Conditions: Schizophrenia
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 336
Healthy volunteers: no

Brief summary:
The primary objective of the study is to evaluate the long-term safety and tolerability of TV-46000. The primary safety and tolerability endpoint is the frequency of all adverse events, including serious adverse events. For new participants, the total duration of participant participation in the study is planned to be up to 80 weeks (including a screening period of up to 4 weeks, a 12-week oral conversion/stabilization stage \[Stage 1\], a 56-week double-blind maintenance stage \[Stage 2\], and a follow-up period \[8 weeks\]). For roll-over participants, the total duration of participant participation in the study is planned to be up to 64 weeks (including up to 56 weeks in the maintenance stage \[Stage 2\] and a follow-up period \[8 weeks\]). Participants who started Stage 2 who relapse or meet 1 or more of the withdrawal criteria should be invited to perform the Early Termination visit as soon as possible within 4 weeks of the last injection. Participants who withdraw from the study before completing the 56-week maintenance stage will have follow-up procedures and assessments performed at their follow-up visits. During the follow-up period, participants will be treated according to the investigator's judgment.

All participants will be treated with active drug.

Detailed description:

Arms:
arm 1: Participants will receive a subcutaneous (SC) injection of TV-46000 at baseline and every 4 weeks (q4w) thereafter for up to 56 weeks. The maximal dose administered to adult participants is comparable to an oral risperidone dose of 5 mg/day, and the maximal dose administered to adolescents is comparable to 4 mg/day. arm 2: Participants will receive an SC injection of TV-46000 at baseline and every 8 weeks (q8w) thereafter, and a placebo SC injection 4 weeks after baseline and q8w thereafter for up to 56 weeks. The maximal dose administered to adult participants is comparable to an oral risperidone dose of 5 mg/day, and the maximal dose administered to adolescents is comparable to 4 mg/day.

Interventions: intervention 1: TV-46000 intervention 2: Placebo
Intervention descriptions: intervention 1: TV-46000 will be administered per dose and schedule specified in the arm description. intervention 2: Placebo matching to TV-46000 will be administered per schedule specified in the arm description.

Protocol document:
Prot_000.pdf: 
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Uncontrolled Study–Schizophrenia
Clinical Study Protocol with Amendment 01
Study TV46000-CNS-30078
1
 
Clinical Study Protocol with Amendment 01
Study Number TV46000-CNS-30078
A Study to Evaluate the Safety, Tolerability, and Effect of Risperidone Extended-Release 
Injectable Suspension (TV-46000) for Subcutaneous Use as Maintenance Treatment in 
Adult and Adolescent Patients with Schizophrenia
A Study to Evaluate Safety, Tolerability, and Effect of TV-46000 in Adults and Adolescents 
with Schizophrenia
A Study to Test if TV-46000 is Safe for Maintenance Treatment of Schizophrenia
(The SHINE Study – Safety in Humans of TV-46000 sc INjection Evaluation)
Safety and Tolerability Study (Phase 3)
IND number: 124384;
NDA number: 213586;
BLA number: Not applicable; EudraCT 
number: 2019-000063-24
EMA Decision number of Pediatric Investigation Plan: Not applicable
Article 45 or 46 of 1901/2006 does not apply
Protocol Approval Date: 29 January 2019
Protocol with Amendment 01 Approval Date: 03 June 2020
Sponsor
Teva Branded Pharmaceutical Products R&D, Inc.
145 Brandywine Parkway
West Chester, Pennsylvania 19380
United States of America
Information regarding clinical laboratories and other departments and institutions is 
found in Appendix A
COVID-19 pandemic-related operational updates are provided in Appendix N
This clinical study will be conducted in accordance with current Good Clinical Practice as directed by the 
provisions of the International Council for Harmonisation; United States Code of Federal Regulations, 
and European Union Directives and Regulations (as applicable in the region of the study); national 
country legislation; and the sponsor’s Standard Operating Procedures.
Confidentiality Statement
This document contains confidential and proprietary information (including confidential commercial 
information pursuant to 21CFR§20.61) and is a confidential communication of Teva Branded 
Pharmaceutical Products R&D, Inc. and/or its affiliates. The recipient agrees that no information 
contained herein may be published or disclosed without written approval from the sponsor.
© 2020 Teva Branded Pharmaceutical Products R&D, Inc. All rights reserved.


Uncontrolled Study–Schizophrenia
Clinical Study Protocol with Amendment 01
Study TV46000-CNS-30078
2
AMENDMENT HISTORY
The protocol for study TV46000-CNS-30078 (original protocol dated 29 January 2019) has been 
amended and reissued as follows:
Amendment 01
03 June 2020
(136 patients enrolled to date)
The management of study activities during the COVID-19 
pandemic are detailed in Appendix N.
The following sections are affected:
Section 3.1. General Study Design and Study Schematic 
Diagram;
Section 3.5. Schedule of Study Procedures and 
Assessments;
Section 5.1.1. Test Investigational Medicinal Product;
Section 5.1.2. Placebo Investigational Medicinal Product;
Table 4. Investigational Medicinal Products Used in the 
Study;
Section 5.2.1. Storage and Security;
Section 5.2.3. Accountability;
Section 5.9. Randomization and Blinding;
Section 6. Assessment of Efficacy;
Section 7. Assessment of Safety;
Section 7.4. Clinical Laboratory Tests;
Section 7.6. Vital Signs;
Section 7.7. Electrocardiography;
Section 8.1. Pharmacokinetic Assessment
Section 9.5.3.3. Exploratory Efficacy Analysis;
Section 10. Quality Control and Quality Assurance;
Appendix C. Quality Control and Quality Assurance;
Appendix F. Lost to Follow-Up;
Administrative Letter 02
09 February 2020
Letter of Clarification 01
22 July 2019


Uncontrolled Study–Schizophrenia
Clinical Study Protocol with Amendment 01
Study TV46000-CNS-30078
3
The Summary of Changes to the Protocol includes the corresponding reason/justification for 
each change and is provided in Section 16.


Uncontrolled Study–Schizophrenia
Clinical Study Protocol with Amendment 01
Study TV46000-CNS-30078
4
INVESTIGATOR AGREEMENT
Original Protocol Dated 29 January 2019
Protocol with Amendment 01 Dated 03 June 2020
IND number: 124384;
NDA number: 213586; BLA number: Not applicable; EudraCT 
number: 2019-000063-24
EMA Decision number of Pediatric Investigation Plan: Not applicable
Article 45 or 46 of 1901/2006 does not apply
A Study to Evaluate the Safety, Tolerability, and Effect of Risperidone Extended-Release 
Injectable Suspension (TV-46000) for Subcutaneous Use as Maintenance Treatment in 
Adult and Adolescent Patients with Schizophrenia
(The SHINE Study – Safety in Humans of TV-46000 sc INjection Evaluation)
Principal Investigator: 
Title:
Address of Investigational Center:
Tel:
I have read the protocol with Amendment 01 and agree that it contains all necessary details for 
carrying out this study. I am qualified by education, experience, and training to conduct this 
clinical research study. The signature below constitutes agreement with this protocol and 
attachments, and provides assurance that this study will be conducted according to all 
stipulations of the protocol, including all statements regarding confidentiality, and according to 
national or local legal and regulatory requirements and applicable regulations and guidelines.
I will make available the protocol and all information on the investigational medicinal product 
(IMP) that were furnished to me by the sponsor to all physicians and other study personnel 
reporting to me who participate in this study and will discuss this material with them to ensure 
that they are fully informed regarding the investigational medicinal products (IMPs) and the 
conduct of the study. I agree to keep records on all patient information, IMP shipment and return 
forms, and all other information collected during the study, in accordance with national and local 
Good Clinical Practice (GCP) regulations as well as all other national and international laws and 
regulations.
Principal Investigator
Signature
Date


Uncontrolled Study–Schizophrenia
Clinical Study Protocol with Amendment 01
Study TV46000-CNS-30078
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SPONSOR PROTOCOL APPROVAL


Uncontrolled Study–Schizophrenia
Clinical Study Protocol with Amendment 01
Study TV46000-CNS-30078
6
COORDINATING INVESTIGATOR AGREEMENT
Original Protocol Dated 29 January 2019
Clinical Study Protocol with Amendment 01 Dated 03 June 2020 
IND number: 124384;
NDA number: 213586; BLA number: Not applicable;
EudraCT number: 2019-000063-24
EMA Decision number of Pediatric Investigation Plan: Not applicable
Article 45 or 46 of 1901/2006 does not apply
A Study to Evaluate the Safety, Tolerability, and Effect of Risperidone Extended-Release 
Injectable Suspension (TV-46000) for Subcutaneous Use as Maintenance Treatment in 
Adult and Adolescent Patients with Schizophrenia
(The SHINE Study – Safety in Humans of TV-46000 sc INjection Evaluation)
I have read the protocol with Amendment 01 and agree that it contains all necessary details for 
carrying out this study. I am qualified by education, experience, and training to conduct this 
clinical research study. The signature below constitutes agreement with this protocol and 
attachments, and provides assurance that this study will be conducted according to all 
stipulations of the protocol, including all statements regarding confidentiality, and according to 
national and local legal and regulatory requirements and applicable regulations and guidelines.
I agree to keep records on patient information and other information collected during the study, 
in accordance with my responsibilities under the function of the coordinating investigator and in 
accordance with national and local Good Clinical Practice (GCP) regulations as well as all other 
national and international laws and regulations. In addition, I will assume the responsibility of 
the coordinating investigator according to a separate contract.
Coordinating Investigator:
Title:
 
Address of Investigational Center: 
Tel:  
E-mail:  
Coordinating Investigator
Signature
Date
Executed signature pages are maintained within the Trial Master File.


