
NA 
First 
assessmen
t after first 
dose in 
Period 3(2) 
to 70 
NA 
70(2) to 126 
127 to 
210 (4) 
211 
to 
294 
(4) 
≥295 
(3) (4) 
CGI-S, CGI-S MTS, CGI-I, CGI-I MTS 
Study 
Day 
Last assessment 
before first dose 
in Period 3(1) 
First 
assessment 
after first dose in 
Period 3(1) to 38 
39 to 45 
46 to 
52 
53 to 63 
64 to 
77 
78(2) to 126 
127 to 
210 (4) 
211 
to 
294 
(4) 
≥295 
(3) (4) 
PGI-C 
Study 
Day 
Last assessment 
before first dose 
in Period 3(1) 
NA 
First 
assessment 
after first dose in 
Period 3(2) to 49 
NA 
50 to 63 
NA 
≥64(2) 
NA 
NA 
NA 
CDSS, SUM-D, VAGUS, BCIS 
Study 
Day 
Last assessment 
before first dose 
in Period 3(1) 
NA 
NA 
NA 
NA 
NA 
>Last 
assessment 
before first 
dose in Period 
3(1)(2) to 126 
127 to 
210 
211 
to 
294 
≥295 
(3) (4) 
(1) Use date and time, if available. The first dose in Period 3 is the first dose after the last dose in Period 2. 
(2) Includes any assessments on that study day or later and either (1) within 4 days after last dose for patients not entering the long-term safety 
extension period or (2) up to study day 126 for patients entering the long-term safety extension period. 
(3) As drug intake is not recorded for the long-term extension study, the day of last dose of study drug intake cannot be assessed. Therefore, any 
assessments reported with the Follow-up folder will not be included. 
(4) Not for FTND, CGI-S MTS, CGI-I MTS, SUM-D, VAGUS, BCIS 


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• 
For analysis and reporting: all patients entering Period 3 will be included as per the population definitions in the section 4.1.  
• 
The analysis dataset will contain analysis flags as defined in Table 2.  
• 
All analyses will have 5 treatment arms, per randomization in Period 3: “pbo -> ralmi150”, “pbo -> ralmi45”, “risp -> risp”, “ralmi45 
-> ralmi45”, and “ralmi150 -> ralmi150”. 
• 
Separate listings, summary tables and analyses will be created for these patients. 
 
 


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4.5.2 
Primary Efficacy Endpoint 
The primary efficacy endpoint of the study is the change from baseline in the PANSS 
Total Score at Week 4.  
4.5.2.1 
PANSS Total Scores  
The PANSS is a 30-item rating scale clinician-rated instrument for assessing positive, 
negative, and other symptoms in partients with schizophrenia. 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 Positive Scale assesses 
the features exhibited in schizophrenia that are not present in those with a normal 
mental state. The Negative sub-scale assesses features that are absent in 
schizophrenia but that would be present in those with a normal mental state. The 
General sub-scale assesses the overall severity of the disorder and the risk of 
aggression. PANSS assessments are performed by an approved remote centralized 
rater.  
Each item of the PANSS is rated on a 7-point scale based on the following anchors: 1 = 
Absent, 2 = Minimal, 3 = Mild, 4 = Moderate, 5 = Moderately Severe, 6 = Severe, and 7 
= Extreme.  
The assessment for each of the 30 items is to allow calculation of a total score 
describing overall symptomatology (see Table 4 and Appendix 3).  
Table 4 
PANSS Total Score 
Score 
Number 
of items 
Items 
Total Score 
30 
N01-N07, P01-P07, G01-G16 
If any item contributing to its calculation is missing, then the scores will be set to missing. 
A higher score indicates more positive and negative symptoms. Hence negative values 
for change from baseline indicate improvement in symptoms. 
PANSS is assessed at Screening (day -7 to -3), Day 1 (Baseline), Day 7, Day 14, Day 
21, Day 28/EOT Period 2, Day 56, Day 84/EOT Period 3, Day 112 (FU if patients do not 
participate in the 36-Week Safety Extension Phase). If patients participate in the 
36-Week Safety Extension Phase additional PANSS assessments are done at Week 24 
(Day 168), Week 36 (Day 252), Week 48 (Day 336) and Week 52 (Day 364, FU).   
During Study Period 2: If a participant voluntarily withdraws from the study or is 
withdrawn by the Investigator, the participant will be asked to complete Study Period 2 
EOT visit as soon as possible after the last dose of study drug. This may be sooner than 
Day 28. Participant will also be asked to return to the clinic 4 weeks after the first dose of 


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study drug (at the end of the 4-week Study Period 2) for Week 4 ETV to complete 
assessments of the primary and secondary efficacy outcomes. Participants will also be 
asked to return for the follow-up visit (4 weeks after the last dose of study drug). 
During Study Period 3: If a participant voluntarily withdraws from the study or is 
withdrawn by the Investigator, the participant should return to complete Study Period 3 
EOT visit as soon as possible after the last dose of study drug. This may be sooner than 
Day 84. Participant will also be asked to return for the follow-up visit assessments (4 
weeks after the last dose of study drug). 
All assessments will be assigned to analysis study days according to section 4.5.1. 
RSCAT = PANSS 
4.5.2.2 
Statistical Hypotheses 
The primary objective of the study is to demonstrate that at least one RO6889450 dose 
is significantly different from placebo at Week 4 for the primary endpoint. 
A higher PANSS total score indicates a greater pathology. The change from baseline of 
PANSS total score at Week 4 will be calculated as the total score at Week 4 minus the 
total score at baseline. A negative change from baseline in PANSS total score indicates 
improvement. 
The following null (H0) and alternative (H1) hypotheses will be tested at a one-sided 
α=0.05 level between each RO6889450 dose level and placebo to assess efficacy of 
each RO6889450 dose. 
• 
H0: MEANRO6889450 ≥ MEANplacebo versus 
• 
H1: MEANRO6889450 < MEANplacebo 
where MEANRO6889450 and MEANplacebo refer to the mean change from baseline for 
RO6889450, and placebo, respectively. 
4.5.2.3 
Primary Estimand 
The clinical question of interest is to assess whether RO6889450 is working as an 
antipsychotic, evaluated in the hypothetical scenario that patients continue with there 
randomized drug until Week 4. 
In alignment with the Addendum to ICH E9 [ICH 1998], ICH E9 (R1) [ICH 2019] Fehler! 
Verweisquelle konnte nicht gefunden werden., the primary efficacy estimand is 
described by the following attributes: 


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• 
Target Population: adult patients with schizophrenia as defined by the 
inclusion/exclusion criteria, see Sections 5.1 and 5.2 of the study protocol. 
• 
Variable: change from baseline at Week 4 in PANSS total score. 
• 
Treatment: randomized study drug: placebo, RO6889450 45 mg, RO6889450 150 
mg. Risperidone is added only to check internal validity of the study. 
• 
Population-level summary: difference in variable means between each 
RO6889450 dose arm and placebo treatment arm. 
• 
Intercurrent events (ICE): 
(ICE1) Withdrawal from treatment in Period 2 regardless of reasons for withdrawal. 
The date of the ICE is the date of withdrawal. 
(ICE2) Drug interruption or missed dose of more than 4 consecutive days or more 
than 8 days in total in Period 2. The date of the ICE is the day of the first 
interruption/missed dose as defined.  
(ICE3) Use of antipsychotic medication defined as medication class ‘other 
antipsychotic’. The date of the ICE is the day of first intake of antipsychotic 
medication. 
ICEs will be handled by a hypothetical strategy to estimate what the outcome would 
have been at the designated time point if all patients adhered to their randomized 
treatment through that time point. Consequently, data post ICEs even if collected 
will not be used for the primary estimand, unless data was collected within 4 days 
after last dose before ICE and will be handled under the missing-at-random (MAR) 
assumption in the same way as missing data are handled for the analysis (mixed 
effects model for repeated measues (MMRM)). The frequencies of ICE will be 
summarized by treatment arm. 
4.5.2.4 
Missing Data Assumptions 
For intermittent missing data and missing data after ICE, the missing observations are 
assumed to be similar to those from the other participants in the same treatment group 
with no such missing data. There will be no missing data imputation, data will be 
analysed with MMRM as described in the following section. This is compatible with a 
MAR assumption. 
To understand the pattern of missing data after ICE observed and thus the missing data 
mechanism, the following data will be reviewed: 
• 
Frequency of ICEs by treatment group 


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4.5.2.5 
Statistical Analysis  
Descriptive summary statistics will be presented for the PANSS Total Score up to 
Week 4, for the EAP analysis population by the treatment arm to which participants were 
randomized at baseline (placebo, RO6889450 45 mg, RO6889450 150 mg, risperidone). 
The same descriptive summary statistics will be presented for the change from baseline.  
As primary analysis the change from baseline in PANSS Total Score at Week 4 will be 
analyzed, using a mixed effects model for repeated measures (MMRM) to utilize all the 
data collected over time with consideration of the variance-covariance matrix of the 
repeated measures. Changes from baseline in PANSS total score at study Day 7, 
Day 14, Day 21 and Day 28, will be included. All patients in the EAP will be included. 
The analysis will be repeated for the PP, if applicable. 
The MMRM analysis provides an unbiased estimate of the treatment effect under the 
assumption that missing data are MAR. Published data support the robustness of the 
MMRM analysis regarding protection against type I error and against bias, also in 
situations with a non-negligible proportion of missing data. Using extensive simulations, 
it has been demonstrated that the type I error is only affected to a limited extent and that 
the bias is small under the assumption that 1/3 of the missing data are missing-not-at-
random (MNAR), even when there is a severe imbalance between the treatment groups 
in the proportion of withdrawals [Siddiqui 2009]. 
A treatment-by-time interaction contrast will be constructed to estimate the difference 
between active treatment and placebo in mean change from baseline to Week 4. Least 
squares means per treatment group 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 group and placebo will 
be estimated and also reported with 2-sided 90% confidence intervals. 
The model can be expressed as the following: 
                            Yijk =  + bk + dk + rk + sk + i + tj + (t)ij + ijk.     
Therein Yijk denotes the change from baseline in PANSS Total Score of participant k at 
visit j (j =1 (Day 7), 2 (Day 14), 3 (Day 21), 4 (Day 28)),  denotes the general mean, i 
is the fixed effect of treatment i (i =0 (placebo), 1 (45 mg RO6889450), 2 (150 mg 
RO6889450), 3 (risperidone)), tj is the fixed effect of visit j, and bk is the baseline value of 
the PANSS Total Score on a continuous scale for participant k, (t)ij  is the treatment-by-
time interaction. Furthermore, dk denotes the years since diagnosis of schizophrenia 
disease at time of screening (continuous variable), rk denotes the class variable for the 
region (North America, Eastern Europe, and Asia) of participant k, while sk is a class 
variable for sex (male vs. female) of participant k. The random errors ijk are assumed to 
be independent across different participants, while within each participant an unspecified 


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covariance structure will be modelled. If, unexpectedly, this analysis fails to converge, 
the following structures will be applied, in the following order: heterogeneous Toeplitz, 
first-order ante-dependence, heterogeneous compound symmetry, compound symmetry. 
The Kenward-Roger approximation will be used to estimate denominator degrees of 
freedom. Sex, years since diagnosis of schizophrenia disease at time of screening and 
region will be taken from the eCRF, PANSS Total Score at baseline will be taken from 
the rating vendor.  
4.5.2.6 
Sensitivity Analysis 
Impact of COVID-19 pandemic  
COVID-19 pandemic has started approximately in March 2020, the first patient was 
randomized in September 2020. As all patients have been randomized after start of 
COVID-19 pandemic and patients are treated in clinic until Week 4, COVID-19 pandemic 
is considered as having no relevant impact on the primary estimator. No sensitivity 
analysis will be performed with regards to impact of COVID-19 pandemic. 
4.5.2.7 
Supplementary Analyses 
Treatment policy estimand  
ICEs will be handled with a treatment policy strategy. All observed data until Week 4 will 
be included into the analysis regardless of occurrence of any ICE. Missing values in the 
placebo, the RO6889450 and the risperidone arms will be imputed based on the placebo 
arm using reference based imputation with a Copy Increments from Reference (CIR) 
assumption [Carpenter 2013], [Cro 2020]. CIR assumes that changes in the primary 
endpoint after the ICE in a participant randomized to active drug, here RO6889450 and 
risperidone, can be represented by, i.e., imputed from, that of participants randomized to 
placebo; and that changes after ICE in participants who discontinue from the placebo 
group will exhibit the same future evolution of schizophrenia as subjects in the placebo 
group remaining in the study. This approach does not assume a sustained benefit of 
experimental treatment after the ICE. In the placebo arm, this is compatible with a MAR 
assumption whereas in the active treatment arm, the imputation is under a MNAR 
assumption. Note that the attributes of population, variables, treatment, and population 
level summary will remain the same as for the primary estimand.  
Two separate imputation procedures are used to impute missing values. Firstly, the 
Markov chain Monte Carlo (MCMC) method is used to perform partial imputation to 
obtain datasets with monotone missing patterns (using SAS MI procedure with MCMC 
statement). These steps are repeated to obtain 200 datasets with monotone 
missingness. Then a multiple imputation method is used to impute the monotone 
missing values (SAS MI procedure with MONOTONE REG statement). Each of the 200 
imputed datasets will be analyzed using the same MMRM model as the primary efficacy 
analysis. Results from the analysis of each imputed dataset, i.e. the LS means of each 


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treatment group, the LS mean treatment difference, and their standard errors, will be 
combined using Rubin’s imputation rules (using SAS MIANALYZE procedure) to 
produce pooled LS mean estimates, their standard errors and 90% CI. 
Subgroups 
PANSS Total Score up to Week 4 and change from baseline will be summarized and 
analyzed descriptively by  
– 
Sex (male and female). 
– 
Geographic region (North America, Eastern Europe). It is expected that there is 
no relevant difference in drug effect between geographic regions. 
– 
Median baseline PANSS total.  
– 
Median duration of the disease. 
The primary analysis for the PANSS Total Score at Week 4. 
4.5.2.8 
Adjustment for Multiple Testing 
The primary objective of the study is to demonstrate that at least one RO6889450 dose 
level is significantly (overall type I error rate of 0.1, 2-sided) different from placebo.  
To maintain an overall type I error rate for multiple testing of each of the two RO6889450 
dose levels vs. placebo, the hypotheses described in 0 will be tested for the primary 
efficacy variable applying the Hochberg procedure: 
• 
The larger p-value will be tested at the 0.05 (one-sided) level. When the larger 
pvalue is ≤ 0.05, both null hypotheses are rejected. 
• 
If the larger p-value is > 0.05, the smaller p-value will be tested at the 0.025 level. 
If it is ≤ 0.025, the null hypothesis is rejected. 
Raw p-values for the two hypotheses will be computed using the MMRM method 
described in Section 4.5.2.3.  
The difference between risperidone and placebo will be assessed independently to 
check internal validity of the study. 
4.5.3 
Secondary Efficacy Endpoints 
Descriptive summary statistics will be presented for secondary efficacy endpoints for the 
EAP analysis population by visit and by treatment arm to which participants were 
randomized. The same descriptive summary statistics and will be presented for the 
change from baseline. 


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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.  
4.5.3.1 
PANSS Total Scores at Week 12 
Descriptive summary statistics will be presented for the PANSS Total Score from 
Baseline up to Week 12, for the EAPP3 analysis population (patients who received at 
least one dose of randomized study medication and have at least one efficacy 
assessment in Period 3) by the treatment arm to which participants were randomized at 
baseline/at end of Period 2 (placebo followed by RO6889450 45 mg, placebo followed 
by RO6889450 150 mg, RO6889450 45 mg, RO6889450 150 mg, risperidone). The 
same descriptive summary statistics will be presented for the change from baseline. 
PANSS assessments up to 4 days after last dose in Period 3 will be included in any 
descriptive or statistical analysis. 
Additionally, change from Week 4 will be calculated and summarized descriptively by 
treatment arm. 
The change from baseline in PANSS Total Score at week 12 will be analyzed in the 
EAPP3 analysis population using a mixed effects model for repeated measures (MMRM) 
to utilize all the data collected from baseline to Week 12 with consideration of the 
variance-covariance matrix of the repeated measures.  
The model can be expressed as the following: 
                            Yijk =  + bk + dk + rk + sk + i + tj + (t)ij + ijk.     
Therein Yijk denotes the change from baseline in PANSS Total Score of participant k at 
visit j (j =1 (Week 1), 2 (Week 2), 3 (Week 3), 4 (Week 4), 8 (Week 8), 12 (Week 12)),  
denotes the general mean, i is the fixed effect of treatment i (i =0 (placebo followed by 
45 mg RO6889450), 1 (placebo followed by 150 mg RO6889450), 2 (45 mg 
RO6889450), 3 (150 mg RO6889450), 4 (risperidone)), tj is the fixed effect of visit j, and 
bk is the baseline value of the PANSS Total Score on a continuous scale for participant k, 
(t)ij  is the treatment-by-time interaction. Same covariates as for the primary efficacy 
parameter will be include (dk: years since diagnosis of schizophrenia, rk: region, sk: sex). 
The random errors ijk are assumed to be independent across different participants, 
while within each participant an unspecified covariance structure will be modelled. If, 
unexpectedly, this analysis fails to converge, the following structures will be applied, in 
the following order: heterogeneous Toeplitz, first-order ante-dependence, 
heterogeneous compound symmetry, compound symmetry. The Kenward-Roger 
approximation will be used to estimate denominator degrees of freedom. The model-


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based estimates and the 90% CI for the change from baseline for individual treatment 
arms and combined 45 mg RO6889450 (45 mg RO6889450 plus placebo followed by 45 
mg RO6889450) and 150 mg RO6889450 (150 mg RO6889450 plus placebo followed 
by 150 mg RO6889450) treatment treatment arms will be presented.  
Sensitivity analysis: 
Impact of COVID-19: Remote scale administration. Remote scale administration was 
authorized in exceptional cases during 8 weeks out-patient period due to COVID-19 
related restrictions. In case a substantial number (>10%) assessments were done 
remotely or at home a sensitivity analysis will be conducted for which all PANSS 
assessments performed remotely will be excluded and treated as missing data. All other 
aspects of the primary analysis will remain the same. 
AICure data: a sensitivity analysis might be performed using only AICure confirmed drug 
intake to derive the date of last drug intake.  
Subgroup 
PANSS Ttotal Score up to Week 4 and 12 and change from baseline and Week 4 will be 
summarized and analyzed descriptively the subgroup of  
– 
Patients with at least 20% improvement from baseline PANSS total score. 
4.5.3.2 
PANSS Symptom Factor Scores 
PANSS-PSFS and PANSS-NSFS factors scores at Week 4 and Week 12 are secondary 
endpoints and are calculated from PANSS items as displayed in Table 5.  
Table 5 
PANSS Factor Scores 
Score 
Number 
of items 
Items 
Negative Symptom Factor Sum Score (Marder) 
7 
N01-N04, N06, G07, G16 
Positive Symptom Factor Sum Score (Marder) 
8 
P01, P03, P05, P06, N07, G01, 
G09, G12 
[Marder 1997][Marder 1997] 
If any item contributing to its calculation is missing, then the score will be set to missing. 
Higher scores indicate more positive and negative symptoms. Hence negative values for 
change from baseline indicate improvement in symptoms. 
Descriptive summary statistics will be presented for the PANSS PSFS and NSFS factor 
scores as for the PANSS total score. 