Uncontrolled Study–Schizophrenia
Clinical Study Protocol with Amendment 01
Study TV46000-CNS-30078
7
CLINICAL STUDY PROTOCOL SYNOPSIS
Study TV46000-CNS-30078
Title of Study: A Study to Evaluate the Safety, Tolerability, and Effect of Risperidone 
Extended-Release Injectable Suspension (TV-46000) for Subcutaneous Use as Maintenance 
Treatment in Adult and Adolescent Patients with Schizophrenia
(The SHINE Study – Safety in Humans of TV-46000 sc INjection Evaluation)
Sponsor: Teva Branded Pharmaceutical Products R&D, Inc.
Investigational New Drug Number: 124384
New Drug Application Number: 213586
Biological License Application (BLA) Number: Not applicable
EudraCT Number: 2019-000063-24
European Medicines Agency Decision number of Pediatric Investigation Plan: Not 
applicable
Article 45 or 46 of 1901/2006 does not apply
Name of Test Investigational Medicinal Product (IMP): Risperidone extended-release 
injectable suspension (TV-46000) for subcutaneous (sc) use
EudraVigilance code for the IMP, if applicable: SUB10335MIG
Type of the Study: Safety and Tolerability Study (Phase 3)
Indication: Maintenance treatment of schizophrenia
Is this study conducted to investigate the New Use of an approved, marketed product? No
Number of Investigational Centers Planned: The study is planned to be conducted in 
approximately 100 investigational centers (new centers and those that participated in 
Study TV46000-CNS-30072 [the RISE Study]).
Countries Planned: The study is planned to be conducted in the United States and Bulgaria.
Planned Study Period: The study is expected to start in Quarter 1 (Q1) 2019 and last until 
approximately Quarter 1 (Q1) 2021.
Number of Patients Planned (total): The total number of patients that are planned to be 
enrolled is up to approximately 300 patients. Adolescent patients will only be enrolled in the US; 
any enrolled adolescents will be in addition to the aforementioned total.
Study Population: Male and female patients, 13 to 65 years of age, who have a confirmed 
diagnosis of schizophrenia, are clinically stable, and are eligible for risperidone treatment. The 
study population will consist of 2 subgroups:

Patients rolling over from the Phase 3 pivotal efficacy Study TV46000-CNS-30072
(roll-over patients)

New patients (patients not rolling over from Study TV46000-CNS-30072)


Uncontrolled Study–Schizophrenia
Clinical Study Protocol with Amendment 01
Study TV46000-CNS-30078
8
Primary and Secondary Objectives and Endpoints
The primary objective and endpoint are presented below. There are no secondary study 
objectives and endpoints.
Objectives
Endpoints
The primary objective of the study 
is to evaluate the long-term safety 
and tolerability of TV-46000 
administered in adult and adolescent 
patients with schizophrenia.
The primary endpoint is the frequency of all adverse events, 
including serious adverse events.
Exploratory Objectives and Endpoints
Exploratory objectives and endpoints are as follows:
Objectives
Endpoints
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Uncontrolled Study–Schizophrenia
Clinical Study Protocol with Amendment 01
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9
Objectives
Endpoints
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Uncontrolled Study–Schizophrenia
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10
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Uncontrolled Study–Schizophrenia
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General Study Design: This is a multicenter, double-blind, parallel-group study to evaluate the 
long-term safety, tolerability, and efficacy of TV-46000 administered every month (q1m) or 
every 2 months (q2m) at doses of 50 to 250 mg sc (equivalent to 2 to 5 mg/day of oral 
risperidone) for up to 56 weeks in adult and adolescent patients with schizophrenia. As a 
precautionary measure, adolescent patients will receive doses equivalent to 2 to 4 mg/day oral 
risperidone.
Eligible female and male patients with schizophrenia who did not experience a relapse and 
completed the Phase 3 pivotal efficacy Study TV46000-CNS-30072 (roll-over patients) and new 
patients (who did not participate in Study TV46000-CNS-30072) may enter this long-term study 
if they meet the inclusion/exclusion criteria and provide informed consent or assent, as 
applicable. 
For adolescent patients, it is mandatory that a parent/caregiver accompanies the patient to each 
visit and serves as a reliable informant. It is recommended that a caregiver is identified for each 
adult patient. Local requirements should be followed. The caregiver may be contacted in case of 
loss of contact with the patient or to provide additional information about the patient, if needed. 
Adult patients could be accompanied by caregivers to visits.
A. New Patients: Screening through beginning of Stage 2
For new patients, the study duration will consist of a screening period (up to 4 weeks), a 
conversion/stabilization stage (12 weeks on oral risperidone, Stage 1), a double-blind, 
active-treatment maintenance stage (up to 56 weeks; Stage 2), and a follow-up period (8 weeks).
Screening: These patients will undergo screening procedures/assessments within 4 weeks before 
the start of Stage 1. Adult patients (aged 18-65) should have had a diagnosis of schizophrenia for 
>1 year, and adolescent patients (aged 13-17) should have had a diagnosis of schizophrenia for 
>6 months (diagnosis must be reconfirmed by Structured Clinical Interview for Diagnostic and 
Statistical Manual of Mental Disorders, 5th Edition [DSM-5] [SCID-5]) and have been generally 
responsive to antipsychotics in the past year based on discussions with family members or 
healthcare professionals. Adult patients should also have had ≥1 episode of relapse in the last 
24 months. Patients will provide informed consent or assent, as applicable, at the screening visit, 
before any study-related procedures or assessments are performed.


Uncontrolled Study–Schizophrenia
Clinical Study Protocol with Amendment 01
Study TV46000-CNS-30078
12
Stage 1 (12-week oral conversion and stabilization stage): New patients on any antipsychotic 
(other than clozapine) who can benefit from conversion to oral risperidone based on the 
investigator’s judgment will be converted to oral risperidone to stabilize the patients on the 
treatment. Oral risperidone (at a dose of 2 to 5 mg/day, based on clinical judgment) will be given 
for 12 weeks to ensure that the patients can tolerate risperidone and that the doses are adequate to 
treat their positive symptoms. Adolescent patients will receive a maximal dose of 4 mg/day. 
Patients will come to the clinic for 4 visits (weeks -12, -10, -8, and -4) for various assessments 
and dose adjustments. Additional visits may be required for dose adjustments. Patients will be 
evaluated using the Positive and Negative Syndrome Scale (PANSS), Clinical Global Impression 
of Severity (CGI-S), Abnormal Involuntary Movement Scale (AIMS), Barnes Akathisia Rating 
Scale (BARS), Simpson-Angus Scale (SAS), Columbia Suicide Severity Rating Scale (C-SSRS), 
Calgary Depression Scale for Schizophrenia (CDSS), Clinical Global Impression-Severity of 
Suicidality (CGI-SS), and Clinical Global Impression-Improvement. Additionally, telephone 
contact will take place at weeks -6 and -2, or more frequently if required in the judgment of the 
investigator.
Stability (as assessed at the baseline visit) is defined as meeting all of the following criteria for at 
least 4 consecutive weeks prior to the baseline visit:

outpatient status
Patients who require a stabilization dose below 2 mg/day will not be randomized in the study. As 
a precautionary measure, adolescent patients who will require a stabilization dose of more than 
4 mg/day during the stabilization stage will not be randomized.
If a patient withdraws from the study prior to the randomization (baseline) visit (Visit 6), the 
case report form for the patient’s last visit will be marked as “Not Continuing”, and the reason 
for discontinuation will be recorded. No extra testing or procedures will be required in addition 
to the regular visits.
During the baseline visit, new patients who meet the stability criteria will be randomized in a 
1:1 manner to receive TV-46000 q1m or q2m sc injections at the TV-46000 dose equivalent to 
the oral dose on which they were stabilized in Stage 1 of this study and will enter Stage 2 of the 
study (double-blind maintenance stage) described below.
B. Roll-Over Patients: Screening through beginning of Stage 2
For roll-over patients, the study duration will consist of a double-blind, active-treatment 
maintenance stage (up to 56 weeks; Stage 2) and a follow-up period (8 weeks).
Roll-over patients will begin this study at the baseline visit and start at Stage 2 of the study 
(double-blind maintenance stage). For these patients, the end-of-treatment (EoT) visit in Study 


Uncontrolled Study–Schizophrenia
Clinical Study Protocol with Amendment 01
Study TV46000-CNS-30078
13
TV46000-CNS-30072 will serve as the baseline visit. Some baseline procedures will be 
performed as part of the EoT visit in the TV46000-CNS-30072 study, and the results will be 
transferred to this study's clinical database.
During Stage 2 of this study, patients who were treated with TV-46000 q1m or q2m during 
Study TV46000-CNS-30072 will continue their assigned arm and dose from Study TV46000-
CNS-30072. Patients who were treated with placebo during Study TV46000-CNS-30072 will be 
randomized in a 1:1 manner to receive TV-46000 q1m or q2m sc injections at the TV-46000 
dose equivalent to the oral dose on which they were stabilized in Stage 1 of Study TV46000-
CNS-30072.
C. New and Roll-Over Patients: Stage 2
After patients are assigned to receive TV-46000 q1m or q2m sc injections during the baseline 
visit, the study will continue on an outpatient basis. The maximal dose of TV-46000 
administered to adult patients will be equivalent to an oral risperidone dose of 5 mg/day, and the 
maximal TV-46000 dose administered to adolescents will be equivalent to 4 mg/day oral 
risperidone. All patients will attend in-clinic visits q1m (ie, the dosing visits) and will undergo 
various procedures and assessments as detailed in the Schedule of Study Procedures and 
Assessments. Throughout the duration of the study, telephone contact will take place weekly 
between clinic visits. 
Patients who complete all scheduled visits will have EoT/early termination (ET) procedures and 
assessments performed at week 56 and follow-up procedures and assessments performed at 
weeks 60 and 64. 
Per definition, an exacerbation in symptoms during Stage 1 (new patients) cannot be defined as a 
relapse event, since relapse events can only occur following stabilization and randomization. 
Patients who started Stage 2 who relapse or meet 1 or more of the withdrawal criteria should be 
invited to perform the ET visit as soon as possible within 4 weeks of the last injection. 
Patients who withdraw from the study before completing the 56-week maintenance stage will 
have follow-up procedures and assessments performed at their follow-up visits. During the 
follow-up period, patients will be treated according to the investigator’s judgment.
Brief Summary of Study Design for the Trial Registry(s): The purpose of the study is to 
evaluate the long-term safety, tolerability, and efficacy of TV-46000 administered q1m or q2m
for up to 56 weeks in adult and adolescent patients with schizophrenia. The study will include 
male and female patients, 13 to 65 years of age, who have a confirmed diagnosis of 
schizophrenia, are clinically stable, and are eligible for risperidone treatment. The study 
population will consist of 2 subgroups: i) patients rolling over from the Phase 3 pivotal efficacy 
Study TV46000-CNS-30072 (roll-over patients) and ii) new patients (patients not rolling over 
from Study TV46000-CNS-30072). Roll-over patients who were assigned to either TV-46000 
q1m or q2m during Study TV46000-CNS-30072 will be assigned via the IRT to continue the 
same dosing frequency and same dose as in Study TV46000-CNS-30072. Roll-over patients who 
were assigned to placebo during Study TV46000-CNS-30072 and new patients will be 
randomized to receive sc doses of either TV-46000 q1m or TV-46000 q2m in a 1:1 ratio. The 
doses of TV-46000 will be equivalent to 2 to 5 mg/day of oral risperidone, and the maximal 
TV-46000 dose administered to adolescents will be equivalent to 4 mg/day oral risperidone. The 
primary safety and tolerability endpoint is the frequency of all adverse events, including serious 


Uncontrolled Study–Schizophrenia
Clinical Study Protocol with Amendment 01
Study TV46000-CNS-30078
14
adverse events. For new patients, the total duration of patient participation in the study is planned 
to be up to 80 weeks (including a screening period of up to 4 weeks, a 12-week oral 
conversion/stabilization stage [Stage 1], a 56-week double-blind maintenance stage [Stage 2], 
and a follow-up period [8 weeks]). For roll-over patients, the total duration of patient 
participation in the study is planned to be up to 64 weeks (including up to 56 weeks in the 
maintenance stage [Stage 2] and a follow-up period [8 weeks]). Patients who started Stage 2 who 
relapse or meet 1 or more of the withdrawal criteria should be invited to perform the ET visit as 
soon as possible within 4 weeks of the last injection. Patients who withdraw from the study 
before completing the 56-week maintenance stage will have follow-up procedures and 
assessments performed at their follow-up visits. During the follow-up period, patients will be 
treated according to the investigator’s judgment.
Method of Randomization and Blinding:
To avoid unblinding, all patients enrolled in Study TV46000-CNS-30078 will be assigned to a 
treatment group via the Interactive Response Technology (IRT) at their baseline visit according 
to the following specifications: 

New patients will be randomized via the IRT to receive sc injections of either 
TV-46000 q1m or TV-46000 q2m in a 1:1 ratio. Randomization will be stratified by 
the dose of oral risperidone on which the patient was stabilized during Stage 1 (2/3, 4, 
or 5 mg/day). The dose of TV-46000 will be equivalent to the 2 to 5 mg/day dose of 
oral risperidone on which the patient was stabilized in Stage 1. As a precautionary 
measure, adolescent patients who will require a stabilization dose of more than 4 
mg/day during the stabilization stage will not be randomized. Patients who are 
randomized to TV-46000 q1m will receive an sc injection of TV-46000 at baseline 
and every 4 weeks (q4w) thereafter. To ensure blinding, patients who are randomized 
to TV-46000 q2m will receive an sc injection of TV-46000 at baseline and every 
8 weeks (q8w) thereafter and an sc injection of placebo 4 weeks after baseline and 
q8w thereafter.

Roll-over patients who were assigned to TV-46000 q1m during Study TV46000-
CNS-30072 will be assigned via the IRT to continue the same dosing frequency and 
same dose as in Study TV46000-CNS-30072. Note that the EoT visit in 
Study TV46000-CNS-30072 will serve as the baseline visit for roll-over patients in 
this study (ie, roll-over patients receive their last injection of IMP at the EoT visit in 
Study TV46000-CNS-30072 and receive their next injection at week 4 in this study).
They will receive an sc injection of TV-46000 at the EoT visit in Study 
TV46000-CNS-30072 and q4w thereafter (ie, weeks 4, 8 and so on in this study).

Roll-over patients who were assigned to TV-46000 q2m during Study TV46000-
CNS-30072 will be assigned via the IRT to continue the same dosing frequency and 
same dose as in Study TV46000-CNS-30072. Note that the EoT visit in Study 
TV46000-CNS-30072 will serve as the baseline visit for roll-over patients in this 
study (ie, roll-over patients receive their last injection of IMP at the EoT visit in 
Study TV46000-CNS-30072 and receive their next injection at week 4 in this study).
To maintain the blind, they will be injected q4w, but will alternate between 
TV-46000 sc and placebo injections. Their injection at week 4 will depend on their 
injection at the EoT visit of Study TV46000-CNS-30072 (ie, if their last injection in 


Uncontrolled Study–Schizophrenia
Clinical Study Protocol with Amendment 01
Study TV46000-CNS-30078
15
Study TV46000-CNS-30072 was placebo, then their Study TV46000-CNS-30078 
week 4 injection will be TV-46000 and vice versa).

Roll-over patients who were assigned to placebo during Study TV46000-CNS-
30072 will be randomized via the IRT to receive sc injections of either TV-46000 
q1m or TV-46000 q2m in a 1:1 ratio. Randomization will be stratified by the dose of 
oral risperidone on which the patient was stabilized during Stage 1 (2/3, 4, or 5 
mg/day). The dose of TV-46000 will be equivalent to the 2 to 5 mg/day dose of oral 
risperidone (adolescent TV-46000 doses will be equivalent to 2 to 4 mg/day oral 
risperidone) on which the patient was stabilized in Stage 1 of Study TV46000-CNS-
30072. Note that the EoT visit in Study TV46000-CNS-30072 will serve as the 
baseline visit for roll-over patients in this study (ie, roll-over patients receive their last 
injection of IMP at the EoT visit in Study TV46000-CNS-30072 and receive their 
next injection at week 4 in this study). Patients who are randomized to TV-46000 
q1m will receive an sc injection of TV-46000 at week 4 in this study and q4w 
thereafter. To ensure blinding, patients who are randomized to TV-46000 q2m will 
receive an sc injection of TV-46000 at week 4 in this study and q8w thereafter, and 
an sc injection of placebo at week 8 and q8w thereafter.
Patients and investigators will remain blinded to the identity of the treatment administered to 
each patient. Due to the differences between TV-46000 and placebo and the alternation between 
placebo and TV-46000 for the TV-46000 q2m arm, an unblinded nurse, who is not associated 
with rating the patient (including assessment of the injection site if needed) and is independent 
from the study team, will be required at each site to administer the drug. 
Additional measures to mitigate the risk of unblinding will include the following:

The unblinded nurse will prepare the syringe for injection in a room separate from the 
patient.

The unblinded nurse will wrap a blinding film (so that the original appearance is 
masked) around the barrel of the syringe.

To maintain the patient blind, a cover will be used over the injection site during 
treatment administration. 

The unblinded nurse will administer the injection to the patient (additional details 
about administering the injection can be found in the Pharmacy Manual).
The sponsor’s clinical personnel (and delegates) involved in the study will not be blinded to the 
identity and dosing regimens of the IMPs received by the new patients during the course of this 
study.
Since the roll-over of patients from Study TV46000-CNS-30072 into this study is expected to 
occur prior to Study TV46000-CNS-30072 database lock, the sponsor’s clinical personnel (and 
delegates) involved in the TV46000-CNS-30072 study will be blinded to the identity of their
IMP treatment assignments in the TV46000-CNS-30072 and TV46000-CNS-30078 studies, until 
the TV46000-CNS-30072 database is locked for final analysis and the IMP assignment is known. 
However, certain personnel (ie, site unblinded pharmacist/nurse, IRT study staff, and Clinical 
Supply Chain) who have been unblinded since the beginning of the TV46000-CNS-30072 study, 


Uncontrolled Study–Schizophrenia
Clinical Study Protocol with Amendment 01
Study TV46000-CNS-30078
16
will remain unblinded during the roll-over transition period until the database of Study 
TV46000-CNS-30072 is locked.  
Investigational Medicinal Products: Dose, Pharmaceutical Form, Route of Administration, 
and Administration Rate
Test IMP: TV-46000 will be supplied as a ready-to-use, extended-release injectable product in a 
single-use 2-mL vial or as a 1 mL Luer lock prefilled syringe containing 50, 75, 100, 125, 150, 
200, or 250 mg of risperidone. TV-46000 contains 30% (weight by weight) risperidone.
The product will be stored under refrigerated conditions (2°C to 8°C [36°F to 46°F]), protected 
from light, and kept in the outer carton until use. Under these conditions, the product is frozen. 
Preparation of the syringes and dose administration will be performed according to a detailed set 
of instructions that will be contained in a separate document from the protocol and shall be 
provided to the investigative teams before the beginning of the study.
Each syringe will be prepared immediately prior to dosing. Time between preparation of the 
syringe and administration to the patient will be recorded. The administration will be performed 
by a trained medical professional according to local regulations. Measures to mitigate the risk of 
unblinding will be implemented. During administration, care must be taken to avoid inadvertent 
injection into a blood vessel. Additional details about sc injection administration can be found in 
the Pharmacy Manual and the Investigator’s Brochure for TV-46000.
In the event that prefilled syringes of TV-46000 become unavailable during the study, the 
unblinded nurse responsible for study drug administration will use vials (instructions on how to 
use vials can be found in the Pharmacy Manual).
Reference IMP: None.
Placebo IMP: TV-46000 Placebo is available as an extended-release injectable product supplied 
in a single-use 2-mL vial or prefilled syringe. TV-46000 Placebo should be stored under 
refrigerated conditions (2°C to 8°C [36°F to 46°F]), protected from light, and kept in the outer 
carton until use. Under these conditions, the product is frozen. 
TV-46000 Placebo is composed of the same vehicle as TV-46000 (biodegradable polymers and 
biocompatible organic solvent).
For patients in the TV-46000 q2m group, placebo will be administered by sc injection on the 
months between each injection of TV-46000.
The volume of the TV-46000 Placebo (0.31 mL) chosen for the study has been selected as an 
approximate match to the intermediate volume of the TV-46000 q1m and q2m doses used in this 
study. 
Additional details about sc injection administration can be found in the Pharmacy Manual.