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The primary analysis described for the PANSS Total Score at Week 4 and the analysis 
described for the PANSS Total Score at Week 12 will be applied to the PANSS PSFS 
and NSFS. The models will use the same covariates (baseline value of the PANSS Total 
Score on a continuous scale, years since diagnosis of schizophrenia disease at time of 
screening (continuous variable), region (North America, Eastern Europe, and Asia), sex 
(male vs. female)). Additionally, the baseline factor scale value will be added to the 
model. 
Subgroup 
PANSS NS and NSFS up to Week 4 and 12 and change from baseline and Week 4 will 
be summarized and analyzed descriptively the subgroup of  
– 
Patients classified prominently negative as per the algorithm described in 
[Hopkins 2020] at baseline. 
– 
Patients with at least 20% improvement from baseline PANSS total score at the 
Week 4 assessment. 
Supplementary Analysis: Seven-factor model scores  
The PANSS item scores of each subject at each visit will be transformed using the 
uncorrelated PANSS score matrix (UPSM, see Appendix 4), to obtain the scores of 7 
transformed PANSS factors [Hopkins 2018]:  
• 
POS: Positive  
• 
DIS: Disorganized  
• 
NAA: Negative apathy/avolition  
• 
NDE: Negative deficit of expression  
• 
HOS: Hostility  
• 
ANX: Anxiety 
• 
DEP: Depression 
The transformation will be done as follows: 
[PANSS Data](N×30) ∗ [UPSM](30×7) = [Transformed PANSS Factor Data](N×7) 
where 
[PANSS Data](N×30) is a matrix with N PANSS assessments and 30 columns containing 
the scores of 30 PANSS items ordered in the same way as shown in UPSM. 
[UPSM](30×7) is a matrix with 30 rows (one for each PANSS item) and 7 columns (one for 
each of the 7 transformed PANSS factors). 


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[Transformed PANSS Factor Data](N×7) is the transformed matrix with N sets of scores 
for the 7 transformed PANSS factors. 
If any item contributing to its calculation is missing, then the score will be set to missing. 
The primary analysis described for the PANSS Total Score at Week 4 and the analysis 
described for the PANSS Total Score at Week 12 will be applied to the PANSS NAA and 
NDE factors. The models will use the same covariates (baseline value of the PANSS 
Total Score on a continuous scale, years since diagnosis of schizophrenia disease at 
time of screening (continuous variable), region (North America, Eastern Europe, and 
Asia), sex (male vs. female)). Additionally, the baseline factor scale value will be added 
to the model. 
4.5.3.3 
PANSS Total and Symptom Factor Score Responder  
The proportion of participants with at least 20% or 50% improvement from baseline on 
PANSS total score and the proportion of participants with at least 20% or 50% 
improvement from baseline in the PANSS PSFS and NSFS are secondary efficacy 
endpoints.  
The number and percentage of of participants with at least 20%, 30% or 50% 
improvement from baseline on PANSS total score, PSFS and NSFS will be summarized 
descriptively (30% was added as payers are looking more on 30% than on 20%). 
Percentage improvement from baseline (%IfB) is calculated as  
%𝐼𝑓𝐵𝑤4 =
−1∗(𝑃𝐴𝑁𝑆𝑆𝑊𝑒𝑒𝑘 𝑥−𝑃𝐴𝑁𝑆𝑆𝐵𝐿)
𝑃𝐴𝑁𝑆𝑆𝐵𝐿−30 
 𝑥 100 , 
The proportion of participants with at least 20%, 30% or 50% improvement from baseline 
at Week x (x=1, 2, 3, 4, 8, 12) on PANSS total score, PANSS PSFS and NSFS will be 
derived. The numerator will be the number of participants with a Week x PANSS 
assessment and with at least 20%, 30% or 50% improvement from baseline at Week x. 
The denominator will be the number of patients in EAP (Weeks 1- 4) and EAPP3 (Week 
8 and 12), i.e., patients with missing PANSS scores at Week x, e.g., due to drop out, will 
be regarded as having had no improvement: 
𝑟𝑒𝑠𝑝𝑝=
𝑁(%𝐼𝑓𝐵𝑝,𝑤4)
𝑁(𝑎𝑛𝑎𝑙𝑦𝑠𝑖𝑠 𝑝𝑜𝑝𝑢𝑙𝑎𝑡𝑖𝑜𝑛)  , 
where respp is the proportion of participants with at least p% improvement (p=20, 30 or 
50), N(…) is the number of participants fulfilling the criteria in the brackets.  
The proportion of responders will be summarized descriptively for the EAP analysis 
population by timepoint (Week 1, 2, 3 and 4) and the treatment arm to which participants 
were randomized at baseline. 


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The proportion of responders will be summarized descriptively for the EAPP3 analysis 
population by timepoint (Week 8 and 12) and the treatment arm to which participants 
were randomized at baseline and end of Period 2 (5 arms). 
4.5.3.4 
CGI-S and CGI-I 
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 
considers 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 
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). On the scale, the value 0 corresponds to ‘Not 
assessed’, which will be excluded from the analyses. 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 is assessed at Screening (day -7 to -3), Day 1 (Baseline), Day 7, Day 14, 
Day 21, Day 28/EOT Period 2, Day 35, Day 42, Day 49, Day 56, Day 70, Day 84/EOT 
Period 3, Day 112 (FU if patients do not participate in the 36-Week Safety Extension 
Phase). If patients participate in the 36-Week Safety Extension Phase additional 
assessments are done at Week 24 (Day 168), Week 36 (Day 252), Week 48 (Day 336) 
and Week 52 (Day 364, FU).  
All assessments will be assigned to analysis study days according to section 4.5. 
The CGI-S scores and change from baseline will be summarized descriptively. 
The primary analysis described for the PANSS Total Score at Week 4 and the analysis 
described for the PANSS Total Score at Week 12 will be applied to the CGI-S score. The 
models will use the covariates: baseline value of the PANSS Total Score on a 
continuous scale, years since diagnosis of schizophrenia disease at time of screening 
(continuous variable), region (North America, Eastern Europe, and Asia), sex (male vs. 
female). Additionally, the baseline CGI-S score value will be added to the model. 
QSCAT = CGI, QSTEST = CGI02-Severity 
CGI-I  
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 


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from 1 (very much improved) to 7 (very much worse) where the value 0 corresponds to 
‘Not assessed’, which will be excluded from any analyses. The values 1 to 7 might 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.  
The CGI-I is assessed at Day 7, Day 14, Day 21, Day 28/EOT Period 2, Day 35, Day 42, 
Day 49, Day 56, Day 70, Day 84/EOT Period 3, Day 112 (FU if patients do not 
participate in the 36-Week Safety Extension Phase). If patients participate in the 
36-Week Safety Extension Phase additional assessments are done at Week 24 (Day 
168), Week 36 (Day 252), Week 48 (Day 336) and Week 52 (Day 364, FU).   
All assessments will be assigned to analysis study days according to section 4.5. 
The The CGI-I scores will be summarized descriptively for EAP (Period 2) and EAPP3 
(Period 3). There is not baseline value for CGI-I, therefore no change from baseline can 
be derived. 
QSCAT = CGI, QSTEST = CGI02-Improvement 
4.5.3.5 
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 one to two most troubling 
symptoms (MTS) (see Appendix 5). 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.  
CGI-S MTS and CGI-I MTS will be evaluated at the same timepoints than CGI-S and 
CGI-I for the double-blind 4 weeks and 12 weeks treatment periods but will not be 
assessed during the 36-Week Safety Extension Phase. The same time windows for 
assignment to analysis study days as for CGI-S and CGI-I will be used. 
The The CGI-S MTS (MTS1, MTS2, and the average score) and the change from 
baseline will be summarized for EAP (Period 2) and EAPP3 (Period 3). The The CGI-I 
MTS (MTS1, MTS2, and the average score) will be summarized for EAP (Period 2) and 
EAPP3 (Period 3). 
CGI-S MTS: QSCAT = CLINICAL GLOBAL IMPRESSIONS FOR MOST TROUBLING 
SYMPTOMS - SEVERITY SCORE - BP41743 VERSION, QSTEST = CSMT6-CGI-S-
MTS1, CSMT6-CGI-S-MTS2 


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CGI-I MTS: QSCAT = CLINICAL GLOBAL IMPRESSIONS FOR MOST TROUBLING 
SYMPTOMS - IMPROVEMENT SCORE - BP41743 VERSION, CSMT7-CGI-I-MTS1, 
QSTEST = CSMT7-CGI-I-MTS1, CSMT7-CGI-I-MTS2 
 
4.5.3.6 
Readiness for Discharge from Hospital 
The Readiness for Discharge Questionnaire (RDQ) is a tool used to assess inpatients 
with schizophrenia on their readiness for discharge, independent of socio-economic 
factors. The RDQ consists of five items using a 4-level Likert scale to assess 
suicidality/homicidality, control of aggression/impulsivity, activities of daily living, 
medication-taking, and delusions/hallucinations interfering with functioning and global 
status. The sixth item examines the overall clinical state of the patient using the CGI-S 
as an anchor. A final question assesses readiness for discharge. The RDQ has been 
shown to be significantly correlated with PANSS total and factor scores as well as actual 
discharge.  
Readiness for discharge is assessed at Day 7, Day 14, Day 21, Day 28/EOT Period 2. 
Time from first randomized treatment intake to readiness for discharge as assessed by 
the RDQ or actual discharge or censoring if the participant discontinues from study 
Period 2 early is a secondary endpoint. 
The first documented date of readiness for discharge or actual discharge (RD) will be 
used. Data from patients who have not been ready for discharge before or at end of 
Period 2 and for whom the date of actual discharge is not known, either because the 
patient discontinued from the study before being ready for discharge or actually 
discharged or because the date of actual discharge is not known, will be included in the 
analysis as censored observations (censoring date = date of discontinuation/completion 
of Period 2).  
The RDQ is collected by Medavante and mapped to SDTM domain QS (QSCAT= 
RDDQ). A patient is considered ready for discharge if the question “Based on your 
clinical judgment of symptomatic improvement, and independent of social or economic 
factors, is this subject ready for discharge?” (QS.TESTCD=RDDQ108) is answered 
‘YES’.  
The date of actual discharge, if known, is collected on the Hospitalization eCRF form.  
A patient is considered as discontinued from the study Period 2 if there is a record in the 
SDTM DS domain for Period 2 with DSTERM is other than COMPLETED. The date of 
study Period 2 discontinuation is taken from the DS.DSSTDTC. If there are more than 
one records indicating discontinuation, the earliest date is taken. The date of 
discontinuation will be the censoring date for patients who have not been ready for 
discharge and no actual discharge date is available.  


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The Kaplan-Meier method will be used to estimate median time to RD for each treatment 
arm (placebo, RO6889450 45 mg, RO6889450 150 mg, risperidone). The 2-sided log-
rank test, stratified by region (North America, Eastern Europe, and Asia), baseline 
PANSS total (80-95 and 96 and above), duration of the disease (≤ 5 years and > 5 
years), and sex will be used to compare time to RD between each of the RO6889450 
arms and the placebo arm.  
QSCAT = RDDQ 
4.5.4 
Exploratory Endpoints 
 
4.5.4.1 
Sleep, Mood, Well-being, Cognitive Functioning and Treatment 
Expectancy 
To evaluate the changes in Sleep, Mood and Well-being, Cognitive Functioning and 
Treatment Expectancy in total up to 28 questionnaires for assessment of Sleep, Mood, 
Well-being and Cognitive Functioning and Treatment Expectancy will be presented on 
the smartphone as part of AiCure app or the Medavante Virgil platform at selected time 
points that will appear as random to the participant (Appendix 10). Assessments are 
optional. Participants continuing in the 36-Week Safety Extension Phase will have the 
option to continue using this smartphone app for the first 4 weeks (Weeks 13-16).  
Questions are:  
• 
S00101: How did you sleep last night? 
• 
S00102: How are you feeling today? 
• 
S00103: How is your energy level today? 
• 
S00104: How is your concentration and memory today? 
• 
S00105: Do you expect that the study drug will help you? 
• 
S00106: Do you think the drug is helping you? 
• 
S00107: Do you think you were taking placebo or study 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.  
Scales are assessed as follows:  
Baseline: S00101, S00102, S00103, S00104, S00105 


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Day 28: S00101, S00102, S00103, S00104, S00106, S00107 
Days 4, 17, 39, 53, 66, 79:  S00101, S00102, S00103, S00104, S00106 
Days 10, 23, 32, 38, 45, 52, 59, 61, 63, 74, 80: S00101, S00102, S00103, S00104 
QNN-GENERAL - this asks about sleep, mood, memory/concentration and is scheduled 
from 4:00 am-23:59 pm on days 1, 11, 17, 24, 31, 38, 40, 42, 53, 57, 59, 67, 70, 74, 77, 
80, 84, 87. This questionnaire can be completed at any time within the scheduled 
window, regardless of dosing status. 
QNN-GENERAL(POST) - this asks about sleep, mood, memory/concentration and is 
scheduled from 4:00 am-23:59 pm on days 0, 3, 7, 10, 13, 17, 20. As this is a post dose 
questionnaire, it can only be completed after dosing had been completed. 
QNN-GEN&TREAT - this asks about sleep, mood, memory/concentration and also if the 
participant thinks the drug is helping them and is scheduled from 4:00 am-23:59 pm on 
days 4, 18, 32, 45, and 58. This questionnaire can be completed at any time within the 
scheduled window, regardless of dosing status. 
Period 2:  
• 
For analysis and reporting: all patients entering Period 2 will be included as per the 
population definitions in the section 4.1.  
• 
Summaries will use the collection time points as per schedule.  
• 
All analyses will have 4 treatment arms, as per randomization in Period 2. 
• 
The analysis dataset will contain all assessment results.  
 
Period 3: 
• 
For analysis and reporting: all patients entering Period 3 will be included as per the 
population definitions in the section 4.1.  
• 
Summaries will use the collection time points as per schedule.  
• 
All analyses will have 5 treatment arms, per randomization in Period 3: “pbo -> 
ralmi150”, “pbo -> ralmi45”, “risp -> risp”, “ralmi45 -> ralmi45”, and “ralmi150 -> 
ralmi150”. 
• 
The analysis dataset will contain all assessment results. 
 
Long-Term Safety Extension: 
 
Same rules as for Period 3 will be applied.  
 