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17
Investigational Medicinal Products Used in the Study
IMP name
Test IMP
Placebo IMP
Trade name and INN, if 
applicable, or 
company-assigned number
TV-46000; risperidone extended-release 
injectable suspension for sc 
administration
TV-46000 Placebo
Formulation
Sterile extended-release injectable 
product
Sterile extended-release injectable 
product
Unit dose strengths/dosage 
levels
 
 
 
Further dosing instructions are detailed in the Pharmacy Manual.
Treatment
Dosing volume (mL)
 
Storage conditions
Store under refrigeration at 2-8°C 
(36-46°F); protect from light; keep 
product in outer carton.
Store under refrigeration at 2-8°C 
(36-46°F); protect from light; keep 
product in outer carton.
Route of administration
sc injection in abdomen or upper arm 
(per investigational center in which the 
patient is enrolled); the injection site 
that is chosen for an individual patient 
should remain consistent throughout the 
study.
sc injection in abdomen or upper 
arm (per investigational center in 
which the patient is enrolled); the 
injection site that is chosen for an 
individual patient should remain 
consistent throughout the study.
Dosing instructions
Injections will be administered q1m or 
q2m per the patient’s assigned treatment 
group.
The injection will be administered by an 
unblinded independent nurse.
Placebo injections will be 
administered every other month 
only to patients in the q2m 
treatment group.
The injection will be administered 
by an unblinded independent nurse.
Packaging
Manufacturer


Uncontrolled Study–Schizophrenia
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18
 
 
 
Duration of Patient Participation and Maximal Exposure to IMP:
For new patients (ie, patients not rolling over from the pivotal efficacy study), the total duration 
of patient participation in the study is planned to be up to 80 weeks (including a screening period 
of up to 4 weeks, a 12-week oral conversion/stabilization stage [Stage 1], a 56-week maintenance 
stage [Stage 2], and a follow-up period [8 weeks]). 
For patients rolling over from the pivotal efficacy Study TV46000-CNS-30072, the total duration 
of patient participation in the study is planned to be up to 64 weeks (including up to 56 weeks in 
the maintenance stage [Stage 2] and a follow-up period [8 weeks]). 
TV-46000 will be administered either q1m or q2m during the maintenance stage at an equivalent 
of 2 to 5 mg/day of oral risperidone. As a precautionary measure, adolescents will not receive a 
TV-46000 dose that is equivalent to more than 4 mg/day oral risperidone.
Study Duration: The study duration will be approximately 25 months, from Quarter 1 (Q1) 
2019 to Quarter 1 (Q1) 2021.
End of Study: End of study is defined as the date when the last patient in Stage 2 has completed 
all efficacy and safety assessments at the final visit per protocol (Follow-up Visit 2).
Plans for Treatment or Care after the Patient Has Ended Participation in the Study: In 
cases where the patient is withdrawn from this study, no further treatment is planned by the 
sponsor after the patient completes their participation in this study. In addition, continued access 
to IMP will not be provided to study participants once the study ends. Investigators should advise 
the study participants to return to the care of their primary physicians. Patients may be treated in 
the meantime per investigator judgment and instruction as applicable.
Inclusion Criteria: Patients may participate in this study only if they meet all of the following 
criteria: 
Patients Rolling Over from the Pivotal Efficacy Study TV46000-CNS-30072
a.
The patient must sign and date the informed consent document. For adolescent 
patients, written informed consent will be obtained from each patient’s parent or legal 
guardian, and written assent will be obtained from each patient.
b. The patient must have participated in the pivotal efficacy study (Study 
TV46000-CNS-30072) without experiencing relapse events and without important 
protocol deviations.
c.
If the patient was taking antidepressants or mood stabilizers (including the 
cytochrome P450 [CYP] 2D6 inhibitors fluoxetine, paroxetine, and duloxetine) in 
Study TV46000-CNS-30072, no dose changes or initiation of treatment with these 
medications will be permitted.
d. The patient must be willing and able to comply with study restrictions and willing to 
return to the investigational center for the required visits throughout the duration of 
the study period, including for the follow-up procedures and assessments as specified 
in this protocol.


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19
e.
The patient, in the investigator’s judgment, requires chronic treatment with an 
antipsychotic medication.
f.
The patient, in the investigator’s judgment, can benefit from participation in this 
study.
g. The patient is able to understand the nature of the study and follow protocol 
requirements, including the prescribed dosage regimens (oral and sc administration) 
and non-use of prohibited concomitant medications; can read and understand the 
written word in order to complete patient-reported outcomes measures; and can be 
reliably rated on assessment scales.
h. The patient has had a stable place of residence for the previous 3 months before the 
baseline visit in this study, and changes in residence are not anticipated over the 
course of study participation.
i.
The patient has no significant life events (such as pending loss of housing, family 
status change, long travel abroad, surgery, etc) that could affect study outcomes 
expected throughout the period of study participation.
j.
The patient is a male or female of any ethnic origin, 13 through 65 years of age (note 
the exception for roll-over patients who may have exceeded 65 years of age during 
the course of Study TV46000-CNS-30072; these patients will still be permitted to 
participate in this study). 
k. The patient is in adequate health as determined by medical and psychiatric history, 
medical examination, electrocardiogram (ECG), serum chemistry, hematology, 
urinalysis, and serology.
l.
Women of childbearing potential and sexually active female adolescents must agree 
not to try to become pregnant, and, unless they have exclusively same-sex partners, 
must agree to use a highly effective method of contraception and agree to continue 
use of this method beginning 1 month before the first administration of study drug 
and for the duration of the study and for 120 days after the last injection of study 
drug. Highly effective methods of contraception include the following:

combined estrogen and progestogen hormonal contraception (oral, intravaginal, 
transdermal) associated with inhibition of ovulation; these should be initiated at 
least 1 month before the first dose of IMP.

progestogen-only hormonal contraception (oral, injectable, implantable) 
associated with inhibition of ovulation; these should be initiated at least 1 month 
before the first dose of IMP.

intrauterine device (IUD) and intrauterine hormone-releasing system in place at 
least 2 months before screening

bilateral tubal occlusion

vasectomized partner provided that he is the sole sexual partner and has received 
medical assessment of the surgical process

Sexual abstinence is only considered a highly effective method if defined as 
refraining from heterosexual intercourse in the defined period. The reliability of 
sexual abstinence needs to be evaluated in relation to the duration of the clinical 
study and the preferred and usual lifestyle of the patient.


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20
m. The patient, if adult or adolescent male, is surgically sterile, or, if capable of 
producing offspring, has exclusively same-sex partners or is currently using an 
approved method of birth control and agrees to the continued use of this method for 
the duration of the study (and for 120 days after the last dose of study drug). Male 
patients with sex partners who are women of childbearing potential must use 
condoms even if surgically sterile. In addition, male patients may not donate sperm 
for the duration of the study and for 120 days after taking the study drug.
New Patients (Not Rolling Over from the Pivotal Efficacy Study TV46000-CNS-30072)
a.
[Revision 01] The patient is an adult (age 18-65) and has a diagnosis of schizophrenia 
according to the DSM-5 for >1 year (diagnosis must be reconfirmed by SCID-5) and 
≥1 episode of relapse in the last 24 months, OR the patient is an adolescent (age 13-
17) with a diagnosis of schizophrenia according to the DSM-5 for > 6 months 
(diagnosis must be reconfirmed by SCID-5). 
b. The patient has been responsive to an antipsychotic treatment (other than clozapine) 
in the past year based on investigator judgment (and discussions with family 
members, caregivers, or healthcare professionals as applicable).
c.
The patient has provided written informed consent and is competent to do so. For 
adolescent patients, written informed consent will be obtained from each patient’s 
parent or legal guardian, and written assent will be obtained from each patient.
d. The patient, in the investigator’s judgment, requires chronic treatment with an 
antipsychotic medication.
e.
The patient, in the investigator’s judgment, can benefit from participation in this 
study.
f.
The patient is able to understand the nature of the study and follow protocol 
requirements, including the prescribed dosage regimens (oral and sc administration) 
and non-use of prohibited concomitant medications; can read and understand the 
written word in order to complete patient-reported outcomes measures; and can be 
reliably rated on assessment scales.
g. The patient has a PANSS total score lower than 100 at screening.
h. The patient has had a stable place of residence for the previous 3 months before 
screening, and changes in residence are not anticipated over the course of study 
participation.
i.
The patient has no significant life events (such as pending loss of housing, family 
status change, long travel abroad, surgery, etc) that could affect study outcomes 
expected throughout the period of study participation.
j.
The patient is a male or female of any ethnic origin, 13 through 65 years of age.
k. The patient has a body mass index between 18.0 and 38.0 kg/m2, inclusive. 
l.
The patient is in adequate health as determined by medical and psychiatric history, 
medical examination, ECG, serum chemistry, hematology, urinalysis, and serology.
m. Women of childbearing potential and sexually active female adolescents must agree 
not to try to become pregnant, and, unless they have exclusively same-sex partners, 
must agree to use a highly effective method of contraception and agree to continue 
use of this method beginning 1 month before the first administration of study drug 
and for the duration of the study and for 120 days after the last injection of study 
drug. Highly effective methods of contraception include the following:


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21

combined estrogen and progestogen hormonal contraception (oral, intravaginal, 
transdermal) associated with inhibition of ovulation; these should be initiated at 
least 1 month before the first dose of IMP.

progestogen-only hormonal contraception (oral, injectable, implantable) 
associated with inhibition of ovulation; these should be initiated at least 1 month 
before the first dose of IMP.

IUD and intrauterine hormone-releasing system in place at least 2 months before 
screening

bilateral tubal occlusion

vasectomized partner provided that he is the sole sexual partner and has received 
medical assessment of the surgical process

Sexual abstinence is only considered a highly effective method if defined as 
refraining from heterosexual intercourse in the defined period. The reliability of 
sexual abstinence needs to be evaluated in relation to the duration of the clinical 
study and the preferred and usual lifestyle of the patient.
n. The patient, if adult or adolescent male, is surgically sterile, or, if capable of 
producing offspring, has exclusively same-sex partners or is currently using an 
approved method of birth control and agrees to the continued use of this method for 
the duration of the study (and for 120 days after the last dose of study drug). Male 
patients with sex partners who are women of childbearing potential must use 
condoms even if surgically sterile. In addition, male patients may not donate sperm 
for the duration of the study and for 120 days after taking the study drug.
o. The patient must be willing and able to comply with study restrictions and willing to 
return to the investigational center for the required visits throughout the duration of 
the study period, including for the follow-up procedures and assessments as specified 
in this protocol.
Randomization Criteria for New Patients:
The following criteria are randomization criteria and must be fulfilled at the baseline visit before 
randomization in addition to other relevant inclusion criteria:
a.
The patient has not experienced mental or physical deterioration, which prevents 
participation in the study per investigator judgement.
b. The patient has demonstrated good compliance in following protocol requirements 
during Stage 1 of the study.

If the investigator or the sponsor determines that the patient was not in 
compliance with the study protocol, the case will be evaluated on a case-by-case 
basis, and the investigator and the sponsor will determine whether the patient will 
be randomized in the double-blind period (Stage 2).
c.
The patient has been stabilized per the following criteria for at least 4 consecutive 
weeks prior to the baseline visit:

outpatient status


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22

PANSS total score ≤80
 
 
 
Exclusion Criteria: Patients may not participate in this study if they meet any of the following 
criteria:
Patients Rolling Over from the Pivotal Efficacy Study TV46000-CNS-30072
a.
The patient has a finding in the baseline 12-lead ECG that is considered clinically 
significant in the judgment of the investigator.
b. Poor compliance with study procedures (in the opinion of the investigator or sponsor) 
during the pivotal efficacy Study TV46000-CNS-30072. This should be discussed on 
a case-by-case basis.
New Patients (Not Rolling Over from the Pivotal Efficacy Study TV46000-CNS-30072) and 
Roll-Over Patients
a.
The patient has a current clinically significant DSM-5 diagnosis other than 
schizophrenia, including schizoaffective disorder, major depressive disorder, bipolar 
disorder, delirium, dementia, or amnestic or other cognitive disorders, or borderline, 
paranoid, histrionic, schizotypal, schizoid, or antisocial personality disorder.
b. The patient is currently on clozapine or has received electroconvulsive therapy in the 
last 12 months.
c.
The patient has a history of epilepsy or seizures, neuroleptic malignant syndrome, 
tardive dyskinesia, or other medical condition that would expose the patient to undue 
risk.
d. The patient has a positive serology for human immunodeficiency virus (HIV)-1, 
HIV-2, hepatitis B surface antigen, and/or hepatitis C. If serology is positive for 
hepatitis C but the ribonucleic acid test is negative and the patient has no history of 
liver disease, enrollment will be considered following discussion between the 
investigator and the medical monitor as needed.
e.
The patient has current or a history of known hypersensitivity to risperidone or any of 
the excipients of TV-46000 or the oral formulation of risperidone used in the 
stabilization phase.
f.
The patient has a substance use disorder, including alcohol and benzodiazepines but 
excluding nicotine and caffeine.
g. The patient has a significant risk of violent behavior based on the patient’s medical 
history or the investigator’s judgement. 
h. The patient has a significant risk of committing suicide based on the patient’s medical 
history or the investigator’s judgement and/or the C-SSRS (lifetime). Patients with a 
C-SSRS (current) positive response to suicidal ideation items 3, 4, or 5 are not 
eligible.


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23
i.
The patient has a clinically significant deviation from normal in the physical 
examination.
j.
The patient has clinically significant findings in biochemistry, hematology, ECG, or 
urinalysis results.
k. If the patient has a prolonged QTcF interval (defined as a QTcF interval of 
>450 msec for males and >470 msec for females) at screening or baseline, calculated 
as the mean of the triplicate ECG measurements, eligibility will be decided on a 
case-by-case basis following discussion between the investigator and the sponsor.
l.
The patient has any clinically significant uncontrolled medical condition (treated or 
untreated). The investigator may discuss with the medical monitor as needed.
m. The patient is a pregnant or lactating female.
n. The patient has any disorder that may interfere with drug absorption, distribution, 
metabolism, or excretion (including gastrointestinal surgery).
o. The patient has any other disease or condition that, in the opinion of the investigator, 
would make participation not in the best interest of the patient or that could prevent, 
limit, or confound the protocol-specified assessments. 
p. The patient has used an investigational drug other than TV-46000 within 3 months 
prior to screening or has participated in a non-drug clinical trial within 30 days prior 
to screening.
q. The patient is using or consuming medications prohibited in this study.
r.
Vulnerable patients (eg, people kept in detention).
Statistical Considerations
Sample Size Rationale: This study is safety-oriented in nature; therefore, no formal hypothesis 
testing is planned. Based on regulatory requirements, up to approximately 300 patients are 
planned to be enrolled in Stage 2 of this study in order to collect data on at least 100 patients
exposed to TV-46000 for at least 1 year. Adolescent patients will only be enrolled in the US; any 
enrolled adolescents will be in addition to the aforementioned total.
Analysis Sets
Intent-to-Treat Analysis Set: The intent-to-treat (ITT) analysis set will include all randomized 
patients who were randomized either in Study TV46000-CNS-30072 or in Study TV46000-CNS-
30078.
In the ITT analysis set, treatment will be assigned based on the TV-46000 treatment to which the 
patients were randomized in this study, regardless of which treatment they actually received.
The ITT analysis set will include all randomized patients, including new patients who did not 
take any IMP. 
Safety Analysis Set: The safety analysis set will include all patients who receive at least 1 dose 
of TV-46000 during this study. In the safety analysis set, treatment will be assigned based on the 
treatment the patients actually received, regardless of the treatment to which they were 
randomized, unless otherwise specified. 
Per-Protocol Analysis Set: The per-protocol analysis set will include all patients in the safety 
analysis set who have no important protocol deviations. In this analysis set, treatment will be 
assigned based on the treatment the patients actually received. 


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24
Pharmacokinetics Analysis Set: The pharmacokinetics analysis set will include all patients 
from the safety analysis set who also have ≥1 plasma concentration measurement.
Additional Analysis Sets: Additional analysis sets will be defined in the statistical analysis plan. 
Efficacy Analysis: Efficacy analysis will be descriptive and will be described in the statistical 
analysis plan.
Multiple Comparisons and Multiplicity: No adjustments will be made for the preplanned 
multiple comparisons/endpoints.
Safety Analysis: Safety analyses will be performed on the safety analysis set. 
Safety assessments and time points are provided in the Schedules of Study Procedures and 
Assessments.
All adverse events will be coded using the Medical Dictionary for Regulatory Activities. Each 
patient will be counted only once in each preferred term or system organ class category for the 
analyses of safety. Summaries will be presented for all adverse events (overall and by severity), 
including adverse events determined by the investigator to be related to the test IMP (ie, 
reasonable possibility, defined as related or with missing relationship), serious adverse events, 
and adverse events causing withdrawal from the study. Summaries will be presented by source of 
patients (new patients and roll-over patients) and by treatment group as well as total. Summaries 
will include both incidence and person-time incidence (number of events divided by the total 
exposure to drug). A summary table of adverse events that includes adverse events from Study 
TV46000-CNS-30072 for roll-over patients will be presented as well. Patient listings of serious 
adverse events and adverse events leading to withdrawal will be presented.
Changes in laboratory, ECG, and vital sign measurement data will be summarized descriptively. 
All values will be compared with predefined criteria to identify potentially clinically significant 
values or changes, and such values will be listed.
The use of concomitant medications will be summarized by therapeutic class using descriptive 
statistics.
Descriptive statistics for allowed rescue medications will be presented by treatment group.
Safety outcomes, including changes from baseline in extrapyramidal symptoms (EPS) scale 
scores (BARS, AIMS, and SAS) and CDSS during Stage 2, will be presented using descriptive 
statistics by treatment group.
The incidence of treatment-emergent adverse events related to EPS will be summarized by the 
following event categories: akathisia, dyskinesia, dystonia, parkinsonism, and tremor. The
C-SSRS and CGI-SS will be used to assess the risk of suicide events during the study. 
Descriptive statistics will be presented by treatment group.
If any patient dies during the study, a listing of deaths will be provided, and all relevant 
information will be discussed in the patient narrative included in the clinical study report.
Selected safety data will also be presented by site of injection (abdomen versus arm) and by age 
group (adolescents [ages 13 through 17] and adults [18 years of age or older]), as applicable.