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The Likert scale scores and change from baseline will be summarized by scheduled 
assessment day for EAP (Period 2) and EAPP3 (Period 3). Question “Do you think you 
were taking placebo or study drug?” will be summarized by treatment arm. Baseline is 
scheduled Day 1. 
QSCAT=LIKERT SCALE ASSESSMENT – BP41743 VERSION.  
4.5.4.2 
Recovering Quality of Life (ReQoL-20) 
ReQoL-20 measures mental health service users’ own perspectives of ‘recovery’ and 
quality of life and consist of 20 mental health questions. The scoring options of the items 
are: None of the time, Only occasionally, Sometimes, Often, and Most or all of the time. 
The assessment will not be performed in non-English speaking countries without 
linguistic validated translation. This applies also to patients who do not speak English as 
a first language but are living in an English-speaking country. Validated translations of 
the ReQoL-20 were available in other study languages. 
The positively worded questions are: Q2, Q4, Q5, Q7, Q8, Q10, Q11, Q15 and Q19. 
They are scored from 0 to 4. Example: 
The negatively worded questions are: Q1, Q3, Q6, Q9, Q12, Q13, Q14, Q16, Q17, Q18 
and Q20. The scores are reversed for the negatively worded items which are scored 
from 4 to 0. Example: 
 
The ReQoL-20 sum score will be calculated from the numbers for questions 1-20. The 
minimum score is 0 and the maximum is 80, where 0 indicates poorest quality of life and 
80 indicates highest quality of life. If a maximum of two questions are unanswered in the 
whole measure, the mean value of the other responses is used to fill the gap to calculate 
the overall index. If three or more questions are unanswered, then the overall index 
score cannot be calculated. 
The ReQoL-20 is assessed at Day 1 (Baseline), Day 14, Day 28/EOT Period 2, Day 56, 
Day 84/EOT Period 3, Day 112 (FU if patients do not participate in the 36-Week Safety 
Extension Phase). If patients participate in the 36-Week Safety Extension Phase 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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additional assessments are done at Week 24 (Day 168), Week 36 (Day 252), Week 48 
(Day 336) and Week 52 (Day 364, FU).  
All assessments will be assigned to analysis study days according to section 4.5. 
The change from baseline in ReQoL-20 sum scores and the change from baseline will 
be summarized for EAP (Period 2) and EAPP3 (Period 3). Higher values indicate better 
quality of life, hence positive values for change from baseline indicate improvement. 
The proportion of participants with at least 10 points improvement from baseline in 
ReQoL-20 at Week 4 and Week 12, respectively, will be derived. The numerator will be 
the number of participants with a Week 4 or Week 12 ReQoL-20 assessment, 
respectively, and with at least 10 points improvement from baseline in sum score at 
Week 4 or Week 12, respectively. The denominator will be the number of patients in 
EAP (Week 4) and EAPP3 (Week 12), i.e. patients with missing data will be regarded as 
having had no improvement: 
𝑖𝑚𝑝𝑟=
𝑁(10𝑝𝑡𝑠 𝑖𝑚𝑝𝑟𝑜𝑣𝑒𝑚𝑒𝑛𝑡)
𝑁(𝑎𝑛𝑎𝑙𝑦𝑠𝑖𝑠 𝑝𝑜𝑝𝑢𝑙𝑎𝑡𝑖𝑜𝑛)  , 
where impr is the proportion of participants with at least 10 points improvement, N(…) is 
the number of participants fulfilling the criteria in the brackets.  
The proportion of of participants with at least 10 points improvement in ReQoL-20 sum 
score will be summarized descriptively for the EAP analysis population by timepoint (Day 
1, 14, and 28) and the treatment arm to which participants were randomized at baseline. 
The proportion will be summarized descriptively for the EAPP3 analysis population by 
timepoint (Day 56 and 84) and the treatment arm to which participants were randomized 
at baseline and end of Period 2 (5 arms). 
Time from first randomized treatment intake to 10 points improvement in ReQoL-20 sum 
score or censoring if the participant discontinues the study early will be caluclated. 
The first documented date of 10 points improvement in ReQoL-20 sum score will be 
used. Data from patients for whom no 10 points improvement (or more) is documented 
will be included in the analysis as censored observations (censoring date = date of last 
ReQoL-20 assessment).  
The Kaplan-Meier method will be used to estimate median time to 10 points 
improvement in ReQoL-20 sum score for each treatment arm (RO6889450 45 mg, 
RO6889450 150 mg, placebo, risperidone).  
QSCAT = REQOL-20 


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4.5.4.3 
Patient Global Impression-Change (PGI-C) 
The generic Global Impression is a measure commonly used in clinical trials to provide 
concise information on overall health state compared to the previously assessed 
protocol specified time point. The change component is intended as a measure of 
change in health state and can be adapted for participant selfassessment (PGI-C). A 
7-point participant-based (PGI-C) global impression of change will be employed. 
PGI-C: 1 = Very much improved; 2 = Much improved; 3 = Somewhat improved; 4 = No 
change; 5 = Somewhat worse; 6 = Much worse; 7 = Very much worse.  
PGI-C is assessed at Day 7, Day 14, Day 21, Day 28/EOT Period 2, Day 42, Day 56, 
Day 84/EOT Period 3, Day 112 (FU if patients do not participate in the 36-Week Safety 
Extension Phase).  
All assessments will be assigned to analysis study days according to section 4.5. 
PGI-C will be summarized for EAP (Period 2) and EAPP3 (Period 3). Higher values 
indicate worsening, hence negative values for change from baseline indicate 
improvement. 
QSCAT = PGI 
4.5.4.4 
Inflammatory Biomarkers and Cognitive Subtype 
To assess the relationship between the levels of inflammatory biomarkers and cognitive 
subtype.  
A dedicated exploratory biomarker assessment is performed to investigate the role of the 
immune system in the study population and assess the potential predictive value of 
these markers to the ralmitaront response. 
Analysis will be described in separate document. 
4.5.4.5 
Calgary Depression Scale for Schizophrenia (CDSS) 
The CDSS is a scale used to assess the level of depression in schizophrenia (assess 
depressive symptoms separate from positive, negative and extrapyramidal symptoms). 
The instrument has nine items with a 4-point Likert scale (ranging from 0 = absent, 1 = 
mild, 2 = moderate, 3 = severe) (see Appendix 12). The CDSS is applied by the local 
investigator.  
CDSS is assessed at Day 1 (Baseline), Day 28/EOT Period 2, Day 84/EOT Period 3 and 
Day 112 (FU if patients do not participate in the 36-Week Safety Extension Phase). If 
patients participate in the 36-Week Safety Extension Phase additional assessments are 
done at Week 24 (Day 168), Week 36 (Day 252), Week 48 (Day 336) and Week 52 (Day 
364, FU).  


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All assessments will be assigned to analysis study days according to section 4.5. 
The total score is calculated by the sum of all 9 item scores. Higher scores indicate 
worse symptoms. Missing items will be replaced by the average of the remaining items. 
CDSS total score and change from baseline will be summarized for EAP (Period 2) and 
EAPP3 (Period 3). Higher values indicate a higher level of depression, hence negative 
values for change from baseline indicate improvement. 
QSCAT = CDSS 
4.5.4.6 
Scale to Assess Unawareness of Mental Disorder (SUMD-9) 
The Scale to Assess Unawareness of Mental Disorder (SUMD) short form is a 9-item 
clinician-reported outcome designed to measure current awareness of mental illness 
(see Appendix 13). The instrument consists of three general items and six symptom 
items. Each item is scored on a 3-point Likert scale, with following response options: “not 
applicable” (0), “aware” (1), “somewhat/unaware” (2) and “severely unaware” (3), hence 
higher scores indicating poorer awareness.  
SUMD-9 is assessed at Day 1 (Baseline), Day 28/EOT Period 2, Day 84/EOT Period 3 
and Day 112 (FU if patients do not participate in the 36-Week Safety Extension Phase).  
All assessments will be assigned to analysis study days according to section 4.5. 
To evaluate the changes in the level of insight into mental disorder the total sum score 
over all 9 items and the subscores Awareness of Disease (sum of items 1-3), Awareness 
of Positive Symptoms (sum of items 4-6) and Awareness of Negative Symptoms (sum of 
items 7-9) will be calculated and summarized for EAP (Period 2) and EAPP3 (Period 3). 
Higher values indicate indicating poorer awareness, hence negative values for change 
from baseline indicate improvement. 
QSCAT = SUMD-9 
4.5.4.7 
VAGUS insight into Psychosis Scale 
The VAGUS is the insight into psychosis scale with both self-report and clinician-rated 
versions. The assessment will not be performed in non-English speaking countries 
without linguistic validated translation. This applies also to patients who do not speak 
English as a first language but are living in an English-speaking country. Validated 
translations of VAGUS-SR and VAGUS-CR were available in other study languages. 
VAGUS Self-reported (VAGUS-SR) 
The VAGUS-SR is a 10-item patient reported outcome measure designed to measure 
clinical insight into psychosis (Appendix 14). Each item utilizes a 10-point Likert scale 
ranging from “strongly disagree” (0) to “strongly agree” (10). Four sub scores, Illness 


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Awareness (2 items), Symptom Attribution (4 items), Awareness of Need for Treatment 
(3 items) and Awareness of Negative Consequences (1 item) are generated form this 
instrument. Items 2, 3, 7 and 8 are reverse scored, hence 10 minus the actual score. 
Each sub score is summed and then divided by the number of responses. The total 
score is the sum of scores divided by 4 (Appendix 15). 
VAGUS Clinician-reported (VAGUS-CR) 
VAGUS-CR is a 5-item clinician reported outcome measure designed to measure clinical 
insight into psychosis (Appendix 16). Each item utilizes a 10-point Likert scale ranging 
from “strongly disagree” (0) to “strongly agree” (10). Four sub scores, Illness Awareness 
(1 item), Symptom Attribution (2 items), Awareness of Need for Treatment (1 items) and 
Awareness of Negative Consequences (1 item) are generated by this instrument. Item 4 
is reverse scored, hence 10 minus the actual score. Each sub score is summed and 
then divided by the number of responses. The total score is the sum of scores divided by 
4 (Appendix 17).  
VAGUS-SR and VAGUS-CR are assessed at the same time points as SUMD-9. All 
assessments will be assigned to analysis study days according to section 4.5. 
To evaluate the changes in the level of insight into mental disorder the VAGUS-SR and 
VAGUS-CR total scores as provided by the vendor and change from baseline will be 
summarized for EAP (Period 2) and EAPP3 (Period 3). Higher scores indicate more 
insight into psychosis, hence positive values for change from baseline indicate 
improvement. 
QSCAT = VAGUS-SR and VAGUS-CR 
4.5.4.8 
Beck Cognitive Insight Scale (BCIS) 
The BCIS is a 15-item patient-reported outcome. The instrument was developed to 
evaluate patients’ self-reflectiveness and their overconfidence in their interpretations of 
their experiences. It encompasses two sub scales covering self-reflectiveness (9 items) 
and self-certainty (6 items). Each item utilizes a 4-point scale ranging from “do not agree 
at all” (0) to “agree completely” (3). Items 1, 3, 4, 5, 6, 8, 12, 14, and 15 are summed to 
form the self-reflectiveness score, whereas items 2, 7, 9, 10, 11, and 13 are summed to 
form the self-certainty score. A composite index of the BCIS reflecting cognitive insight is 
calculated by subtracting the score for the self-certainty scale from that of the self-
reflectiveness scale, see Appendix 18. 
BCIS is assessed at the same time points as SUMD-9. All assessments will be assigned 
to analysis study days according to section 4.5. 
To evaluate the changes in the level of insight into mental disorder the BCIS sub scores 
as provided by the vendor and the calculated composite score and change from baseline 


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will be summarized for EAP (Period 2) and EAPP3 (Period 3). Higher self-reflectiveness 
scores are better, hence higher values for change from baseline indicate improvement. 
Higher self-certainty scores are worse, hence negative values for change from baseline 
indicate improvement. Higher composite scores indicate more cognitive insight, hence 
positive values for change from baseline indicate improvement.  
QSCAT = BCIS 
4.5.4.9 
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 6. The higher the total Fagerstrom score, the more 
intense is the participant’s physical dependence on nicotine.  
FTND is assessed at screening, Day 1 (baseline), Day 14, Day 28/EOT Period 2, Day 
56, Day 84/EOT Period 3 and Day 112 (FU).  
All assessments will be assigned to analysis study days according to section 4.5. 
In general, if at least one item score is missing or not ratable, the sum score will be set 
to missing. 
The FTND items and sum score and the change from baseline in items and sum score 
will be summarized by assessment visit and randomized treatment arm. Mean change 
from baseline in items and sum score and 90% calculated confidence intervals will be 
displayed by time for subgroups of trough concentration at week 2 (cut by Q1, median, 
Q4) including patients who were smokers at baseline. 
QSCAT = FTND 
4.5.4.10 
Ecological Momentary Assessment (EMA) 
To explore the effects of RO6889450 on levels and patterns of social and general 
activity and psychotic symptoms. 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. EMA will 
be used to assess the participants’ functioning associated to positive and negative 
symptoms in schizophrenia through the use of smartphones. A pop-up visualization will 


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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, see 
Appendix 20. EMA assessment will not be performed in Japan.  
All assessments will be assigned to analysis time windows according to the following 
table. 
Table 6 
EMA Time Windows 
Analysis 
Window 
Label  
Week 4 
Week 5 
Week 6 
… 
Week 12 
… 
Week 16 
 
EMA 
Study 
Day 
22 to Last 
assessment 
before first 
dose in 
Period 3(1) 
First 
assessment 
after first 
dose in 
Period 3(1) 
to 35 
36 to 42 
… (2) 
119 to 126 
… (2) 
106 to 112 
(1) Latest assessment prior to intake of first study medication. Use date and time, if available. 
(2) Go on in 7 days steps. 
• 
For analysis and reporting: all patients entering Period 3 will be included as per the 
population definitions in the section 4.1.  
• 
Summaries will use the time windows as above and analysis flags as defined below.  
• 
Analyses will have 5 treatment arms, per randomization in Period 3: “pbo -> 
ralmi150”, “pbo -> ralmi45”, “risp -> risp”, “ralmi45 -> ralmi45”, and “ralmi150 -> 
ralmi150”. 
• 
Analysis: 
– ANAFLAG = ‘Y’ if (1) the assessment is in time window AND (2) the assessment 
is within 4 days after the last dose of study drug. 
– Percentage of answers based on total questions per patient and time window will 
be calculated. Individual percentages per time window, treatment arm and 
question will be summarized (mean, median, etc). 
As a starting point, questions 1 and 2 will be combined into a patient status (home alone, 
home with someone, away) and the percentage of each status per patient and time 
window will be calculated. The patient percentages will be summarized per time window 
and treatment group for Period2 and Period 3.  
Futher analyses may be conducted depending on the number of patients participating in 
EMA questions. 
QSCAT = EMA BP41743 VERSION 


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4.5.4.11 
Feedback questions 
To assess patients’ perception of changes relative to their condition and relevance and 
ease of understanding of the PRO instruments used in the study patients are asked two 
sets of questions once at the end of hospitalization (Week 4 visit). In the first set, 
patients are asked if they have experienced changes in relation to their condition. If they 
respond yes, they will be asked to further describe this change. Responses will be 
captured as free text and closed questions. 
In the second set of questions, patients are asked to provide their feedback on the 
following PRO instruments (ReQoL-20, BCIS, VAGUS, SUMD-9) from an ease of 
understanding and relevance (ReQoL-20) perspective. These question uses a 5-point 
Likert scale ranging from “strongly agree” to “strongly disagree” plus a “no opinion” 
option. The assessment should take approximately 5-10 minutes to administer.  
The assessment will not be performed in non-English speaking countries without 
linguistic validated translation. This applies also to patients who do not speak English as 
a first language but are living in an English-speaking country. Validated translations of 
the ReQoL-20 were available in other study languages. 
Non-freetext questions will be summarized by randomized treatment arm. 
QSCAT=BP4173 FEEDBACK QUESTIONNAIRE 
4.5.4.12 
Premorbid Adjustment Scale (PAS) 
Premorbid Adjustment Scale (PAS) assesses functioning across four developmental 
stages: childhood (up to 11 years), early adolescence (12–15 years), late adolescence 
(16–18 years) and adulthood (19 years and beyond); and five domains: sociability/ 
withdrawal, peer relationships, scholastic performance, adaptation to school and socio-
sexual functioning, in addition 9 items general scale that assesses, the level of best 
functioning achieved by the individual, as well as items related to characteristics of 
illness onset, energy level, education and independence (see Appendix 11). 
PAS is administered by raters and assesses life periods up to 1 year before the onset of 
psychotic illness and consists of up to 17 items (depending on disease onset), and each 
item is assessed on a 0-6 Likert scale, where lower numbers indicate normal, healthy 
functioning and higher numbers suggest pathologic development.  
The PAS is administered as part of Day 14 assessments. 
The ratings received for each item in a section are summed and expressed as total 
score divided by the possible score. The possible score indicates the highest score 
obtainable by adding the maximum score for all items completed. Thus, if a subject 
receives ratings of 2, 3, 3, and 2 for the four items in the childhood section, the total 
score for that section is 10.  The possible score is 24 (6+6+6+6), and the total score 


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divided by the possible score is .42. When no information is available for a particular 
item, the item is not scored. The score for the section then is expressed as total 
score/possible score for the items rated. For example, if only three out of four of the 
items in the preceding example are scored, possible score becomes 18 (6+6+6) instead 
of 24. If the patient received the same ratings as in the previous example, except for one 
undatable last item, the total section score would be 8 (2+3+3). In this case, total 
score/possible score is 8/18 or .44. 
An overall score for the whole scale will be calculated by averaging the subscale scores 
for all the subscales rated for the patient. An average is preferred to a total score in 
order to avoid bias that would occur in cases in which the sum of a few highly scored 
subscales would result in the same score as the sum of several moderately or low-
scored subscales, when age of onset of illness or lack of information leads to some 
subscales being left out. 
The PAS total average score wil be summarized for the EAP by treatment group. 
To evaluate relationship between the premorbid functioning and treatment response, 
PANSS Total Score up to Week 4 and change from baseline will be summarized and 
analyzed descriptively by subgroups defined by the median total average PAS score in 
the EAP at baseline.  
The primary analysis for the PANSS Total Score at Week 4 and the analysis for the 
PANSS Total Score at Week 12 will be applied to the subgroups. 
QSCAT = PAS-SI 
4.5.4.13 
PANSS, CGI-S and CGI-I at Week 48 
Changes from baseline in the PANSS total and factor scores, CGI-S and CGI-I at Week 
48. Analysis by the following groups: risperidone, RO6889450 45 mg, RO6889450 150 
mg, placebo/ RO6889450 45 mg, placebo/RO6889450 150 mg 
To observe the effect of treatment with two doses of RO6889450 (45 mg and 150 mg) 
up to 48 weeks. 
4.5.5 
Additional Analyses 
4.5.5.1 
Local vs Central PANSS Assessment 
Analysis of local versus central PANSS assessment for Japanese patients will be 
described in a separate document. 
4.5.5.2 
WASI-II/WAIS-IV 
The Wechsler Abbreviated Scale of Intelligence, Second Edition (WASI-II) is an 
intelligence test designed to estimate IQ in individuals. The WASI-II will be administered 
according to standard instructions, as part of Day 14 assessments. 