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25
For continuous variables, descriptive statistics (n, mean, standard deviation, median, minimum, 
and maximum) will be provided for actual values and changes from baseline to each time point. 
For categorical variables, patient counts and percentages will be provided.
Safety data collected in Stage 1 will also be summarized using descriptive statistics for new 
patients.
Tolerability Analysis: In cases where an adverse event related to an injection site reaction is 
reported, an assessment of the sc injection site (ie, local tolerability [skin at injection site]) will 
be made. The presence and severity of erythema, swelling, induration, and pain at the injection 
site may be assessed and summarized using descriptive statistics.
Pharmacokinetic Analysis: Pharmacokinetic analysis will be descriptive and will be described 
in the statistical analysis plan.
Pharmacokinetic/Pharmacodynamic Analysis: The results of the 
pharmacokinetic/pharmacodynamic analysis (if relevant data permit) will be presented in a 
separate report.
Biomarker and Pharmacogenetics Analysis: Genetic variation in CYP2D6, and corresponding 
metabolizer status, will be assessed using descriptive statistics for an association with 
pharmacokinetic endpoints. Biomarker and pharmacogenetics analysis plans and results will be 
reported separately from the main study results.
Planned Interim Analysis: There will be a planned data cut with statistical output produced 
before the New Drug Application submission.


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26
TABLE OF CONTENTS
TITLE PAGE...................................................................................................................................1
AMENDMENT HISTORY .............................................................................................................2
INVESTIGATOR AGREEMENT...................................................................................................4
COORDINATING INVESTIGATOR AGREEMENT...................................................................6
CLINICAL STUDY PROTOCOL SYNOPSIS...............................................................................7
TABLE OF CONTENTS...............................................................................................................26
LIST OF TABLES.........................................................................................................................32
LIST OF FIGURES .......................................................................................................................33
LIST OF ABBREVIATIONS........................................................................................................34
1.
INTRODUCTION AND BACKGROUND INFORMATION.....................................37
1.1.
Introduction...................................................................................................................37
1.2.
Findings from Nonclinical and Clinical Studies...........................................................39
1.2.1.
Nonclinical Studies .......................................................................................................39
1.2.2.
Clinical Studies .............................................................................................................40
1.2.2.1.
Clinical Pharmacology Studies .....................................................................................40
1.2.2.2.
Clinical Safety and Efficacy Studies.............................................................................41
1.3.
Known and Potential Benefits and Risks to Patients ....................................................41
1.3.1.
Known and Potential Benefits and Risks of the Test Investigational Medicinal 
Product(s)......................................................................................................................41
1.3.2.
Overall Benefit and Risk Assessment for This Study...................................................42
2.
STUDY OBJECTIVES AND ENDPOINTS................................................................43
2.1.
Primary and Secondary Study Objectives and Endpoints.............................................43
2.1.1.
Justification of Primary Endpoint .................................................................................43
2.2.
Exploratory Objectives and Endpoints .........................................................................43
3.
STUDY DESIGN..........................................................................................................47
3.1.
General Study Design and Study Schematic Diagram..................................................47
3.2.
Planned Number of Patients and Countries ..................................................................52
3.3.
Justification for Study Design and Selection of Population .........................................52
3.4.
Stopping Rules for the Study ........................................................................................53
3.5.
Schedule of Study Procedures and Assessments ..........................................................53
4.
SELECTION AND WITHDRAWAL OF PATIENTS ................................................65
4.1.
Patient Inclusion Criteria...............................................................................................65


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4.1.1.
Patients Rolling Over from the Pivotal Efficacy Study TV46000-CNS-30072 ...........65
4.1.2.
New Patients (Not Rolling Over from the Pivotal Efficacy Study TV46000-
CNS-30072) ..................................................................................................................66
4.1.3.
Randomization Criteria for New Patients .....................................................................68
4.2.
Patient Exclusion Criteria .............................................................................................68
4.2.1.
Patients Rolling Over from the Pivotal Efficacy Study TV46000-CNS-30072 ...........68
4.2.2.
New Patients (Not Rolling Over from the Pivotal Efficacy Study TV46000-
CNS-30072) and Roll-Over Patients.............................................................................69
4.3.
Withdrawal Criteria and Procedures for the Patient .....................................................70
4.3.1.
General Withdrawal Criteria.........................................................................................70
4.3.2.
Study-Specific Patient Withdrawal Criteria and Procedures ........................................71
4.3.3.
Pharmacokinetic Sampling in Case of Patient Withdrawal ..........................................72
4.4.
Replacement of Patients................................................................................................72
4.5.
Rescreening...................................................................................................................72
4.6.
Screening Failure ..........................................................................................................73
5.
TREATMENTS ............................................................................................................74
5.1.
Investigational Medicinal Products Used in the Study.................................................74
5.1.1.
Test Investigational Medicinal Product ........................................................................74
5.1.1.1.
Starting Dose and Dose Levels .....................................................................................74
5.1.1.2.
Dose Modification and Dose Stratification...................................................................75
5.1.2.
Placebo Investigational Medicinal Product...................................................................75
5.2.
Preparation, Handling, Labeling, Storage, and Accountability for IMPs.....................77
5.2.1.
Storage and Security .....................................................................................................77
5.2.2.
Labeling.........................................................................................................................77
5.2.3.
Accountability...............................................................................................................77
5.3.
Justification for Investigational Medicinal Products.....................................................78
5.3.1.
Justification for Dose of Test Investigational Medicinal Product.................................78
5.3.2.
Justification for Use of Placebo Investigational Medicinal Product.............................78
5.4.
Other Medicinal Products/Non-Investigational Medicinal Products............................78
5.5.
Treatment after the End of the Study............................................................................79
5.6.
Restrictions....................................................................................................................79
5.6.1.
Activity..........................................................................................................................79
5.6.2.
Specific Beverages........................................................................................................79


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5.6.3.
Blood Donation.............................................................................................................79
5.7.
Prior and Concomitant Medication or Therapy ............................................................80
5.8.
Procedures for Monitoring Patient Compliance............................................................81
5.9.
Randomization and Blinding ........................................................................................82
5.10.
Maintenance of Randomization and Blinding...............................................................84
5.10.1.
Maintenance of Randomization ....................................................................................84
5.10.2.
Blinding and Unblinding...............................................................................................84
5.10.3.
Data Monitoring Committee .........................................................................................84
5.11.
Total Blood Volume......................................................................................................85
6.
ASSESSMENT OF EFFICACY...................................................................................86
6.1.
Assessments of Efficacy ...............................................................................................86
6.1.1.
Clinical Global Impression–Improvement (CGI-I).......................................................86
6.1.2.
Positive and Negative Syndrome Scale (PANSS) ........................................................86
6.2.
Other Assessments ........................................................................................................86
6.2.1.
Structured Clinical Interview for DSM-5 (SCID-5) .....................................................86
6.2.2.
Quality of Life Scales....................................................................................................87
6.2.2.1.
Schizophrenia Quality of Life Scale (SQLS)................................................................87
6.2.2.2.
5-Level EuroQol Five Dimensions Questionnaire (EQ-5D-5L)...................................87
6.2.3.
Drug Attitudes Inventory 10-item Version (DAI-10)...................................................87
6.2.4.
Personal and Social Performance Scale (PSP)..............................................................87
6.2.5.
Healthcare Resource Utilization ...................................................................................87
6.2.6.
Clinical Global Impression of Severity (CGI-S)...........................................................88
7.
ASSESSMENT OF SAFETY.......................................................................................89
7.1.
Adverse Events..............................................................................................................89
7.1.1.
Definition of an Adverse Event.....................................................................................89
7.1.2.
Recording and Reporting of Adverse Events................................................................90
7.1.3.
Severity of an Adverse Event........................................................................................90
7.1.4.
Relationship of an Adverse Event to the Investigational Medicinal Product ...............91
7.1.5.
Serious Adverse Events.................................................................................................91
7.1.5.1.
Definition of a Serious Adverse Event..........................................................................92
7.1.5.2.
Expectedness.................................................................................................................92
7.1.5.3.
Reporting a Serious Adverse Event ..............................................................................93
7.1.6.
Protocol-Defined Adverse Events of Special Interest...................................................95


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7.1.7.
Protocol Deviations Because of an Adverse Event.......................................................95
7.2.
Pregnancy......................................................................................................................95
7.3.
Medication Error and Special Situations Related to the Investigational 
Medicinal Products........................................................................................................96
7.4.
Clinical Laboratory Tests..............................................................................................96
7.4.1.
Serum Chemistry, Hematology, and Urinalysis............................................................97
7.4.2.
Other Clinical Laboratory Tests....................................................................................98
7.4.2.1.
Virology and Thyroid Screening Tests .........................................................................98
7.4.2.2.
Human Chorionic Gonadotropin Tests .........................................................................98
7.4.2.3.
Urine Drug Screen.........................................................................................................98
7.4.2.4.
Prolactin ........................................................................................................................98
7.5.
Physical Examinations ..................................................................................................98
7.6.
Vital Signs.....................................................................................................................99
7.7.
Electrocardiography......................................................................................................99
7.8.
Assessment of Local Tolerability and Pain.................................................................100
7.8.1.
Erythema and Edema Assessment ..............................................................................100
7.8.2.
Induration and Nodule Assessment.............................................................................100
7.8.3.
Injection Pain Intensity Assessment............................................................................100
7.9.
Assessment of Suicidality ...........................................................................................101
7.9.1.
Columbia Suicide Severity Rating Scale (C-SSRS) ...................................................101
7.9.2.
Clinical Global Impression-Severity of Suicidality (CGI-SS)....................................101
7.10.
Study-Specific Assessments of Safety........................................................................102
7.10.1.
Abnormal Involuntary Movement Scale (AIMS) .......................................................102
7.10.2.
Barnes Akathisia Rating Scale (BARS)......................................................................102
7.10.3.
Simpson-Angus Scale (SAS) ......................................................................................102
7.10.4.
Calgary Depression Scale for Schizophrenia (CDSS) ................................................102
7.11.
Other Assessments ......................................................................................................103
8.
ASSESSMENT OF PHARMACOKINETICS/ 
PHARMACODYNAMICS/BIOMARKERS/ PHARMACOGENOMICS................104
8.1.
Pharmacokinetic Assessment......................................................................................104
8.2.
Pharmacokinetic/Pharmacodynamics Assessment......................................................105
8.3.
Assessment of Exploratory Biomarkers......................................................................105
8.4.
Pharmacogenetics........................................................................................................105