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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 assessment will not be performed in non-English speaking countries without 
linguistic validated translation. This applies also to patients who do not speak English as 
a first language but are living in an English-speaking country. If validated translations 
become available, they may be used. In Japan, the Wechsler Adult Intelligence Scale – 
Fourth edition (WAIS-IV) will be used as an equivalent scale. 
The following composite scores of the WASI-II will be summarized by randomized 
treatment group in the EAP: VCI, PRI, FSIQ-2 and FSIQ-4. 
QSCAT=WASI-E2, ZDCAT = WAIS-E4 US ENGLISH VERSION 
4.5.5.3 
WRAT4/JART 
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, 
as part of Day 14 assessments. The age-corrected standard score obtained will be used 
as pre-morbid IQ estimate. The assessment will not be performed in non-English 
speaking countries without linguistic validated translation. This applies also to patients 
who do not speak English as a first language but are living in an English-speaking 
country. If validated translations become available, they may be used. Equivalent scales 
may be used, if available. In Japan, the Japanese Adult Reading Test (JART) will be 
used as an equivalent scale. 
The Word Reading Standard Score of the WRAT4 will be summarized by treatment 
group in the EAP. 
QSCAT = WRAT4, ZDCAT = JART 25 
4.5.5.4 
PANSS IC 
The PANSS-Informant Checklist (PANSS-IC) is an informant questionnaire designed to 
supplement the PANSS by collecting information about the participant’s symptoms and 
behaviors during the past seven days from the informant. 
The information is meant to be gathered from an informant such as a caregiver or from a 
treating clinician or site personnel during the inpatient stay who has had significant 
contact with the participant during the reference period. During the interview, the 
informant will be asked for their observations about the participant’s symptoms and 


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behaviors, this information may be used to inform ratings of fourteen PANSS items (i.e., 
Positive = P1, P3, P4, P5, P6, P7; Negative = N2, N4 and General = G5-G6, G7, G8, 
G14, G16). For each item, it will be assessed if the symptom is present or not, 
subsequent questions will then assess the frequency, severity or interference of the 
symptom. Collecting informant data is particularly helpful for subjects who are unwilling 
or unable to accurately report their symptoms during the interview. The checklist does 
not provide any direct study data but is simply used to assist the independent rater in 
rating the PANSS. However, the questions informing negative items might be scored as 
displayed in Appendix 20. and summarized by treatment group and time interval. 
RSCAT = PANSS-IC V2019 
4.6 
PHARMACOKINETIC AND EXPOSURE-RESPONSE ANALYSES 
The objective of the PK review is to determine the dose-exposure relationship of 
RO6889450 and if indicated explore the relationship between plasma exposure of 
RO6889450 and effect or exposure of RO6889450 or M5 and safety signals.  
Plasma concentrations of RO6889450 and, if applicable, RO6889450-derived 
metabolite(s) 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.   
Population PK analyses using nonlinear mixed effects modelling will be performed to 
analyze the sparse dose-plasma concentration-time data of RO6889450 If deemed 
necessary, data may be pooled with data from other studies with RO6889450 (and 
derived metabolite(s) if available and applicable) in order to improve the parameter 
estimates of the model. 
AUCss, Cmax of RO6889450 and, if feasible, of RO6889450-derived metabolite(s) at week 
4, as well as other PK parameter as appropriate will be estimated.  
Population PK and exposure-response described in the next section will be performed 
by the pharmacometrician.  
4.6.1 
Pharmacodynamic Analyses 
An exploratory graphical analysis of the relationship between pharmacokinetic exposure 
and efficacy based on the pharmacokinetic population will be performed by the 
pharmacometrician. The analysis will initially focus on the primary endpoint PANSS Total 
score up to 4 weeks, but other (secondary) efficacy parameters may also be investigated 
(e.g. PANSS-PSFS and PANSS-NSFS) as approporiate. In addition, the data up to 12 
weeks treatment will also be evaluated.  
For the exploratory graphical exposure-efficacy analyses, (model based) Cave,ss  will be 
used either as a continuous covariate or as grouping variable. Other exposure metrics, 


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such as cumulative Cave may also be investigated. Graphical displays will include (but 
are not limited to) efficacy outcome measure vs. exposure by visit, and efficacy outcome 
measure vs. time, with trend lines split by exposure category (e.g. placebo, Low, 
Medium and High Tertile of Cave,ss). The effect of subpopulations (e.g., sex, region) 
and PANSS Total score at baseline, will also be investigated. 
If warranted after review of initial graphical displays, a model-based approach may be 
considered to quantify the exposure-effect relationship for PANSS Total (or other 
efficacy metric as indicated by the graphical analysis).  
If appropriate based on the initial read-out of the data, an exposure-response anlaysis 
may also be performed for identified safety signals as well as investigating the risk of 
drop out from the trial. 
Results from pharmacometric analyses may be reported in a document separate from 
the clinical study report. 
4.7 
SAFETY ANALYSES 
The safety analysis will be conducted to compare the safety and the tolerability of 
treatment with RO6889450 (45mg, 150 mg), or risperidone with placebo. Safety 
assessments included 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. 
If not otherwise stated, all safety data will be explored for the initial 4 weeks double-blind 
treatment period (period 2) and, as available, separately for the 8 weeks double-blind 
period (period 3) and the 48 weeks long-term safety extension period.  
Four treatment groups will be analysed for period 2: 
– 
placebo,  
– RO6889450 45mg,  
– RO6889450 150mg, 
– 
risperidone.   
Five treatment groups will be analysed in period 3 and the 48 weeks long-term safety 
extension:  
– 
placebo-> RO6889450 45mg,  
– 
placebo-> RO6889450 150mg,  


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– RO6889450 45mg,  
– RO6889450 150mg. 
– 
Risperidone 
4.7.1 
Definition of Time Windows 
Table 7 
Analysis Time Windows for Double Blind Treatment Period 2 
Applicable to all patients 
Analysis Window 
Label  
Baseline 
Day 3 
Day 7 
Day 14 
Day 21 
Day 28 
Planned Study Day 
1 
3 
7 
14 
21 
28 
C-SSRS 
Study Day 
 
≤ 1(1)  
NA 
2 to 10(2) 
11 to 17 
18 to 24 
≥ 25(3) 
Laboratory, Body Weight, ESRS-A 
Study Day 
 
≤ 1(1)  
NA 
NA 
2 to 21 
NA 
≥ 22(3) 
ECG 
Study Day 
 
≤ 1(1) 
NA 
2 to 10(2) 
2 to 21 
NA 
≥ 22(3) 
Vital Signs 
Study Day 
 
≤ 1(1) 
2 to 5 
6 to 10(2) 
11 to 17 
18 to 24 
≥ 25(3) 
(1) Latest assessment prior to intake of first study medication. Use date and time, if available. 
(2) May include assessments on day 1 if AFTER time of first study medication. 
(3) Includes any assessments on that study day or later and prior to the date of first dose in the 
double blind extension treatment period (Period 3). 
• 
For analysis and reporting: all patients entering Period 2 will be included as per the 
population definitions in the section 4.1.  
• 
Summaries will use the time windows as above and analysis flags as defined below 
and only include the time windows shown in the table.  Hence summaries will not 
include “screening” or “follow-up”.  
• 
Listings will include the analysis window label as above as well as the label which 
was assigned in the database.  All values, also duplicates per window, will be 
included in listings.  
• 
All analyses will have 4 treatment arms, as per randomization in Period 2. 
• 
The analysis dataset will contain all assessment results. An analysis flag will be 
created to indicate the values that will enter the respective stats analysis and 
associated summary tables:  
– ANAFLAG = ‘Y’ if the assessment (1) is in time window AND (2) the assessment 
is within 4 days after the last dose of study drug. If more than one assessment is 
in the same time window after applying (1) and (2) the assessment that is closest 
to planned study day (see above) will be selected. 
 


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Table 8 
Analysis Time Windows for Double Blind Extension Period 3 
Applicable to all patients randomized to Period 3 
Analysis 
Window 
Label  
Period 3 
Baseline 
Day 35 
Day 42 
Day 49 
Day 56 
Day 70 
Day 84 
Laboratory, ESRS-A 
Study Day 
Last 
assessment 
before first 
dose in 
Period 3(2)  
NA 
NA 
NA 
First 
assessmen
t after first 
dose in 
Period 3(2) 
to 70 
NA 
≥70(2) 
C-SSRS 
Study Day 
Last 
assessment 
before first 
dose in 
Period 3(1) 
First 
assessme
nt after 
first dose 
in Period 
3(1) to 38 
39 to 45 
46 to 52 
53 to 63 
64 to 77 
≥78(2) 
ECG 
Study Day 
Last 
assessment 
before first 
dose in 
Period 3(1) 
NA 
First 
assess
ment 
after 
first 
dose in 
Period 
3(2) to 49 
NA 
50 to 63 
NA 
≥64(2) 
Vital Signs, Body Weight 
Study Day 
Last 
assessment 
before first 
dose in 
Period 3(1) 
NA 
First 
assess
ment 
after 
first 
dose in 
Period 
3(2) to 49 
NA 
50 to 63 
64 to 77 
≥78(2) 
(1) Use date and time, if available. 
(2) Includes any assessments on that study day or later and either (1) within 4 days after last dose 
for patients not entering the long-term safety extension period or (2) up to study day 126 for patients 
entering the long-term safety extension period. 
• 
For analysis and reporting: all patients entering Period 3 will be included as per the 
population definitions in the section 4.1.  
• 
The analysis dataset will contain analysis flag as defined in Table 7Fehler! 
Verweisquelle konnte nicht gefunden werden..  
• 
All analyses will have 5 treatment arms, per randomization in Period 3: “pbo -> 
ralmi150”, “pbo -> ralmi45”, “risp -> risp”, “ralmi45 -> ralmi45”, and “ralmi150 -> 
ralmi150”. 
• 
Separate listings, summary tables and analyses will be created for these patients. 
 


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Table 9 
Analysis Time Windows for Long-Term Safety Extension 
Applicable to all patients entering the Long-Term Safety Extension 
 
Analysis Window Label  
Week 24 
Week 36 
Week 48 
Laboratory Values, ECG, Vital Signs, Body Weight, C-SSRS, ESRS-A 
Study Day 
 
127 to 210 
211 to 294 
≥295(1) 
(1) As drug intake is not recorded for the long-term extension study, the day of last dose of study 
drug intake cannot be assessed. Therefore, any assessments reported with the Follow-up folder 
will not be included. 
 
Separate listings, summary tables and analyses will be created for these patients. 
 
4.7.2 
Exposure of Study Medication 
Exposure of randomized study medication will be summarized for the initial 4 weeks 
double-blind treatment period (period 2) and, as available, for the 8 weeks double-blind 
period (period 3): 
• 
Duration of treatment (days) in period 2, which will be calculated from the first day of 
randomized double-blind study medication intake as recorded in the eCRF to the last 
day of study medication intake in the initial 4 weeks double-blind treatment period 
(period 2) as recorded in the eCRF, i.e., last dosing date in period 2 minus first 
dosing date inpriod 2 plus 1 day. 
• 
Duration of treatment (days) in period 3, which will be calculated from the first day of 
randomized double-blind study medication intake after end of period 3 as recorded in 
the AiCure app to the last day of dosing as recorded in the AiCure app, i.e., last 
dosing date in period 3 minus first dosing date in period 3 plus 1 day. 
• 
Number of doses over the intital 4-weeks double-blind treatment period (period 2) 
derived from the number of days at which randomized double-blind treatment was 
taken as recorded in the eCRF. 
• 
Number of doses over the period 3 derived from the number of days at which 
randomized double-blind treatment was taken as recorded in the AiCure app. 
• 
Total cumulative dose (mg) over the intital 4-weeks double-blind treatment period 
(period 2) as recorded in the eCRF. 
• 
Total cumulative dose (mg) over period 3 as recorded in the AiCure app. 
• 
Extent of compliance with randomized double-blind RO6889450 (%). Treatment 
compliance for each participant will be calculated as cumulative actually taken dose 
during the intital 4-weeks double-blind treatment period (period 2) divided by the 
 
 
 
 
 
 


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planned dose. The planned dose is the cumulative planned dose over 28 days, i.e., 
150mg×28 days or 45mg×28 days. 
 
4.7.3 
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 arm with numbers and percentage of 
participants experiencing Aes.  
AEs will be summarized separately 
(1) for the 4-weeks double-blind treatment period (Period 2) including all patients 
who received at least one study medication in Period 2 and Aes from day of first 
onset of study medication in Period 2 until the day before first study medication 
intake in the 8-weeks double-blind extension treatment period (Period 3) if the 
patient received study medication in Period 3, or until the last day of study 
medication intake in Period 2 plus 4 days if the patient did not receive study 
medication in Period 3. Aes will be displayed by the four randomized treatment 
groups (placebo, RO6889450 45 mg, RO6889450 150 mg, risperidone), 
(2) for Period 3 including all patients who received at least one study medication in 
Period 3 and Aes from the first day of study medication intake in Period 3 until 
the last day of study medication intake in Period 3 plus 4 days. Aes will be 
displayed by the two placebo/ RO6889450 groups (placebo/45 mg RO6889450, 
placebo/150 mg RO6889450) and the three randomized active treatment arms 
(RO6889450 45 mg, RO6889450 150 mg, risperidone), 
(3) combined for Period 2 and Period 3 including all patients who received at least 
one active study medication (RO6889450 45 mg, RO6889450 150 mg, 
risperidone) in Period 2 or Period 3. Patients who switched from placebo to 
RO6889450 45 mg or RO6889450 150 mg will be added to the respective 
treatment arm. Aes from the first day of active study medication intake in Period 
2 or Period 3 until the last day of study medication intake in Period 3 plus 4 days. 
For patients who switched from placebo to RO6889450 45 mg or RO6889450 
150 mg only Aes from the day of first RO6889450 will be included. Aes will be 
displayed by the three active treatment arms (RO6889450 45 mg, RO6889450 
150 mg, risperidone),  
(4) for the 36-Week Safety Extension Phase including all all patients who received at 
least one active study medication (RO6889450 45 mg, RO6889450 150 mg, 
risperidone) in the 36-Week Safety Extension Phase. Aes will be displayed by 
the two placebo/ RO6889450 groups (placebo/45 mg RO6889450, placebo/150 


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mg RO6889450) and the three randomized active treatment arms (RO6889450 
45 mg, RO6889450 150 mg, risperidone), 
(5)  for the follow-up period including all patients with at least one dose of study 
medication in Period 2 or Period 3 or the 36-Week Safety Extension Phase and 
Aes from day 5 after the last treatment until 28 days later. Aes will be displayed 
by 6 arms: placebo (only), placebo/45 mg RO6889450, placebo/150 mg 
RO6889450, RO6889450 45 mg, RO6889450 150 mg, risperidone. 
Table 10 
Adverse Event Time Windows 
Study Period 
 
Patients Included 
Time Window 
Follow-up 
All treated  
Day 5 after the last treatment until 
28 days later 
36-Week Safety Extension 
Phase 
All treated in the 36-
Week Safety 
Extension Phase 
First day of study medication intake 
in the in the 36-Week Safety 
Extension Phase until the last day 
of study medication intake in in the 
36-Week Safety Extension Phase 
plus 4 days. 
Period 3 double-blind 8 weeks 
extension treatment period 
All treated in Period 3 
First day of study medication intake 
in Period 3 until the last day of 
study medication intake in Period 3 
plus 4 days. 
Period 2 double-blind 4 weeks 
treatment period 
All treated in Period 2 
Day of first onset of study drug in 
Period 2 until the day before first 
study medication intake in Period 3, 
or until the last day of study 
medication intake in Period 2 plus 4 
days if the was patient did receive 
treatment in Period 3. 
Baseline Sign and Symptoms 
All treated 
Before first study drug intake 
 
For output templates please refer to Appendix 7. 
Intensity and relationship to study treatment will be summarized 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.  


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All SAEs and Aes that led to death, and Aes that led to withdrawal of study treatment will 
also be summarized by treatment arm.  
Abuse liability Aes will be summarized. MedDRA Baskets and/or preferred terms to be 
included in that summary are provided in Appendix 8  
AE summaries by study periods will be produced as displayed in the following table: 
Type of AE summary 
Period 2 
Period 3 
Period 2+3 
FU 
AE summary 
x 
x 
x 
x 
SAE summary 
x 
x 
- 
- 
By relationship 
x 
x 
- 
- 
By greatest intensity 
x 
x 
- 
- 
Leading to discontinuation of 
treatment 
x 
x 
- 
- 
Leading to interruption of 
treatment 
x 
x 
- 
- 
Abuse liability Aes 
x 
x 
- 
- 
 
The following rules will be applied for AEs with missing onset or end dates: 
• 
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. 
4.7.4 
Clinical Laboratory Tests 
A central laboratory designated by the Sponsor will be used for all laboratory testing 
required during the study except for dipstick urinalysis, urine dipstick alcohol test, drugs 
of abuse, urine pregnancy test and COVID-19 test (when not performed centrally). The 
central laboratory should be used for all laboratory testing whenever possible (including 
unscheduled and follow-up laboratory testing, if needed).   


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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.  
For this IA only the following laboratory parameters will be analysed: 
• 
Lipids: cholesterol, low-density lipoproteins (LDL) cholesterol, high-density 
lipoproteins (HDL) cholesterol, triglycerides 
• 
Clinical chemistry: blood glucose (fasting), HbA1c, ALT, ALP, AST, CRP, 
creatinine, total and direct bilirubin 
Outputs for the following laboratory parameters will be prepared for review in case of 
need: 
• 
Clincial chemistry: sodium, potassium, chloride, bicarbonate, fasting glucose, 
glycated hemoglobin, urea, protein, albumin, phosphate calcium, urate, lactate 
dehydrogenase. 
• 
Haematology: leucocytes, erythrocytes, hemoglobin, hematocrit, platelets, 
differential count (neutrophils, eosinophils, basophils, monocytes, lymphocytes). 
• 
Coagulation: INR, aPTT, PT. 
• 
Urinalysis: specific gravity, dipstick: pH, glucose, protein, blood, ketones, 
bilirubin, urobilinogen, nitrite, leukocyte esterase and any performed microscopy. 
Chemistry and lipids as well the other laboratory parameters are assessed at Screening 
(day -7 to -3), Day 1 (Baseline), Day 14, Day 28/EOT Period 2, Day 56, Day 84/EOT 
Period 3, Day 112 (FU if patients do not participate in the 36-Week Safety Extension 
Phase). If patients participate in the 36-Week Safety Extension Phase additional 
assessments are done at Week 24 (Day 168), Week 36 (Day 252), Week 48 (Day 336) 
and Week 52 (Day 364, FU).  
Chemistry, lipids and other laboratory parameters assessments will be assigned to 
analysis study days according to section 4.7.1. 
Laboratory results from central laboratory q2labsolutions that are below the lower limit of 
quantification (LLOQ) or or above the upper limit of quantification (ULOQ) will be 
reported as character results of “<[LLOQ]” or “>[ULOQ]”. Numeric values will be derived 
as LLOQ/2 for values below LLOQ and as ULOQ for values above ULOQ. 
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 


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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 for EAP (Period 2) and EAPP3 (Period 3). Baseline is the patient’s 
last observation prior to initiation of randomized double-blind study treatment in Period 2.  
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 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. 
4.7.5 
Electrocardiograms (ECG) data analysis 
Sites will be provided with ECG equipment by the central ECG analysis vendor. ECG 
recordings will be electronically transferred to a central ECG analysis vendor.   
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. For this IA 
only QTcF values will be analyzed. 
Twelve-lead ECG recording will be obtained at Screening (day -7 to -3), Day 7, Day 14, 
Day 28/EOT Period 2, Day 42, Day 56, Day 84/EOT Period 3, Day 112 (FU if patients do 
not participate in the 36-Week Safety Extension Phase). If patients participate in the 
36-Week Safety Extension Phase additional assessments are done at Week 24 (Day 
168), Week 36 (Day 252), Week 48 (Day 336) and Week 52 (Day 364, FU).  
ECG assessments will be assigned to analysis study days according to section 4.7.1.  
Summary statistics for actual heart rate 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.  
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. 


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Mean (+/- SEM) plots will be presented by scheduled time point and randomized 
treatment arm. ECG parameter shift tables from baseline to highest post-baseline value 
will be provided for Period 2 and Period 3.  
The analysis will be based on the safety analysis population grouped according to the 
treatment assigned at randomization. 
4.7.6 
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 
summary tables. 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. 
4.7.7 
Vital Signs, Body Weight and BMI 
Orthostatic vital signs are vital signs taken when the patient moves from supine to 
standing position.  
Systolic blood pressure, diastolic blood pressure and heart rate are assessed in supine 
as well as standing position at Screening (day -7 to -3), Day 1 (Baseline), Day 3, Day 7, 
Day 14, Day 21, Day 28/EOT Period 2, Day 42, Day 56, Day 70, Day 84/EOT Period 3, 
Day 112 (FU if patients do not participate in the 36-Week Safety Extension Phase). If 
patients participate in the 36-Week Safety Extension Phase additional assessments are 
done at Week 24 (Day 168), Week 36 (Day 252), Week 48 (Day 336) and Week 52 (Day 
364, FU). 


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Blood pressure and heart rate assessments will be assigned to analysis study days 
according to section 4.7.1. 
Body weight is assessed at Screening (day -7 to -3), Day 1 (Baseline), Day 14, Day 
28/EOT Period 2, Day 42, Day 56, Day 70, Day 84/EOT Period 3, Day 112 (FU if 
patients do not participate in the 36-Week Safety Extension Phase). If patients 
participate in the 36-Week Safety Extension Phase additional assessments are done at 
Week 24 (Day 168), Week 36 (Day 252), Week 48 (Day 336) and Week 52 (Day 364, 
FU).  
Body weight assessments will be assigned to analysis study days according to to section 
4.7.1. 
BMI is calculated as weight (kg) / height (m)2 (height as measured at baseline).  
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 
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.  
Orthostatic vital signs are vital signs taken when the patient moves from supine to 
standing position. The definition of Postural Orthostatic Tachycardia (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, 
orthostatic systolic and diastolic blood pressure and heart rate will be calculated as 
standing minus supine systolic and diastolic blood pressure and heart rate, respectively. 
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 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. 
4.7.8 
Columbia-Suicide Severity Rating Scale (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. 
The “baseline” version will be completed at the Screening visit (day -7 to -3) and a “since 
last visit” version will be completed at subsequent visits at Day 1, Day 7, Day 14, Day 
21, Day 28/EOT Period 2, Day 35, Day 42, Day 49, Day 56, Day 70, Day 84/EOT Period 


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3, Day 112 (FU if patients do not participate in the 36-Week Safety Extension Phase). If 
patients participate in the 36-Week Safety Extension Phase additional assessments are 
done at Week 24 (Day 168), Week 36 (Day 252), Week 48 (Day 336) and Week 52 (Day 
364, FU).  
C-SSRS assessments will be assigned to analysis study days according to section 4.7.1. 
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 9).  
The analysis will be based on the safety analysis population grouped according to the 
treatment assigned at randomization. 
QSCAT = C-SSRS BASELINE/SCREENING VERION and C-SSRS SINCE LAST VISIT 
4.7.9 
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).  
The assessments will be carried out at the Screening visit (day -7 to -3), and subsequent 
visits Day 14, Day 28/EOT Period 2, Day 56, Day 84/EOT Period 3, Day 112 (FU if 
patients do not participate in the 36-Week Safety Extension Phase). If patients 
participate in the 36-Week Safety Extension Phase additional assessments are done at 
Week 24 (Day 168), Week 36 (Day 252), Week 48 (Day 336) and Week 52 (Day 364, 
FU).  
ESRS-A assessments will be assigned to analysis study days according to section 4.7.1. 
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.  
The analysis will be based on the safety analysis population grouped according to the 
treatment assigned at randomization. 
QSCAT = ESRSA 


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4.8 
MISSING DATA HANDLING 
Generally, in summaries, all data from the respective analysis population regardless of 
completeness by Week 4 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, unless specified otherwise. 
4.9 
PATIENT DATA LISTINGS 
Listings will only be prepared if a CSR is written.  
5. 
REFERENCES 
[Carpenter 2013] Carpenter JR, Roger JH, Kenward MG. Analysis of longitudinal trials 
with protocol deviation: a framework for relevant, accessible assumptions, and inference 
via multiple imputation. J Biopharm Stat. 2013;23(6):1352-71. Doi: 
10.1080/10543406.2013.834911. PMID: 24138436. 
[Cro 2020] Cro, Suzie & Morris, Tim & Kenward, Michael & Carpenter, James. (2020). 
Sensitivity analysis for clinical trials with missing continuous outcome data using 
controlled multiple imputation: A practical guide. Statistics in Medicine. 39. 
10.1002/sim.8569. 
[Hopkins 2018] Hopkins SC, Ogirala A, Loebel A, Koblan KS. Transformed PANSS 
factors intended to reduce pseudospecificity among symptom domains and enhance 
understanding of symptom change in antipsychotic- treated patients with schizophrenia. 
Schizophr Bull 2018;44(3):593-602.  
[Hopkins 2020] Hopkins SC, Ogirala A, Loebel A, Koblan KS. Characterization of 
specific and distinct patient types in clinical trials of acute schizophrenia using an 
uncorrelated PANSS score matrix transform (UPSM). Psychiatry Research 294 (2020) 
113569. 
[ICH 1998] ICH E9 Statistical Principles for Clinical Trials. 1998. 
[ICH 2019] ICH E9 (R1) addendum on estimands and sensitivity analysis in clinical trials 
to the guideline on statistical principles for clinical trials. 2019. 
[Khan 2017] Khan A, Liharska L, Harvey PD, Atkins A, Ulshen D, Keefe R.S.E. Negative 
symptom dimensions of the positive and negative syndrome scale across geographical 
regions: implications for social, linguistic, and cultural consistency. Innov Clin Neurosci 
2017; 14:30–40. 


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[Marder 1997] Marder SR, Davis JM, Chouinard G. The effects of risperidone on the five 
dimensions of schizophrenia derived by factor analysis: combined results of the North 
American trials. J Clin Psychiatry 1997;58:538–46.     
[Siddiqui 2009] Siddiqui O, Hung HMJ, O’Neill R. MMRM vs. LOCF: A comprehensive 
comparison based on simulation study and 25 NDA datasets. J Biopharm Stat. 2009; 19: 
227-246. 
 
 


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APPENDIX 1 
PROTOCOL SYNOPSIS 
PROTOCOL TITLE: 
A PHASE II, MULTI-CENTER, RANDOMIZED, DOUBLE-BLIND, 
PARALLEL GROUP, PLACEBO-CONTROLLED TRIAL OF THE 
EFFICACY AND THE SAFETY OF RO6889450 (RALMITARONT) 
VS. PLACEBO IN PATIENTS WITH AN ACUTE EXACERBATION 
OF SCHIZOPHRENIA OR SCHIZOAFFECTIVE DISORDER. 
SHORT TITLE 
EFFECT OF RO6889450 VERSUS PLACEBO IN PATIENTS WITH 
AN ACUTE EXACERBATION OF SCHIZOPHRENIA OR 
SCHIZOAFFECTIVE DISORDER 
PROTOCOL NUMBER: 
BP41743 
VERSION: 
4 
TEST PRODUCT: 
RO6889450 
PHASE: 
II 
 
RATIONALE 
RO6889450 is a novel compound and a partial agonist of the trace amine-associated receptor 1 
(TAAR1) for the treatment of schizophrenia. RO6889450 is currently in Phase II clinical 
development.  
TAAR1 is a class A G protein coupled receptor (GPCR). It is expressed in the amygdala, 
hypothalamus, subiculum, and rhinal cortices as well as areas of the brain where modulation of 
dopaminergic (ventral tegmental area) and serotonergic (dorsal raphe nucleus) neuronal activity 
occurs. TAAR1 partial agonists have been shown to modulate dopaminergic, serotonergic, and 
glutamatergic neurotransmission, and have demonstrated anti-psychotic, anti-addictive, stress 
response, and glucose-regulating activity in nonclinical models. By targeting overlapping brain 
circuits that are implicated in psychotic and affective symptoms, and reward processing, as well 
as brain and peripheral circuits that regulate energy homeostasis, RO6889450 represents a 
potential novel therapy for the treatment of psychotic and affective disorders, including 
schizophrenia and schizoaffective disorder. 
In schizophrenic patients, the F-DOPA signal is increased indicating an abnormal increase in 
presynaptic dopamine synthesis capacity. Elevated dopamine synthesis capacity, as measured 
by [18F]-DOPA, is seen in people with schizophrenia and correlates with the degree of 
psychosis in patients who are treatment responsive. In rodents, the F-DOPA signal was 
significantly decreased by RO6889450, which provides initial evidence that RO6889450 may 
normalize a key abnormality of the dopamine system in patients with schizophrenia. These 
results indicate a potential utility of RO6889450 in the treatment of patients with acute 
exacerbation of schizophrenia. Recently, results of a Phase II trial with the investigational 
product SEP-363856, characterized as a TAAR1 and 5HT1a agonist, have shown improvement 
in patients with acute exacerbation of schizophrenia at 4 weeks. A 6-month open-label 
extension period following the 4-week study was associated with continued improvement as 
assessed by the Positive and Negative Syndrome Scale (PANSS) total score and Clinical 
Global Impression Severity (CGI-S) with minimal effects on metabolic parameters and 
extrapyramidal symptoms. In addition, negative symptoms continued to show improvement 
during a 26-week, open-label treatment as assessed by the Brief Negative Symptom Scale total 
score and the Marder PANSS negative symptom factor score. 


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This Phase II study will be conducted to further investigate and confirm whether the 
administration of RO6889450 as a monotherapy treatment in patients with an acute 
exacerbation of schizophrenia can improve the symptoms of schizophrenia. The 36-Week 
Safety Extension Phase of this study will aim to evaluate long-term safety, tolerability, and 
selected effectiveness outcomes. 
 
OBJECTIVES AND ENDPOINTS 
 
Objectives 
Endpoints 
Primary 
• 
To compare the effect of 4-week 
treatment with two doses of 
RO6889450 (45 mg and 150 mg) vs. 
placebo in participants with acute 
symptoms of schizophrenia or 
schizoaffective disorder.  
• 
Change from baseline at Week 4 in 
the Positive and Negative Syndrome 
Scale (PANSS) total score. 
Secondary 
• 
To compare the effect of two doses 
of RO6889450 (45 mg and 150 mg) 
with placebo on symptoms of 
schizophrenia or schizoaffective 
disorder as assessed with PANSS.  
• 
Proportion of participants with at 
least 20% or 50% improvement from 
baseline on PANSS total score. 
• 
Changes from baseline in the 
PANSS factor scores and proportion 
of participants with at least 20% or 
50% improvement from baseline in 
the PANSS factor scores. 
• 
To compare the effect of two doses of 
RO6889450 (45 mg and 150 mg) with 
placebo on: Clinical Global 
Impression Severity (CGI-S) and 
improvement (CGI-I).  
• 
Change from baseline (CGI-S and 
CGI-S MTS scores) 
• 
CGI-I and CGI-I MTS scores 
• 
To compare the effect of two doses 
of RO6889450 (45 mg and 150 mg) 
with placebo on time-to-readiness for 
discharge from inpatient unit. 
• 
Time from first randomized treatment 
intake to readiness for discharge as 
assessed by the Readiness for 
Discharge Questionnaire (RDQ) or 
actual discharge or censoring if the 
participant discontinues the study 
early. 


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Objectives 
Endpoints 
• 
To compare the safety and tolerability 
of 4 weeks of treatment with two 
doses of RO6889450 (45 mg and 150 
mg) vs. placebo. 
• 
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 standing 
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, and urinalysis test results. 
• 
Change from baseline in Columbia-
Suicide Severity Rating Scale (C-
SSRS) and Extrapyramidal symptom 
rating scale, abbreviated (ESRS-A). 
• 
To observe the effect of treatment of 
two doses of RO6889450 (45 mg and 
150 mg) up to 12 weeks. 
• 
Proportion of participants with at least 
20% or 50% improvement from 
baseline on PANSS total score. 
• 
Changes from baseline in the PANSS 
factor scores and proportion of 
participants with at least 20% or 50% 
improvement from baseline in the 
PANSS factor scores. 
• 
CGI-S and CGI-S MTS. 
• 
CGI-I and CGI-I MTS. 
• 
To observe the safety and tolerability 
of extended treatment with two doses 
of RO6889450 (45 mg and 150 mg) 
up to 12 weeks. 
• 
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 standing 
vital signs recordings. 
• 
Change from screening in 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, and urinalysis test results. 
• 
Change from baseline in C-SSRS and 
ESRS-A.  


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Objectives 
Endpoints 
• 
To evaluate the pharmacokinetics 
(PK) of RO6889450 and 
RO6889450-derived metabolite(s). 
• 
Concentration per time point. 
• 
AUCss of RO6889450 and, if feasible, 
RO6889450- derived metabolite(s) at 
Week 4. 
• 
Cmax of RO6889450 and, if feasible, 
RO6889450-derived metabolite(s) at 
Week 4. 
• 
Other PK parameters as appropriate. 
Exploratory 
• 
To evaluate the changes in Sleep, 
Mood, Well-being, Cognitive 
Functioning and Treatment 
Expectancy. 
• 
Smartphone App Questionnaire.  
• 
To assess the changes in ReQoL. 
• 
Change in ReQoL from baseline, 
proportion of patients with 10 points 
improvement or more. 
• 
To compare the effect of two doses 
of RO6889450 (45 mg and 150 mg) 
with placebo on: Patient Global 
Impression – Change (PGI-C). 
• 
PGI-C. 
• 
To assess the relationship between 
the levels of inflammatory biomarkers 
and cognitive subtype. 
• 
Differences in levels of inflammatory 
biomarkers between subgroups of 
patients defined by pre-morbid and 
current IQ estimate (Wide Range 
Achievement Test [WRAT-4] and 
Wechsler Abbreviated Scale of 
Intelligence – Second Edition [WASI-
II]). 
• 
To evaluate the change in the level 
of depression in schizophrenia 
measured by Calgary Depression 
Scale for Schizophrenia (CDSS) up 
to 48 weeks. 
• 
Calgary Depression Scale for 
Schizophrenia. 
• 
To evaluate the changes in the level 
of insight into mental disorder. 
• 
Scale to Assess Unawareness of 
Mental Disorder (SUMD). 
• 
VAGUS insight into Psychosis Scale. 
• 
Beck Cognitive Insight Scale (BCIS). 
• 
To explore the changes in nicotine 
addiction measured by Fagerström 
Test for Nicotine Dependence. 
• 
Fagerström Test for Nicotine 
Dependence. 
• 
To explore the effects of RO6889450 
on levels and patterns of social and 
general activity and psychotic 
symptoms 
• 
Ecological Momentary Assessment 
• 
To assess patients perception of 
changes relative to their condition 
and relevance and ease of 
understanding of the PRO 
instruments used in the study 
• 
Feedback questions 
• 
To evaluate relationship between the  
premorbid functioning and treatment 
response 
• 
Premorbid Adjustment Scale (PAS) 


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Objectives 
Endpoints 
• 
To observe the effect of treatment 
with two doses of RO6889450 
(45 mg and 150 mg) up to 48 weeks 
• 
Changes from baseline in the PANSS 
total and factor scores at Week 48. 
Analysis by the following groups: 
risperidone, RO6889450 45 mg, 
RO6889450 150 mg, 
placebo/RO6889450 45 mg, 
placebo/RO6889450 150 mg. 
• 
CGI-S 
• 
CGI-I  
• 
To observe the safety and 
tolerability of long-term treatment 
with RO6889450 up to 48 weeks 
• 
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 standing 
vital signs recordings. 
• 
Change from screening in 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, and urinalysis test 
results. 
• 
Change from baseline in C-SSRS and 
ESRS-A. 
 
OVERALL DESIGN 
This is a Phase II, multi-center, randomized, double-blind, parallel group, placebo-controlled 
study in participants with an acute exacerbation of schizophrenia or schizoaffective disorder. 
Study Design 
Participants who are experiencing an exacerbation of their schizophrenia, starting no later than 
8 weeks prior to the screening visit, will be included.  
After eligibility is confirmed during the screening period (Study Period 1), approximately 280 
participants will be randomized outside Japan (United States [US] and rest of the world [ROW]) 
in equal proportions (approximately 70 per group) to one of the following treatments: 150 mg 
QD of RO6889450, 45 mg QD of RO6889450, placebo, or risperidone 4 mg QD (titration period: 
2 mg of risperidone on Day 1, 4 mg of risperidone from Day 2) in a double-blind fashion for 
4 weeks. In addition to these 280 participants, approximately 28 participants will be recruited in 
Japan. 
Outside Japan randomization will be based on region (North America, Eastern Europe, and 
Asia), baseline PANSS total (80-95 and 96 and above), duration of the disease (≤ 5 years 
and > 5 years), and sex. In Japan randomization will be stratified according to baseline PANSS 
total (80-95 and 96 and above). Participants must remain as inpatients throughout Study Period 
1 and during the 4 weeks of the double-blind treatment period (Study Period 2).  
After completion of the 4-week Study Period 2, the participants may enter a double-blind 
extension period (Study Period 3) if agreed between Investigator and participant based on 
clinical status.   