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9.
STATISTICS ..............................................................................................................107
9.1.
Sample Size and Power Considerations......................................................................107
9.2.
Analysis Sets...............................................................................................................107
9.2.1.
Intent-to-Treat Analysis Set........................................................................................107
9.2.2.
Safety Analysis Set .....................................................................................................107
9.2.3.
Per-Protocol Analysis Set ...........................................................................................107
9.2.4.
Pharmacokinetics Analysis Set ...................................................................................107
9.2.5.
Enrolled Patients Set ...................................................................................................108
9.2.6.
Additional Analysis Sets.............................................................................................108
9.3.
Data Handling Conventions........................................................................................108
9.4.
Study Population.........................................................................................................108
9.4.1.
Patient Disposition......................................................................................................108
9.4.2.
Demographic and Baseline Characteristics.................................................................108
9.5.
Efficacy Analysis ........................................................................................................108
9.5.1.
Primary Endpoint ........................................................................................................108
9.5.2.
Exploratory Endpoints ................................................................................................109
9.5.3.
Planned Method of Analysis.......................................................................................109
9.5.3.1.
Primary Efficacy Analysis ..........................................................................................109
9.5.3.2.
Sensitivity Analysis.....................................................................................................109
9.5.3.3.
Exploratory Efficacy Analysis....................................................................................109
9.6.
Multiple Comparisons and Multiplicity......................................................................109
9.7.
Safety Analysis ...........................................................................................................109
9.8.
Tolerability Analysis...................................................................................................110
9.9.
Pharmacokinetic Analysis...........................................................................................110
9.10.
Pharmacodynamic Analysis........................................................................................110
9.11.
Pharmacokinetic/Pharmacodynamic Analysis............................................................110
9.12.
Biomarker and Pharmacogenetics Analysis................................................................110
9.13.
Planned Interim Analysis............................................................................................111
9.14.
Reporting Deviations from the Statistical Plan...........................................................111
10.
QUALITY CONTROL AND QUALITY ASSURANCE..........................................112
11.
COMPLIANCE STATEMENT..................................................................................112
12.
DATA MANAGEMENT AND RECORD KEEPING...............................................112
13.
FINANCING AND INSURANCE .............................................................................113


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14.
PUBLICATION POLICY...........................................................................................113
15.
REFERENCES............................................................................................................114
16.
SUMMARY OF CHANGES......................................................................................116
16.1.
Global Amendment 01 (Dated 03 June 2020).............................................................116
16.2.
Administrative Letter 02 (Dated 09 February 2020)...................................................129
16.3.
Letter of Clarification 01 (Dated 22 July 2019)..........................................................131
APPENDIX A.
CLINICAL LABORATORIES AND OTHER DEPARTMENTS AND 
INSTITUTIONS .........................................................................................................133
APPENDIX B.
STUDY PROCEDURES AND ASSESSMENTS BY VISIT.........................135
APPENDIX C.
QUALITY CONTROL AND QUALITY ASSURANCE ..............................145
APPENDIX D.
ETHICS ...........................................................................................................147
APPENDIX E.
BIRTH CONTROL METHODS AND PREGNANCY TESTING.................149
APPENDIX F.
LOST TO FOLLOW-UP .................................................................................151
APPENDIX G.
LIST OF PROHIBITED MEDICATIONS .....................................................152
APPENDIX H.
TOTAL BLOOD VOLUME ...........................................................................154
APPENDIX I.
EXPLORATORY BIOMARKERS SAMPLES ...............................................156
APPENDIX J.
PHARMACOGENETIC ASSESSMENTS......................................................157
APPENDIX K.
PRODUCT COMPLAINTS............................................................................158
APPENDIX L.
DATA MANAGEMENT AND RECORD KEEPING....................................160
APPENDIX M.
PUBLICATION POLICY ..............................................................................163
APPENDIX N.
MANAGEMENT OF STUDY ACTIVITIES DURING COVID-19 .............164


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LIST OF TABLES
Table 1:
Study Procedures and Assessments (In-Clinic Visits and Telephone 
Contacts) - For New Patients Only – Pre-Treatment Period (Screening and 
Stage 1) .......................................................................................................................54
Table 2:
Study Procedures and Assessments (In-Clinic Visits and Telephone 
Contacts) – For New and Roll-Over Patients – Baseline, Double-Blind 
Maintenance Stage (Stage 2), End of Treatment, and Follow-Up..............................58
Table 3:
Conversion Table between Oral Risperidone and TV-46000 Doses..........................75
Table 4:
Investigational Medicinal Products Used in the Study...............................................75
Table 5:
Other Medicinal Products Used in the Study .............................................................79
Table 6:
The Relationship of an Adverse Event to the Investigational Medicinal 
Product........................................................................................................................91
Table 7:
Clinical Laboratory Tests ...........................................................................................97
Table 8:
Questions for Unblinded Nurses Administering Study Drug to Patients 
(When Using Prefilled Syringes Only).....................................................................103


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LIST OF FIGURES
Figure 1:
Overall Study Schematic Diagram .............................................................................50


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LIST OF ABBREVIATIONS
Abbreviation
Term
β-HCG
Beta human chorionic gonadotropin 
ADR
adverse drug reaction
AIMS
Abnormal Involuntary Movement Scale
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AUC
area under the plasma concentration-time curve
BARS
Barnes Akathisia Rating Scale
CA
competent authority
CDMS
clinical data management system
CDSS
Calgary Depression Scale for Schizophrenia
CFR
Code of Federal Regulations (USA)
CGI-I
Clinical Global Impression–Improvement
CGI-S
Clinical Global Impression of Severity
CGI-SS
Clinical Global Impression-Severity of Suicidality
Cmax
maximum observed concentration
COVID-19
Coronavirus disease 2019
CRF
case report form (refers to any media used to collect study data [ie, paper or 
electronic])
CRO
contract research organization
CSR
clinical study report
C-SSRS
Columbia Suicide Severity Rating Scale
CYP
cytochrome P450
DAI-10
Drug Attitudes Inventory 10-item version
DMSO
dimethyl sulfoxide
DSM-5
Diagnostic and Statistical Manual of Mental Disorders, 5th Edition 
ECG
electrocardiogram/electrocardiography
EoS
end of study
EoT
end-of-treatment
EPS
extrapyramidal symptoms
EQ-5D-5L
5-Level EuroQol Five Dimensions Questionnaire


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Abbreviation
Term
ER
emergency room
ET
early termination
FDA
Food and Drug Administration
FSH
Follicle-stimulating hormone
GCP
Good Clinical Practice
GLP
Good Laboratory Practice
GPSP
Global Patient Safety and Pharmacovigilance
HIV
human immunodeficiency virus
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Council for Harmonisation
IEC
Independent Ethics Committee
im
intramuscular
IMP
investigational medicinal product
IRB
Institutional Review Board
IRT
Interactive Response Technology
ITT
intent-to-treat
IUD
intrauterine device
LAI
long-acting injectable
LSO
local safety officer
NDA
New Drug Application
NOAEL
no observed adverse effect level
NPRS
Numeric Pain Rating Scale
OTC
over-the-counter
PANSS
Positive and Negative Syndrome Scale
PI
prescribing information
PopPK
population pharmacokinetic
PSP
Personal and Social Performance Scale
Q1
Quarter 1
Q4
Quarter 4
q1m
every month
q2m
every 2 months


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Abbreviation
Term
q3m
every 3 months
q4w
every 4 weeks
q8w
every 8 weeks
RNA
ribonucleic acid
RSI
reference safety information
RTSM
Randomization and Trial Supply Management
SAS
Simpson-Angus Scale
sc
subcutaneous
SCID-5
Structured Clinical Interview for DSM-5
SOP
Standard Operating Procedure
SQLS
Schizophrenia Quality of Life Scale
SUSAR
suspected unexpected serious adverse reaction
TC
telephone call/teleconference
ULN
upper limit of normal
US(A)
United States (of America)
VC
videoconference


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1.
INTRODUCTION AND BACKGROUND INFORMATION
1.1.
Introduction
Schizophrenia is a severely debilitating psychotic disorder characterized by positive symptoms 
(eg, delusions, hallucinations, and grossly disorganized or catatonic behavior) and negative 
symptoms (eg, affective flattening, alogia, and avolition [New York State Office of Mental 
Health 2011, Stefan 2002]). Cognitive deficits are common; they include impairment of 
executive functioning and attention, as well as difficulties with short- and long-term memory.
The worldwide lifetime morbidity risk of the disorder is about 1% across diverse geographic, 
cultural, and socio-economic regions. Since, in most patients, the disease follows a chronic 
course with long-lasting impairment, long-term treatment with antipsychotic agents is usually 
required. Noncompliance and high discontinuation rates are particularly problematic in patients 
with schizophrenia. Premature discontinuation of antipsychotic drug therapy is a common 
phenomenon; in the Clinical Antipsychotic Trials of Intervention Effectiveness study, 74% of 
patients discontinued their antipsychotic drug within 18 months due to either poor tolerability or 
lack of efficacy. Even among patients who do not explicitly discontinue drug therapy, 
nonadherence to long-term oral medication regimen is one of the most significant therapeutic 
issues in the therapy of schizophrenia and related disorders. As a result, many of these patients 
do not experience the full benefit of antipsychotic drug therapy and suffer frequent relapses or 
exacerbations that require rehospitalization, often in the context of psychiatric emergency 
(Rainer 2008). Thus, the use of a long-acting injectable (LAI) antipsychotic agent may increase 
compliance in patients with schizophrenia (Barnes 1994, Hughes 2007, Keith 2003, Walburn 
2001). In addition, recent evidence suggests that early use of LAI risperidone might carry 
advantages for clinical outcomes in patients with schizophrenia, further supported by 
neuroimaging (Subotnik 2015).
The underlying disease mechanisms and initial approach to the diagnosis and treatment of 
schizophrenia in adolescent patients aged 13 to 17 years and adult patients 18 years of age and 
older are essentially the same. Schizophrenia in children and adolescents is accepted to be 
clinically and biologically similar to adult-onset schizophrenia but with some differences in the 
presentation of the symptoms, relative frequency of core psychotic symptoms (eg, auditory 
hallucinations, delusions, and thought disorder), neurocognitive impairments, 
psychophysiological abnormalities, and the presence of structural brain abnormalities 
(Asarnow 1995, Bo 2016, Rapoport 2005). Pediatric patients display a more severe clinical 
prognosis and a greater neurodegenerative trajectory and can be less responsive to treatment 
compared to patients with adult-onset schizophrenia (Bo 2016). Children and adolescents who 
are diagnosed with schizophrenia display high stability with regard to the phenotypical 
expression of the disorder into adulthood (Hollis 2000). Studies of neuropsychological functions 
and brain structure in patients with schizophrenia have shown the same degenerative patterns, 
regardless of the patient’s age at the onset of the disorder (Weinberger 2011).
The sponsor is developing a risperidone extended-release injectable suspension for subcutaneous 
(sc) use that will deliver therapeutic levels of risperidone over intervals of 1 month (TV-46000 
every month [q1m]) or 2 months (TV-46000 every 2 months [q2m]) to patients with 