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Participants treated with risperidone, or 150 mg QD of RO6889450, or 45 mg QD of 
RO6889450 during the Study Period 2 will continue with their respective treatments in the Study 
Period 3, while participants assigned to placebo will be randomized to either 150 mg QD or 
45 mg QD of RO6889450 in a blinded fashion. Outside Japan randomization will be based on 
region (North America, Eastern Europe, and Asia), baseline PANSS total (80-95 and 96 and 
above), duration of the disease (≤ 5 years and > 5 years), and sex. In Japan randomization will 
be stratified according to baseline PANSS total (80-95 and 96 and above). At the beginning of 
the Study Period 3, participants will be discharged from the hospital or may remain inpatient for 
the first weeks if required according to the clinical judgment of the Investigator. If the participant 
must remain in the hospital beyond the first weeks of Study Period 3 according to the clinical 
judgment of the Investigator, the Investigator will need to obtain approval from the Sponsor. For 
Japan, due to regional differences in health care, Sponsor approval is not required. 
After completion of Study Period 3, participants may be offered continuation in the optional 
36-Week Safety Extension Phase if they meet additional inclusion criteria. Participants will 
continue to receive the same treatments as those they received during Study Period 3, in a 
double-blind fashion. 
The assessment of the primary endpoint (PANSS) will be performed by trained centralized 
raters independent from the investigational sites. Participants who discontinue study medication 
during Study Period 2 are required to complete the Study Period 2 EOT visit as soon as 
possible after the last dose of study drug (if possible, PANSS assessment should be performed 
before rescue medications are taken). These participants are also required to return to the clinic 
4 weeks after the first dose of study drug (at the end of the 4-week Study Period 2) for Week 4 
early termination visit (ETV). Participants will also be asked to return for the follow-up visit 
(4 weeks after the last dose of study drug). 
 
Treatment Groups and Duration 
The investigational medicinal product (IMP) will be one of the following: 150 mg QD of 
RO6889450, 45 mg QD of RO6889450, placebo, or risperidone 4 mg QD (titration period: 2 mg 
of risperidone on Day 1, 4 mg of risperidone from Day 2) in a double-blind fashion for 4 weeks in 
Study Period 2, 8 weeks in Study Period 3, and 36 weeks in the 36-Week Safety Extension 
Phase.  
 
Length of Study 
The total duration of the study for each participant will be approximately 17 weeks (or 53 weeks 
if participating in the 36-Week Safety Extension Phase) divided as follows: 
• 
Study Period 1: Screening: approximately 3 to 7 days (1 week: inpatient). 
• 
Study Period 2: Double-blind treatment period: 28 days (4 weeks: inpatient). 
• 
Study Period 3: Double-blind extension treatment period: 56 days (8 weeks). At 
the beginning of the extension period, participants will be discharged from the hospital 
or may remain inpatient for the first weeks if required according to the clinical 
judgment of the Investigator. 
• 
36-Week Safety Extension Phase (optional): 36 weeks. Participants, who have 
completed Study Period 3 and in the opinion of the Investigator may benefit 
from the prolonged treatment, may enter 36-Week Safety Extension Phase if 
they meet additional eligibility criteria. Participants with worsening of their 
psychiatric or medical status that would preclude their safe participation in 
the 36-Week Safety Extension Phase or their ability to comply with the 
required procedures will not be eligible for the 36-Week Safety Extension 
Phase of this study. 
• 
Study Period 4: Safety follow-up/Follow-up Period for 36-Week Safety 
Extension Phase: 28 days (4 weeks). Mandatory follow-up assessments for all 
participants 4 weeks after the last dose of study drug. 
• 
End of study visit: 1 day 
 


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Participants must be observed/treated on an inpatient basis from Day -3 (at the latest) until Day 
28. Participants will be discharged on Day 28 of the Study Period 2 once all planned study 
activities are done. The inpatient period can be extended into the double-blind extension 
treatment period (Study Period 3) if deemed necessary by the Investigator. 
At the Investigator’s discretion and upon Sponsor notification, a day pass may be granted to 
participants that need to temporarily leave the hospital during the inpatient periods. Urine drug 
screen and alcohol test need to be performed on the return of participant to the hospital. 
 
End of Study 
The end of the study is defined as the date of the last participant, last visit (LPLV) in the study. 
 
PARTICIPANT POPULATION 
The participants in this study will be patients diagnosed with an acute exacerbation of 
schizophrenia or schizoaffective disorder between 18 to 45 years of age, inclusive, who fulfill all 
of the given inclusion criteria. 
 
Inclusion/Exclusion Criteria 
Inclusion Criteria 
Informed Consent 
1. Able and willing to provide written informed consent and to comply with the study protocol 
according to the International Council for Harmonisation (ICH) and local regulations. 
Alternatively, if applicable, a legally authorized representative must be able to consent for the 
participant according to ICH and local regulations. 
Age 
2. Participant must be 18 to 45 years of age inclusive, at the time of signing the informed 
consent. 
Type of Participants and Disease Characteristics 
3. Participants with a DSM-5 diagnosis of schizophrenia or schizoaffective disorder as 
confirmed by the Mini International Neuropsychiatric Interview (MINI). 
4. Disease duration  10 years. 
5. Have a recent acute exacerbation of schizophrenia (or a psychotic exacerbation of 
schizoaffective disorder) of no more than 8 weeks before screening visit and no current signs 
of apparent lack of treatment response. Note: For exacerbations that started between 
8 weeks and 3 months an exception can be authorized upon the discussion with the Medical 
Monitor if well-documented medical history is available that rules out a potential lack of 
treatment response. 
6. At the time of screening, the participant needs to be either hospitalized or requiring inpatient 
psychiatric care according to clinical judgment for the treatment of the acute exacerbation. If 
the participant has been hospitalized for the current exacerbation, the hospitalization has to 
be of a maximum of 1 week prior to screening. For hospitalization between 1 and 2 weeks, an 
exception can be authorized upon the discussion with the Medical Monitor. 
7. In previous exacerbations and hospitalizations, the subject has shown a pattern of response 
to appropriate antipsychotic treatment. 


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8. Medically stable over a period of 3 months (non-psychiatric conditions) prior to screening visit 
and not expected to require hospitalization or change of treatment for non-psychiatric 
conditions for the duration of the study.  
9. Screening and baseline CGI-S   4 (moderate or worse). 
10. Screening and baseline PANSS total score   80.  
11. Based on screening and baseline PANSS, a score of   4 (moderate or worse) on 2 or more 
of the following items: delusions, conceptual disorganization, unusual thought content, 
hallucinatory behavior, or suspiciousness/persecution. 
 
Weight 
12. Body mass index (BMI) between 18 and 35 kg/m2 inclusive. 
Sex 
13. Male and female participants: 
1. 
A female is eligible to participate if she is not pregnant (see Appendix 5, negative serum 
pregnancy test at screening), not breastfeeding, and at least one of the following conditions 
applies: 
a) Women of non-childbearing potential (WONCBP), as defined in Appendix 5. 
b) Women of childbearing potential (WOCBP), who 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/ligation, male sexual partner who is sterilized, 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 (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 preventing drug 
exposure. 
Inclusion Criteria for the Optional 36-Week Safety Extension Phase 
Participants who, according to clinical judgment of the Investigator, may benefit from 
prolonged treatment and meet the following additional inclusion criteria, may be eligible for 
participation in the 36-Week Safety Extension Phase: 
A. 
Completion of the 12-week treatment (Study Periods 2 and 3). 
B. 
Able and willing to provide written informed consent for the 36-Week Safety Extension 
Phase and to comply with the study protocol according to the ICH and local regulations. 
Alternatively, if applicable, a legally authorized representative must be able to consent 
for the participant according to ICH and local regulations.  
C. 
Female participants of childbearing potential must have a negative urine pregnancy test 
at the Week-12 visit and be willing to remain abstinent or continue the use of 
contraceptive methods as described in Inclusion Criterion 13.  


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D. No signs or symptoms of worsening of the psychiatric or medical status that would 
preclude the patient from the participation in the 36-Week Safety Extension Phase or 
affect their ability to comply with the study requirements. 
 
Exclusion Criteria 
General exclusions 
2. Has been inpatient for   2 weeks or have any other hospitalization for acute exacerbation of 
schizophrenia or schizoaffective disorder within the prior 8 weeks or signs of lack of response 
to antipsychotic treatment. 
3. Disease duration longer than 10 years. 
4. Is currently an inpatient on an involuntary basis. 
5. Subject answers “yes” to “Suicidal Ideation” Item 4 (active suicidal ideation with some intent 
to act, without specific plan) or item 5 (active suicidal ideation with specific plan and intent) or 
any suicidal behavior on the C-SSRS assessment within one month from Screening or 
between Screening and Baseline (i.e., since last visit). Significant risk of suicide or harming 
himself / herself or others according to the Investigator’s judgment. 
6. Lifetime history of homicidal behavior. 
7. Moderate to severe substance use disorder within six months (excluding nicotine) as defined 
by DSM-5. 
8. Other current DSM-5 diagnosis (e.g., bipolar disorder, major depressive disorder). 
 
9. 
Medical conditions 
 
10. 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, or endocrine conditions). 
11. Positive result at screening for hepatitis B surface antigen (HbsAg), hepatitis C virus (HCV, 
untreated), or human immunodeficiency virus (HIV)-1 or -2. HCV participants who have been 
successfully treated and who test negative for HCV RNA, may be considered eligible for entry 
into the study. 
12. Tardive dyskinesia that is moderate to severe or requires treatment. 
13. History of neuroleptic malignant syndrome. 


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14. Clinically significant abnormalities in laboratory safety test results (including hepatic and renal 
panels, complete blood count, chemistry panel and urinalysis), including: 
15. a) 
Aspartate aminotransferase (AST), OR alanine aminotransferase (ALT) 2  upper 
limit of normal (ULN), OR total bilirubin > 1.5 ULN with the exception of known Gilbert 
syndrome. 
16. b) 
Serum creatinine > 1.5 ULN. 
NOTE: 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. 
17. 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. 
 
Prior/Concomitant Therapy 
18. Participants for whom risperidone is contraindicated or who have a documented history of 
lack of response or intolerance to risperidone or paliperidone or participants with known 
hypersensitivity to risperidone, paliperidone, or to any excipients in Risperdal. 
19. Participant treated with a long acting injectable antipsychotic (LAI) or other antipsychotics that 
cannot be washed-out during the screening period. See a list of specific medications in 
Section 6.5. 
20. History of electroconvulsive therapy (ECT). 
21. Participant treated with clozapine within 12 months of screening visit or participants treated 
with clozapine at 200 mg/day or above at any time; low dose (200mg/day) use for insomnia 
or dyskinesia 12 months prior to screening visit  may be permitted if approved by the Sponsor 
(or designee; Section 6.5). 
22. Participant currently receiving a psychotropic or other medication used as a psychotropic, 
which cannot be discontinued during the screening period. 
23. Positive urine drug screen for amphetamines, methamphetamines, opiates, buprenorphine, 
methadone, cocaine and barbiturates. In case of positive urine drug screen for cannabinoids 
(including cannabidiol), the participant may be allowed to enter the study if approved by 
Medical Monitor (mild cannabis use disorder or sporadic use of cannabis are considered 
eligible for entry into the study). 
24. 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. 
 
Prior/Concurrent Clinical Study Experience 
25. Participant has previously received RO6889450. 
26. Participant received an investigational drug within 28 days or five times the half-life of the 
investigational drug (whichever is longer) prior to the first study drug administration (study 
Day 1). 


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NUMBER OF PARTICIPANTS 
Approximately 280 participants will be randomized (70 per group: RO6889450 150 mg QD; 
RO6889450 45 mg QD; risperidone 4 mg QD; and placebo) outside Japan (US and ROW). In 
addition to these 280 participants, approximately 28 participants will be recruited in Japan. 
Outside Japan randomization will be based on region (North America, Eastern Europe, and 
Asia), baseline PANSS total (80-95 and 96 and above), duration of the disease (≤ 5 years 
and > 5 years), and sex. In Japan randomization will be stratified according to baseline PANSS 
total (80-95 and 96 and above). Participants must remain as inpatients at a minimum during the 
screening period and during Study Period 2.  
 
CONCOMITANT MEDICATIONS 
Any medication (prescription and over-the-counter [OTC]) taken within 28 days of study screening 
and any non-pharmacological interventions (e.g., individual psychotherapy, cognitive behavioral 
therapy, smoking cessation therapy, and rehabilitative therapy) will be recorded on the 
appropriate electronic case report form (eCRF). 
The Medical Monitor should be contacted if there are any questions regarding concomitant or 
prior therapy. 
 
Anti-psychotic medication 
All anti-psychotics are prohibited in the study during Study Periods 2 and 3, the 36-Week Safety 
Extension Phase, and with a minimum washout period of 72 hours before the initiation of study 
medication. Washout periods for a specific anti-psychotic medication are provided in the table 
below. 
 
Rescue anti-psychotic treatment 
If the clinical state of the participant would require treatment with an anti-psychotic other than 
the study medication, in the judgment of the Investigator, an antipsychotic should be prescribed 
and the participant will be immediately withdrawn from the study drug. Investigators should 
make a reasonable effort to complete a final assessment including efficacy endpoints before 
starting antipsychotic medication. The reasons for use of rescue medication should be 
documented in detail. 
 


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Anti-psychotic and rescue medication 
Type of medication 
Timelines and instructions 
Antipsychotic medication 
• 
asenapine 
• 
chlorpromazine 
• 
fluphenazine 
• 
haloperidol 
• 
iloperidone 
• 
loxapine 
• 
molindone 
• 
olanzapine 
• 
pericyazine 
• 
perospirone 
• 
perphenazine 
• 
prochlorperazine 
• 
quetiapine 
• 
trifluoperazine 
• 
thiothixene 
• 
ziprasidone 
• 
zuclopenthixol 
Permitted as prior medication and during the screening 
period, but prohibited within the 72 hours prior to the first 
dose of study medication, during Study Periods 2 and 3, 
and the 36-Week Safety Extension Phase (blinded 
treatment). 
• 
risperidone 
• 
paliperidone 
Permitted as prior medication and during the 
screening period, but prohibited within the 72 hours 
prior to the first dose of study medication, during 
Study Periods 2 and 3, and the 36-Week Safety 
Extension Phase (blinded treatment). Participant 
excluded if there is a history of lack of response or 
intolerance to risperidone or paliperidone. 
• 
aripiprazole. 2 weeks 
• 
blonanserin, 3 weeks 
• 
brexpiprazole. 3 weeks 
• 
cariprazine. 15 weeks 
• 
aripiprazole LAI (Abilify 
Maintena). 2 months 
• 
aripiprazole lauroxil 
(Aristada). 4 months 
• 
fluphenazine deconate. 
2 months 
• 
haloperidol decanoate. 
2 months 
• 
olanzapine LAI. 2 months 
Permitted as prior medication if had been stopped 
before the indicated wash out periods prior to 
screening visit. 
Note: Single doses (before reaching steady state) of 
aripiprazole, brexpiprazole and blonanserin 
administered to control current exacerbation can be 
authorized upon the discussion with the Medical 
Monitor. 
• 
paliperidone palmitate 
(Invega Sustenna, Invega 
Trinza). 6 months 
• 
risperidone LAI (Risperdal 
Consta). 1 month 
Permitted as prior medication if had been stopped 
before the indicated wash out periods prior to 
screening visit. Participants excluded if there is a 
history of lack of response or intolerance to 
risperidone or paliperidone. 
• 
clozapine  
Excluded any use in previous 12 months before 
screening, and any lifetime use at doses of 200 
mg/day or greater. 
 
 
 


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Non anti-psychotic concomitant medication 
Permitted Therapy 
Non-psychoactive medications, including over-the-counter medications, that are required to 
treat pre-existing conditions or adverse events (Aes) that occur during the study may be used at 
the discretion of the Investigator. 
All therapy and/or medication administered to manage Aes should be recorded on the AE 
eCRF. For further information regarding the management of specific Aes see Appendix 2.  
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. 
Agents designed to prevent pregnancy: intrauterine device in place, oral contraceptives, dermal 
contraceptives, and injectable or implantable hormonal agents are permitted from enrollment 
until the end of the treatment period. 
Concomitant therapy includes any medication, e.g., prescription drugs, OTC drugs, vaccines 
(including those against COVID-19), approved dietary and herbal supplements, nutritional 
supplements and any non-pharmacological interventions (e.g., individual psychotherapy, group 
therapy, 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.  
 
Prohibited Therapy 
All medications (prescription and OTC) taken within 28 days of study screening and any 
non-pharmacological interventions (e.g., individual psychotherapy, cognitive behavioral therapy, 
smoking cessation therapy, and rehabilitative therapy) will be recorded on the appropriate 
eCRF. 
As a general rule, no new concomitant medication or therapies will be permitted, with the 
exception of medications to treat pre-existing conditions or Aes, unless the rationale for 
exception is discussed and clearly documented between the Investigator and the Sponsor. 
Specific prohibited medications are provided in the table below. 
Prohibited Therapies 
Type of medication 
Timelines and instructions 
Illegal substance use (including legal cannabis) : opiates, 
amphetamine, barbiturate, cocaine, cannabis, 
cannabidiol, or hallucinogen  
From enrollment until the end of 
the treatment period 
All psychotropic medications including anxiolytic, 
antidepressants, mood stabilizer, hypnotic, sedative 
medication and St John’s wort except those listed in 
Section 6.5.2.1 permitted therapy and Table 3 restricted 
therapy. 
From enrollment until the end of 
the treatment period. Must be 
discontinued during the screening 
period, regardless of the 
indication for which they have 
been prescribed. 


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Treatment with sedating anti-histamines (such as 
promethazine or diphenhydramine)  
Should not be initiated during the 
treatment period, nor should the 
dose be changed for those 
participants who were already on 
treatment at the time of 
randomization. 
Participants receiving treatment for tardive dyskinesia 
(e.g., valbenazine or deutetrabenazine) are excluded. 
From enrollment until the end of 
the treatment period. 
The following strong CYP3A4 inducers are prohibited: 
carbamazepine, aprepitant, phenytoin. 
From enrollment until the end of 
the treatment period. 
The following strong P-gp inducers are prohibited: 
verapamil, apalutamide. 
From enrollment until the end of 
the treatment period. 
Clinically relevant substrates of P-gp, including quinidine 
and loperamide 
From enrollment until the end of 
the treatment period. 
 


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Restricted Therapy 
The list of restricted therapies is provided in the table below. 
Restricted Therapies 
Type of medication 
Timelines and instructions 
Medication for extrapyramidal 
symptoms (EPS) 
• 
benztropine: up to 4 mg/day (up 
to 2 mg single dose),  
• 
or biperiden up to 6 mg/day (up 
to 2 mg single dose),  
• 
or trihexyphenidyl up to 6 
mg/day (up to 3 mg single dose) 
• 
propanolol (up to 60 mg/day) 
Initiation and dose increase of anticholinergic 
medications should only happen to treat emergent 
EPS related Aes. Treatment should be limited to a 
7-day period. A prescription may be renewed if 
necessary after reevaluation. Continuation of previous 
treatment may be allowed if the patient has been on a 
stable dose for at least 28 days prior to the screening 
period and the Investigator considers it clinically 
required after consultation with the Sponsor or 
Medical monitor. 
Lorazepam or equivalent 
benzodiazepine  
• 
Total dose   6 mg/day of 
lorazepam during screening and 
the first week of the trial 
• 
Total dose   4 mg/day 
lorazepam from Week 2 until 
the end of the Study Period 3. 
• 
Total dose  3 mg/day of 
alprazolam during screening 
and the first week of the trial 
• 
Total dose  2 mg/day of 
alprazolam from Week 2 until 
the end of the Study Period 3 
• 
Total dose   90 mg/day of 
oxazepam during screening and 
the first week of the trial 
• 
Total dose  60 mg/day of 
oxazepam from Week 2 until 
the end of the Study Period 3. 
Benzodiazepine use is permitted provided the patient 
has been receiving a stable dose for at least 3 months 
and the total dose for all uses is < 6mg/day of 
lorazepam. 
Initiation and/or dose increase of lorazepam or 
equivalent benzodiazepine should only happen to 
treat emergent anxiety, akathisia, agitation, or sleep 
disorders, and only within the maximum dose 
described in the left column. 
Lorazepam or equivalent benzodiazepine treatment 
should not be administered within 12 hours prior to 
PANSS assessments. 
Hypnotic or sedative medication 
• 
zolpidem tartrate up to 10 
mg/day,  
• 
or chloral hydrate up to 2 g/day,  
• 
or zaleplon up to 10 mg/day,  
• 
or zopiclone up to 7.5 mg/day 
Hypnotic or sedative medication is preferred treatment 
for sleep disorders rather than lorazepam and 
equivalent benzodiazepines. 
Routine use is allowed to treat sleep disorders if the 
patient takes a stable restricted dose for at least 3 
months prior to the screening period, and only within 
the maximum dose described in the left column. 
Initiation and/or dose increase of hypnotic should only 
happen to treat emergent sleep disorders, and only 
within the maximum dose described in the left column. 
Hypnotic or sedative medications should not be 
administered within 12 hours prior to PANSS 
assessments. 
 


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APPENDIX 2 
SCHEDULE OF ACTIVITIES STUDY BP41743  
Schedule of Activities without 36-Week Extension Safety Phase 
 
Perio
d 1 
Period 2 
Period 3 
Perio
d 4 
 
Double-blind Treatment Period 
(4 weeks) 
Double-blind Extension 
Treatment Period 
(8 weeks) 
Follo
w-up 
Perio
d 
(4 
week
s) 
Visit Name/Study 
Week  
Scree
ninga 
Base
line 
1 
1 
2
s 
3 
4 b,s 
Peri
od 2 
EOT 
4b 
E
T
V 
5 
6 
7 
8s 
1
0 
12 b,s 
Peri
od 3 
EOT 
16b,s, 
ee 
Study Day 
-7 to -
3 
1 
3 
7 
1
4 
2
1 
28 
28 
3
5 
4
2 
49 
56 
7
0 
84 
112 
Visit window 
(  days)x 
 
  1 

 
1 
 

 
1 
 

 
1 
 

 
1 
  1 
 
1 
 

 
2 
 

 
2 
  
2 
  
2 
 

 
3 
  3 
  3 
Written Informed 
Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusio
n criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility 
Assessment Form 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
(X)r 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
FTNDc,v 
X 
X 
 
 
X 
 
X 
 
 
 
 
X 
 
X 
X 
Psychiatric/Medica
l Historybb 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mini International 
Neuropsychiatric 
Interview (MINI) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examd, bb 
X 
 
X 
 
X 
X 
12 lead ECGbb 
X 
 
X 
X 
X 
 
X 
X 
X 
X 
Vitals (supine and 
standing)bb 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
Weight and waist 
circumferencebb,cc 
X 
X 
 
 
X 
 
X 
 
 
X 
 
X 
X 
X 
X 
Previous and 
Concomitant 
Medicationsbb 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Alcohol Testbb,y 
X 
X 
 
 
X 
 
X 
 
 
X 
 
X 
 
X 
X 
Viral serologybb 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood 
Chemistrye,bb 
X 
X 
 
 
X 
 
X 
 
 
 
 
X 
 
X 
X 
Hematologye,bb 
X 
X 
 
 
X 
 
X 
 
 
 
 
X 
 
X 
X 
Coagulatione,bb 
X 
X 
 
 
X 
 
X 
 
 
 
 
X 
 
X 
X 
Lipidse,bb 
 X 
X 
 
 
X 
 
X 
 
 
 
 
X 
 
X 
X 
Urinalysise,bb 
X 
X 
 
 
X 
 
X 
 
 
 
 
X 
 
X 
X 
Prolactinf, bb 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 






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Schedule of Activities for the 36-Week Safety Extension Phase 
(Optional) 
 
36-Week Safety Extension Phase 
 
Follow-up 
Period for 
36-Week 
Safety 
Extension 
Phase b,s 
Visit Name 
Additiona
l 
Assessmen
ts at Week 
12  
Week 24 
Week 36 
Week 48 / 
 
(Addition
al to 
Period 3 
EOT) 
 
 
36-Week 
Safety 
Extension 
EOT 
 
Study Week 
12 
24 
36 
48 
52 
Study Day 
84 
168  
 252 
336  
364 
Visit window (  days)x 
  3 
   
  
  
  
Written Informed Consent 
Xdd  
 
 
 
 
Inclusion criteria for 
extension phase 
X 
 
 
 
 
Physical Examd, bb 
 
X 
X 
X 
X 
12 lead ECGbb 
 
X 
X 
X 
X 
Vitals (supine and standing)bb 
 
X 
X 
X 
X 
Weight and waist 
circumferencebb,cc 
 
X 
X 
X 
X 
Previous and Concomitant 
Medicationsbb 
 
X 
X 
X 
X 
Alcohol Testbb,y 
 
X 
X 
X 
X 
Blood Chemistrye,bb 
 
X 
X 
X 
X 
Hematologye,bb 
 
X 
X 
X 
X 
Coagulatione,bb 
 
X 
X 
X 
X 
Lipidse,bb 
 
X 
X 
X 
X 
Urinalysise,bb 
 
X 
X 
X 
X 
Prolactinf, bb 
 
X 
X 
X 
X 
Urine drug screenbb 
 
X 
X 
X 
X 
Pregnancy Testg bb 
 
X 
X 
X 
 
PK samplesh,bb 
 
X 
X 
X 
 
Plasmai,bb 
 
 X 
X 
X 
 
Safety Samples (plasma and 
serum)bb,ff 
X 
 X 
 X 
 X 
 
PANSSl, v 
 
X 
X 
X 
X 
PANSS-Informant Checklistv 
 
X 
X 
X 
X 
CGI-Sv 
 
X 
X 
X 
X 
CGI-Iv 
 
X 
X 
X 
X 
CDSSv 
 
X 
X 
X 
X 




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Footnotes for Schedule of Activities Table 1 and Table 2 
a Screening period can be extended up to 10 days upon Medical monitor approval and only in 
the case of delay in availability of laboratory results. 
B EOT, End of Treatment; ETV, Early termination visit. 
During Study Period 2: If a participant voluntarily withdraws from the study or is withdrawn by 
the Investigator, the participant will be asked to complete Study Period 2 EOT visit as soon as 
possible after the last dose of study drug. This may be sooner than Day 28. Participant will 
also be asked to return to the clinic 4 weeks after the first dose of study drug (at the end of the 
4-week Study Period 2) for Week 4 ETV to complete assessments of the primary and 
secondary efficacy outcomes. Participants will also be asked to return for the follow-up visit 
(4 weeks after the last dose of study drug).  
During Study Period 3: If a participant voluntarily withdraws from the study or is withdrawn by 
the Investigator, the participant should return to complete Study Period 3 EOT visit as soon as 
possible after the last dose of study drug. This may be sooner than Day 84. Participant will 
also be asked to return for the follow-up visit assessments (4 weeks after the last dose of study 
drug).  
During 36-Week Safety Extension Phase: If a participant voluntarily withdraws from the 
study or is withdrawn by the Investigator, the participant should return to complete the 36-
Week Safety Extension EOT visit as soon as possible after the last dose of study drug. The 
participant will also be asked to return for the follow-up visit assessments (4 weeks after the 
last dose of study drug). 
For the participants who discontinue study treatment prematurely, if the EOT visit for Study 
Period 2 and 3, and the 36-Week Safety Extension Phase falls into the windows of planned 
visit, only missing assessments need to be completed (see Section Fehler! Verweisquelle 
konnte nicht gefunden werden. And Fehler! Verweisquelle konnte nicht gefunden 
werden. Of the protocol). 
C FTND (Fagerström Test for Nicotine Dependence) excludes cigar, snuff, oral, and vaping (e-
cigarette) users. 
D Height at screening only. 
E All study-required laboratory assessments, with the exception of dipstick urinalysis, urine 
dipstick alcohol test, drugs of abuse, urine pregnancy test and COVID-19 test (when not 
performed centrally), will be performed by a central laboratory. Microscopic urinalysis if 
deemed necessary to be performed centrally (see Appendix 4 of the protocol). 
F Prolactin results will be kept blinded to participants and Investigators. 
G All women of childbearing potential (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. 
H Pre-dose at Week 1 and 2; pre-dose, 1, 2 ( 0.5) and 6 hours ( 0.5) post-dose at Week 4; one 
sample pre-dose at Weeks 6, 8, 12 visits. PK sampling at Week 4 should be performed within 
two days before the Day 28 visit. During outpatient period of the study, PK samples should be 
taken (if possible) as the last assessment after all other assessments have been completed. 
Additional PK samples will be taken at the time of treatment discontinuation and in case of 
overdose. 
I Plasma samples for the exploratory biomarker assessments will be processed centrally. 
j Whole blood samples will be collected for clinical genotyping and will be processed centrally 
(see Section Fehler! Verweisquelle konnte nicht gefunden werden. of the protocol). Any 
other time point can be used if blood volume limits are exceeded at a particular visit day. 


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Footnotes for Schedule of Activities Table 1 and Table 2 (cont.) 
k Participants must be observed/treated on an inpatient basis from Day -3 (at the latest) until 
Day 28. Participants will be discharged on Day 28 of Study Period 2 once all planned study 
activities are done. The inpatient period can be extended into the blinded extension treatment 
period if deemed necessary by the Investigator (see Section Fehler! Verweisquelle konnte 
nicht gefunden werden. of the protocol). 
l Done by centralized raters. 
m IMP dispensing (see Section Fehler! Verweisquelle konnte nicht gefunden werden. of the 
protocol). 
n Phone calls by a case manager at the minimum once weekly are mandatory. During the 
36-Week Safety Extension Phase, phone calls by a case manager once a month are 
mandatory. More frequent phone calls are encouraged. Follow-up phone calls will be made 
approximately 7, 14, and 21 days after the last dose of study drug or after early termination 
(see Section Fehler! Verweisquelle konnte nicht gefunden werden. of the protocol). 
o Study drug  − two tablets (one each from Bottle A and B) and two capsules (from Bottle C) 
except for Day 1 when only one capsule should be taken −  is administered once daily, at 
bedtime, without food and swallowed whole with fluid. Ideally, no food should be consumed for 
at least 2.5 hours before and after the dosing. 
p The Assessment of Sleep, Mood, Well-being and Cognitive Functioning and Treatment 
Expectancy is optional but strongly recommended. In total up to 28 questionnaires for 
assessment of Sleep, Mood, Well-being and Cognitive Functioning and Treatment Expectancy 
will be presented on the smartphone as part of AiCure app at selected time points that will 
appear as random to the participant. During Study Period 2 and for Japanese patients during 
Study Period 3 and Study Period 4, the questions will be captured on Medavante Virgil 
platform. Participants continuing in the 36-Week Safety Extension Phase will have the 
option to continue using this smartphone app for the first 4 weeks (Weeks 13-16). 
q This assessment will not be performed in non-English speaking countries without linguistic 
validated translation. This applies also to patients who do not speak English as a first language 
but are living in an English speaking country. If validated translations become available, they 
may be used. Equivalent scales may be used, if available. 
r After completion of the 4-week Study Period 2, the participants may be re-randomized into a 
double-blind extension period (Study Period 3) if agreed between Investigator and participant 
based on clinical status. Randomization numbers will remain unchanged. 
s The study visit can be split over 2 days within visit window. 
t The use of medication adherence platform via a smartphone app in Japan may not be 
required. 
u EMA is optional but strongly recommended. EMA will be performed 3 times throughout the 
day, 5 days a week (not at the visit day). Assessments between Day 21 and Day 28 will be for 
training purpose and less frequent. EMA will not be performed in Japan. Participants 
continuing in the 36-Week Safety Extension Phase will have the option to continue using 
this smartphone app for the first 4 weeks (Weeks 13-16). 
v 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 Period 2 EOT visit. The scope of the assessment remains the same. Source 
documentation should detail if the assessment has been performed remotely.  


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Footnotes for Schedule of Activities Table 1 and Table 2 (cont.) 
w Unless performed locally within 2 weeks and available documentation can be provided.  
x In exceptional situations (i.e., COVID-19 outbreak), the visit may be split between two days. 
y Alcohol test will be performed using a urine dipstick test. 
z Serious Adverse Event (SAE) only. 
aa If onsite visits during study Period 3 and the 36-Week Safety Extension Phase 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 if approved by Sponsor and relevant health 
authorities, if applicable. This must be confirmed and documented in the participan’'s source 
file. 
bb If the post Period 2 EOT visit study assessments and procedures cannot be administered 
because the visit cannot take place (e.g., due to travel restriction due to an outbreak of 
COVID-19), the Home HealthCare System can be used. The scope of the assessment remains 
the same. Source documentation should detail if the assessment has been performed 
remotely.  
cc For anthropometric measurements of weight and waist circumference the use of the same 
weighing scale and tape measure throughout the study is recommended. 
dd Informed consent form for the 36-Week Safety Extension Phase must be signed prior to 
initiation of any procedures related to the 36-Week Safety Extension Phase. 
ee  Only for participants who completed Study Period 3 but did not enter the optional 36-
Week Safety Extension Phase. 
ff 
Safety blood samples will be taken and may be analyzed if needed, to investigate any new 
clinical safety signal. 
 
 


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APPENDIX 3 
PANSS SYMPTOM FACTORS  
 
Factor 
Original PANSS 
item number 
PANSS item name 
Negative symptoms 
N1 
Blunted affect 
N2 
Emotional withdrawal 
N3 
Poor rapport 
N4 
Passive/apathetic social withdrawal 
N6 
Lack of spontaneity and flow of conversation 
G7 
Motor retardation 
G16 
Active social avoidance 
Disorganized 
thought/cognition 
P2 
Conceptual disorganization 
N5 
Difficulty in abstract thinking 
G5 
Mannerisms and posturing 
G10 
Disorientation 
G11 
Poor attention 
G13 
Disturbance of volition 
G15 
Preoccupation 
Positive symptoms 
P1 
Delusions 
P3 
Hallucinatory behavior 
P5 
Gandiosity 
P6 
Suspiciousness 
N7 
Stereotyped thinking 
G1 
Somatic concern 
G9 
Unusual thought content 
G12 
Lack of judgment and insight 
Uncontrolled 
hostility/excitement 
P4 
Excitement 
P7 
Hostility 
G8 
Uncooperativeness 
G14 
Poor impulse control 
Anxiety/depression 
G2 
Anxiety 
G3 
Guilt feelings 
G4 
Tension 
G6 
Depression 
PANSS symptom factors based on “Marder” PANNS factor analysis published in J Clin 
Psych 58:12, December 1997 p538 [Marder 1997]. 
Expressive Deficit: N01 + N03 + N06 + G07 (Khan) 
Avolition: N01 + N02 + N04 + G16  
 


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APPENDIX 4 
 UNCORRELATED PANSS SCORE MATRIX (UPSM) FOR 
GENERATING TRANSFORMED PANSS FACTOR SCORES 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 


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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. 
 
 
Clinical Global Impression Most Troubling Symptoms – Severity of Illness Scale 
(CGI-S MTS) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
  
 
 
  
  
 
 
  
 
  
 
 
  
 
  
  
  
  
 
 
 
  
  
  
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
   
 
  
 
 
  
 
  
 
  
 
 
 
 
 
 
  
 
 
  
 
 
 
  
 
 
  
 
 
  
 
 
  
 
 
  
 
 
  
 
 
 


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          1–- SYMPTOM NOT PRESENT              
          2–- PRESENCE OF SYMPTOM QUESTIONABLE 
          3–- PRESENT TO A MINOR DEGREE        
          4–- PRESENT TO A MODEST DEGREE       
          5–- PRESENT TO A SIGNIFICANT DEGREE  
          6–- PRESENT TO A SEVERE DEGREE       
          7–- PRESENT TO AN EXTREME DEGREE     
 
Clinical Global Impression Most Troubling Symptoms – Improvement Scale (CGI-I 
MTS) 
          1 – VERY MUCH IMPROVED 
          2 – MUCH IMPROVED 
          3 – MINIMALLY IMPROVED 
          4 – NO CHANGE 
          5 – MINIMALLY WORSE 
          6 – MUCH WORSE 
          7 – VERY MUCH WORSE 
 
 
 
 
 
 


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APPENDIX 6 
FAGERSTÖM TEST OF NICOTINE DEPENDENCE SCORING 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
  
 
 
 
 
 
  
 
 
  
 
 
 
 
   
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
   
 
 
 
  
 
 


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APPENDIX 7 
ADVERSE EVENT TEMPLATES 
Adverse Events During Period 2 
  ___________________________________________________________________________________________ 
                                                                                              
                                                Placebo    RO6889450   RO6889450  Risperidone 
  MedDRA System Organ Class                                 45MG QD    150MG QD     4MD QD    
    MedDRA Preferred Term                        (N=xx)      (N=xx)     (N=xx)      (N=xx)    
  ___________________________________________________________________________________________ 
                                                                                              
  Total number of patients with at least one   xx (xx.x%)  xx (xx.x%) xx (xx.x%)  xx (xx.x%)  
  adverse event                                                                               
                                                                                              
  Overall total number of events                   xx          xx         xx          xx      
                                                                                              
  Gastrointestinal disorders                                                                  
    Total number of patients with at least      x (xx.x%)   x (xx.x%)  x (xx.x%)   x (xx.x%)  
    one adverse event                                                                         
    Total number of events                          x           x          x           x      
    Vomiting                                    x ( x.x%)   x ( x.x%)  x ( x.x%)   x ( x.x%)  
    Nausea                                      x ( x.x%)   x ( x.x%)  x ( x.x%)   x ( x.x%)  
… 
Investigator text for aEs encoded using MedDRA version 23.1. Percentages are based on N in the column 
headings. Only treatment emergent aEs are displayed. For frequency counts by preferred term, multiple 
occurrences of the same AE in an individual are counted only once. For frequency counts of“"Total 
number of event”" rows, multiple occurrences of the same AE in an individual are counted separately. 
Data which has been collected during Periods 2 is included. 
 
Notes:  
• 
Period 2: 4 week in-patient period 
• 
Period 3: 8 weeks out-patient period 
• 
N in the column headings is the number of patients who received at least one 
treatment in Period 2.  
• 
Treatment emergent aEs are those with start date between first treatment in 
Period 2 and the day before first treatment in the 8-weeks double-blind extension 
treatment period (Period 3) if the patient received treatment in Period 3, or the 
last day of treatment in Period 2 + 1 day if the patient did not receive treatment in 
Period 3. 
 
 
 


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Adverse Events During Period 3 
                                                                                              
                                                Placebo P2/   Placebo P2/  RO6889450   RO6889450  Risperidone 
  MedDRA System Organ Class                     RO6889450     RO6889450    45MG QD     150MG QD   4MD QD    
                                                45MG QD P3    150MG QD P3  P2/3        P2/3       P2/3  
    MedDRA Preferred Term                        (N=xx)       (N=xx)      (N=xx)      (N=xx)      (N=xx)    
  ____________________________________________________________________________________________________________ 
                                                                                              
  Total number of patients with at least one   xx (xx.x%)  xx  (xx.x%)  xx (xx.x%)  xx (xx.x%)  xx (xx.x%)   
  adverse event                                                                               
                                                                                              
  Overall total number of events                   xx          xx         xx          xx          xx         
                                                                                              
  Gastrointestinal disorders                                                                  
    Total number of patients with at least      x (xx.x%)   x (xx.x%)  x (xx.x%)   x (xx.x%)   x (xx.x%)    
    one adverse event                                                                         
    Total number of events                          x           x          x           x           x        
    Vomiting                                    x ( x.x%)   x ( x.x%)  x ( x.x%)   x ( x.x%)   x ( x.x%)    
    Nausea                                      x ( x.x%)   x ( x.x%)  x ( x.x%)   x ( x.x%)   x ( x.x%)    
… 
Investigator text for aEs encoded using MedDRA version 23.1. Percentages are based on N in the column headings. For 
frequency counts by preferred term, multiple occurrences of the same AE in an individual are counted only once. For 
frequency counts of“"Total number of event”" rows, multiple occurrences of the same AE in an individual are counted 
separately. Data which has been collected during Period 3 is included. 
 
Notes:  
• 
Period 3: 8 weeks out-patient period 
• 
N in the column headings is the number of patients who received at least one 
treatment in Period 3.  
• 
aEs with start date between first treatment in Period 3 and last treatment in 
Period 3 + 1 day will be included. 
 
 
 


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Adverse Events During Period 2 and 3 
  ____________________________________________________________________________________________________________ 
                                                                                              
                                                RO6889450   RO6889450   Risperidone 
  MedDRA System Organ Class                     45MG QD     150MG QD    4MD QD    
                                                P2/3        P2/3        P2/3  
    MedDRA Preferred Term                       (N=xx)      (N=xx)      (N=xx)    
  ____________________________________________________________________________________________________________ 
                                                                                              
  Total number of patients with at least one   xx (xx.x%)  xx (xx.x%)  xx (xx.x%) 
  adverse event                                                                               
                                                                                              
  Overall total number of events                   xx          xx          xx      
                                                                                              
  Gastrointestinal disorders                                                                  
    Total number of patients with at least      x (xx.x%)   x (xx.x%)   x (xx.x%) 
    one adverse event                                                                         
    Total number of events                          x           x           x 
    Vomiting                                    x ( x.x%)   x ( x.x%)   x ( x.x%) 
    Nausea                                      x ( x.x%)   x ( x.x%)   x ( x.x%) 
… 
Investigator text for aEs encoded using MedDRA version 23.1. Percentages are based on N in the column headings. Only 
treatment emergent aEs are displayed. For frequency counts by preferred term, multiple occurrences of the same AE in an 
individual are counted only once. For frequency counts of“"Total number of event”" rows, multiple occurrences of the 
same AE in an individual are counted separately. Data which has been collected during Periods 2 and 3 is included. 
 
Notes:  
• 
Period 2: 4 week in-patient period 
• 
Period 3: 8 weeks out-patient period 
• 
N in the column headings is the number of patients who received at least one 
treatment in Period 2 or Period 3.  
• 
Treatment emergent aEs are those with start date between first treatment in 
Period 2 and last treatment in Period 3 + 1 day. 
 
 
 


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Adverse Events During Period 2 and 3 
  _____________________________________________________________________________________________________________________ 
                                                                                              
                                            Placebo    Placebo P2/  Placebo P2/  RO6889450   RO6889450   Risperidone 
  MedDRA System Organ Class                 (N=xx)     RO6889450    RO6889450    45MG QD     150MG QD    4MD QD    
                                                       45MG QD P3   150MG QD P3  P2/3        P2/3        P2/3  
    MedDRA Preferred Term                              (N=xx)       (N=xx)       (N=xx)      (N=xx)      (N=xx)    
  _____________________________________________________________________________________________________________________ 
                                                                                              
  Total number of patients with at least    xx (xx.x%)  xx (xx.x%)  xx (xx.x%)   xx (xx.x%)  xx (xx.x%)  xx (xx.x%)   
  one adverse event                                                                               
                                                                                              
  Overall total number of events               xx          xx         xx           xx          xx          xx         
                                                                                              
  Gastrointestinal disorders                                                                  
    Total number of patients with at         x (xx.x%)   x (xx.x%)   x (xx.x%)    x (xx.x%)   x (xx.x%)   x (xx.x%)    
    least  one adverse event                                                                         
    Total number of events                       x           x           x            x           x           x      
    Vomiting                                 x ( x.x%)   x ( x.x%)   x ( x.x%)    x ( x.x%)   x ( x.x%)   x ( x.x%)    
    Nausea                                   x ( x.x%)   x ( x.x%)   x ( x.x%)    x ( x.x%)   x ( x.x%)   x ( x.x%)    
… 
Investigator text for aEs encoded using MedDRA version 23.1. Percentages are based on N in the column headings. For 
frequency counts by preferred term, multiple occurrences of the same AE in an individual are counted only once. For 
frequency counts of“"Total number of event”" rows, multiple occurrences of the same AE in an individual are counted 
separately. Data which has been collected during Follow-up is included. 
 
Notes:  
• Follow-up: after last dose of treatment in Period 2 (if the patient did not 
enter Period 3) or in Period 3 + 28 days. 
• N in the column headings is the number of patients who received at least 
one treatment in Period 2 or Period 3.  
• Treatment emergent aEs are those with start date after last treatment in 
Period 2 (if the patient did not enter Period 3) or in Period 3 until 28 days 
later. 
 
 
 


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APPENDIX 8 
ABUSE LIABILITY MEDDRA TERMS 
Drug abuse and dependence SMQ wide 
Drug withdrawal SMQ wide 
Plus these additional PTs: 
• 
Euphoric mood 
• 
Elevated mood 
• 
Feeling abnormal 
• 
Feeling drunk 
• 
Feeling of relaxation 
• 
Thinking abnormal 
• 
Hallucination 
• 
Inappropriate affect 
• 
Somnolence  
• 
Mood disorders and disturbances 
• 
Psychosis  
• 
Aggression 
• 
Confusion 
• 
Disorientation 
• 
Drug Tolerance 
• 
Habituation 
• 
Drug withdrawal syndrome 
• 
Substance related disorders 
 
Based on MedDRA version 24.0 
 


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APPENDIX 9 
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. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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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. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
     
    
  
 


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APPENDIX 10 ASSESSMENT OF SLEEP, MOOD, WELL-BEING AND 
COGNITIVE FUNCTIONING, AND ASSUMED TREATMENT ASSIGNMENT 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
  
 
 
 
 
 
   
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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APPENDIX 11 PREMORBID ADJUSTMENT SCALE (PAS) 
 
 
 
(cont on next pages) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 


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APPENDIX 12 CALGARY DEPRESSION SCALE FOR SCHIZOPHRENIA 
(CDSS) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
  
 
 
  
 


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APPENDIX 13 THE ABBREVIATED VERSION OF THE SCALE TO ASSESS 
UNAWARENESS IN MENTAL DISORDER IN SCHIZOPHRENIA (SUMD-9)  
 
1. Awareness of mental disorder: In the most general terms, does the subject 
believe that he or she has a mental disorder? 
2. Awareness of the consequences of mental disorder: What is the subject’s 
belief regarding the reason(s) he or she has been unemployed, evicted, 
hospitalized, etc.? 
3. Awareness of the effects of drugs: Does the subject believe that 
medications have diminished the severity of his or her symptoms (if applicable) ? 
4. Awareness of hallucinatory experiences: Does the subject believe that he 
or she experiences hallucinations as such? Rate his or her ability to interpret this 
experience as primarily hallucinatory. 
5. Awareness of delusional ideas: Does the subject believe that he or she 
experiences delusions as such, that is, as internally produced erroneous 
beliefs ? Rate his or her awareness of the implausibility of the belief if applicable. 
6. Awareness of disorganized thoughts: Does the subject believe that his or 
her communications are disorganized? 
7. Awareness of blunted affect: >Rate the subject’s awareness of his or her 
affect as communicated by his or her expressions, voice, gestures, etc. Do not 
rate his or her evaluation of his or her mood. 
8. Awareness of anhedonia: Is the subject aware that his or her behaviour 
reflects an apparent decrease in experiencing pleasure while participating in 
activities normally associated with such feelings? 
9. Awareness of lack of sociality: Is the subject aware that he or she shows no 
interest in social relationships? 
 
 
 


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APPENDIX 14 VAGUS SELF-REPORT VERSION (VAGUS-SR)  
 
Choose the most intense unusual or unique experience from above. 
Write the corresponding letter here _______. 
Indicate the extent to which you agree or disagree at the present moment with each of the 
following statements by circling the appropriate number, keeping in mind your most intense 
experience. 
1) My unusual or unique experiences are due to my mental illness. 
 
2) My unusual or unique experiences are REAL regardless of what other people think about 
them. (e.g. doctors, family, friends, etc.) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Indicate if you have ever had the following unusual or unique experience by reading the question 
and marking ⊠ either Yes or No. 
 
 If ‘NO,’ please go to the next page. 
 If ‘YES’ to the above indicate the extent to which you agree or disagree at the present moment 
with each of the following statements by circling the appropriate number. 
3) The voices other people can’t hear are REAL regardless of what my doctor, family or friends 
believe. 
 
4) My mental illness has caused me to hear voices that other people cannot hear. 
 
PLEASE GO TO THE NEXT PAGE  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Please indicate the extent to which you agree or disagree at the present moment with each of the 
following statements by circling the appropriate number.  
5) I truly believe I have a mental disorder/illness (e.g. Schizophrenia, Schizoaffective Disorder, 
Bipolar Disorder, Depression with Psychosis, etc.). 
 
6) I definitely NEED treatment with an antipsychotic medication. 
 
7) I have always been mentally healthy. 
 
8) I should stop or avoid taking antipsychotic medication. 
 
9) My unusual or unique experiences have led to negative consequences in my life (e.g. 
hospitalization, work, family or social problems). 
 
10) Antipsychotic medications have lessened the intensity of my unusual or unique experiences.
□ Not Applicable as I have never taken antipsychotic medication before. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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APPENDIX 15 VAGUS-SR SCORING SHEET  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
    
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 


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APPENDIX 16 VAGUS CLINICIAN RATED VERSION (VAGUS-CR)  
Read the initial statement (italics) to the participant or patient and then ask the following 
questions in order to gather information to complete the related VAGUS-CR Insight Scale. 
 
“I am interested in your own understanding of your unusual or unique experiences at the present 
moment. I am NOT interested in what others may wish you to believe about your experiences.” 
 Describe your unusual or unique experiences. For example, 
 
2) How do you explain your unusual or unique experiences? At the present moment, what do 
you believe the cause is for these experiences? 
 
3) Do you currently believe you have a mental illness or a psychiatric disorder, such as 
Schizophrenia, Bipolar Disorder or Depression with psychosis, etc.? Please elaborate. 
 
4) Do you think your unusual or unique experiences require treatment? Do you NEED 
antipsychotic medication? Please elaborate. 
 
5) Have you experienced any negative consequences as a result of your unusual or unique 
experiences? 
Or as a result of your emotional or psychiatric problems? (e.g. hospitalization, occupational or 
social dysfunction). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Please indicate the extent to which you agree or disagree at the present moment 
with each of the following statements regarding the participant or patient you are 
rating below. Circle the appropriate number for each statement. Base your 
answers on the structured interview. 
 
1) The subject believes he/she has a mental disorder/illness (e.g. Schizophrenia, 
Schizoaffective Disorder, Bipolar Disorder, Depression with Psychosis, etc.). 
 
2) The subject is aware the auditory hallucinations (past or present) are due to his/her mental 
illness. 
□ Not applicable as the participant has never had auditory hallucinations. 
 
3) The subject is aware that the delusions (past or present) are due to his/her mental illness. 
 
4) The subject believes that he/she should discontinue or avoid taking an antipsychotic 
medication. 
 
5) The subject believes that his/her mental illness has led to negative consequences in his/her 
life (e.g. hospitalization, work, family or social dysfunction). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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APPENDIX 17 VAGUS-CR SCORING SHEET  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 


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APPENDIX 18 BECK COGNITIVE INSIGHT SCALE (BCIS) 
 
Scoring & Interpretation of the Beck Cognitive Insight Scale (BCIS)  
The BCIS is comprised of two subscales: self-reflectiveness and self-certainty. The 
total score for each scale is the sum of the item scores that comprise it (see below). The 
BCIS composite index is calculated as self-reflectiveness minus self-certainty. Poorer 
cognitive insight is indexed by lower scores on the self-reflectiveness subscale, higher 
self-certainty scores, and lower BCIS composite index scores.  
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
  
 
 
  
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
   
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 


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Step 1. Score every item on the BCIS from “0” to “3” according to the following rule:  
• 
“Do Not Agree at All” = 0 
• 
“Agree Slightly” = 1 
• 
“Agree a Lot” = 2 
• 
“Agree Completely” = 3 
 
Step 2. Calculate self-reflectiveness subscale: sum items 1, 3, 4, 5, 6, 8, 12, 14, and 15.  
Step 3. Calculate self-certainty subscale: sum items 2, 7, 9, 10, 11, and 13.  
Step 4. Calculate BCIS composite index: self-reflectiveness minus self-certainty. 
 
 
 


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APPENDIX 19 EMA 
Roche PB41743 Questions and Answers 
Overview: 
• The questions utilize branching logic based upon the first two questions. There are 
three possible branches based upon the first two questions: 
- 
Branch 1: Home Alone 
- 
Branch 2: Home with Someone 
- 
Branch 3: Away 
• Within each branch there are certain questions that have multiple variations based 
upon the answers selected in a previous question. For example, within Branch 1, the 
Questions for 2 and 3 are dependent on the answers selected in Question 1. For each 
answer selected for Question 1, Question 2 and 3 will be repeated with the activity 
selected in Question 1 being substituted for {{Activity}} in Question 2 and 3. So if a 
subject selects “Just Sitting” and “Pacing” for Question 1, Questions 2 and 3 will be 
asked twice, once for the activity “Just Sitting” and once for the activity “Pacing”. 
• When a subject completes all the questions for a branch they will be asked the three 
Follow-Up Questions.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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APPENDIX 20 PANSS IC NEGATIVE QUESTIONS SCORING