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schizophrenia. The product is a new sustained-delivery technology based on biocompatible block 
copolymers dissolved in organic solvents (dimethyl sulfoxide [DMSO] for TV-46000). 
TV-46000 is a new formulation of risperidone that uses this technology; the product is referred 
to as TV-46000 q1m and TV-46000 q2m to designate the 1- and 2-month duration products, 
respectively. There are 4 possible TV-46000 dose strengths for each duration product, 
comparable to 2, 3, 4, and 5 mg/day of oral risperidone. The sponsor will provide a 
single-concentration vial of TV-46000 or prefilled syringes; the dose and the volume 
administered will be comparable to the oral risperidone dose on which the patient will be 
stabilized.
 
The critical importance of optimal compliance with prescribed antipsychotic regimens has been 
repeatedly and convincingly demonstrated in patients with schizophrenia. Adherence increases 
the likelihood of positive outcomes in all aspects of a patient’s life, including better symptom 
control, reduced risk of relapse and rehospitalization, and improved quality of life as well as 
social and occupational functioning. Despite their proven effectiveness, poor adherence to 
prescribed antipsychotic regimens remains the most important driver of suboptimal clinical 
outcomes in patients with schizophrenia (Birnbaum 2008).
The rationale for developing q1m and q2m risperidone products is to improve patient compliance 
and to offer greater convenience to the patient through a reduction in clinic visits in comparison 
to other risperidone products currently on the market. It is intended that therapeutic 
concentrations will be reached within 24 hours of injection. It is anticipated that these advantages 
will reduce the rate of relapse and concomitant impact on patients’ well-being and healthcare 
costs. The efficacy, safety, and tolerability of different durations of TV-46000 administered sc 
versus placebo are currently being studied in the ongoing Phase 3 Study TV46000-CNS-30072 
(the RISE Study).
The purpose of Study TV46000-CNS-30078 is to evaluate the safety and tolerability of different 
durations of TV-46000 administered sc. Experience with TV-46000 in humans is limited, and 
therefore, there are only limited data on adverse drug reactions (ADRs) associated with this 
formulation. However, the safety profile of the active ingredient, risperidone, administered in a 
different long-acting parenteral formulation, has been well characterized. The marketed 
intramuscular (im) risperidone long-acting injection (RISPERDAL CONSTA®, Janssen 
Pharmaceuticals) is generally well tolerated. The most commonly reported ADRs include 
insomnia, anxiety, headache, upper respiratory tract infection, parkinsonism, and depression. The 
occurrence of ADRs appears to be dose-related. Injection of TV-46000 is expected to result in 
less pain than the conventional (oil-based) antipsychotic im depot injections. 
In addition, there is a paucity of data in relation to LAI use in children and adolescents with 
serious mental illness, and existing reports have substantial methodological limitations (Lytle 
2017). Enrollment of adolescents in this study will provide data for evaluating the safety and 
tolerability of TV-46000 in this patient population.


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The Investigator’s Brochure (IB) provides detailed information on the background, 
pharmaceutical particulars, nonclinical experience, and clinical experience with TV-46000.
1.2.
Findings from Nonclinical and Clinical Studies
Brief summaries of nonclinical pharmacology, pharmacokinetics, and toxicology studies and 
clinical studies are provided in the following sections. More detailed information is provided in 
the IB.
1.2.1.
Nonclinical Studies
The nonclinical pharmacology and toxicology of risperidone have been well established for oral 
and im administration both in vitro and in vivo. Nonclinical studies evaluating genotoxicity, 
carcinogenicity, chronic toxicology, and reproductive and developmental toxicology of 
risperidone are publicly available in published literature or prescribing information (PI) of 
approved oral or im risperidone products.
Injection of TV-46000 sc to rats and dogs elicited pharmacological signs typical of risperidone. 
In rats only, transient stress-related signs were detected in some of the animals. Pathological 
findings could be divided into systemic pharmacologically related changes 
 
 
 
 
 
Local reaction in rats and dogs was a 
typical foreign body local absorptive reaction. Residual fibrotic capsules at the sites of injection 
were still evident 
 after injection in 
 
 but their size showed a trend toward reduction. In 3 single-dose 
pharmacokinetic and local tolerance non-Good Laboratory Practice (GLP) studies in mini pigs, 
TV-46000 was administered as a single dose 
. In these studies, the sc lesions 
were milder than in rats or dogs; however, 2 cases of generalized erythema 
 
. Both cases were non-life-threatening, and 1 was self-limited. 
 
 In single-dose GLP toxicology studies in both rats and dogs, a no observed adverse 
effect level (NOAEL), and therefore, a margin of safety, could not be determined under the 
experimental conditions of the studies performed because expected adverse reactions related to 
the pharmacological actions of risperidone were noted at all dose levels. Similarly, a NOAEL 
(and therefore, a margin of safety) could not be determined in the multiple-dose toxicity study in 
dogs because of decreased size and weight of male and female reproductive organs that were 
observed at all tested dose levels of the study drug. These changes are known risperidone 
pharmacological effects. Overall, TV-46000 
 and its vehicle 
 
 were well tolerated locally and systematically in rats, dogs, and mini pigs at all doses 
tested. The mutagenic potential of the 
 in TV-46000 was tested in a GLP Ames test, 
and no increase in frequency of revertants was noted.
To summarize, nonclinical studies reported by Teva evaluated 
 TV-46000 
 administered by sc injection. 


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Subsequent clinical investigations 
 have 
demonstrated that this formulation is more suited to a 1- and 2-month dosing interval; however, 
the nonclinical data that have been generated are still relevant for the ongoing clinical 
development program.
1.2.2.
Clinical Studies
1.2.2.1.
Clinical Pharmacology Studies
One pilot Phase 1 exploratory pharmacokinetic study (Study RISPE1ZG15EU) in healthy 
subjects to evaluate the safety, tolerability, and pharmacokinetics of TV-46000 has been 
completed. The study demonstrated that TV-46000, administered at sub-therapeutic doses of 
12.5 or 25 mg, was safe and well tolerated when administered as an sc injection to either the 
posterior upper arm or the abdomen. There was no overall change in the total exposure (area 
under the plasma concentration-time curve [AUC]), maximum observed concentration (Cmax), or 
rate of absorption irrespective of injection site (ie, arm or abdomen) or rubbing of the injection 
site following sc injection of TV-46000. 
In a Phase 1 single and multiple ascending dose study (TV46000-SAD-10055) to evaluate the 
safety, tolerability, and pharmacokinetics of TV-46000 in patients with schizophrenia or 
schizoaffective disorder, a total of 99 patients with schizophrenia or schizoaffective disorder 
were allocated into 8 sequential cohorts of 12 patients each. Study participants were clinically 
stable patients who were currently on antipsychotic treatment of oral risperidone. The study 
included 5 single-dose cohorts (50 to 225 mg) and 2 multiple-dose cohorts (75 and 150 mg) 
administered once-monthly for 3 consecutive months. In addition, interchangeability of injection 
site was assessed via administration of a similar dose (225 mg) to the abdomen and to the upper 
arm. 
All doses of TV-46000 attained therapeutic plasma concentrations within 24 hours. Study results 
supported TV-46000 dosing intervals for 4 to 8 weeks based on therapeutic total active moiety 
plasma concentration. Population pharmacokinetic (PopPK) modeling and simulation have been 
used to select the q1m and q2m doses of TV-46000 for the Phase 3 study, on the basis of 
matching the average exposure level of total active moiety for the 2, 3, 4, and 5 mg/day doses of 
oral risperidone.
 
 
 
 
 
 
 
 
 
The comparison between different sites of injection showed that either the abdomen or arm could 
be used for sc injection without significantly altering the controlled-release drug delivery of 
risperidone.


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Additional information on TV-46000 and risperidone pharmacokinetics can be found in the IB.
1.2.2.2.
Clinical Safety and Efficacy Studies
As of October 2017, the safety and efficacy of oral risperidone have been evaluated in clinical 
studies in a total of 9803 adult and pediatric patients exposed to 1 or more doses of risperidone 
for up to 3 years, including a total of 2687 patients who received oral risperidone in 
double-blind, placebo-controlled studies. The most common adverse events (reported in ≥5% of 
risperidone-treated patients and with a frequency twice that of placebo) were parkinsonism, 
akathisia, dystonia, tremor, sedation, dizziness, anxiety, blurred vision, nausea, vomiting, upper 
abdominal pain, stomach discomfort, dyspepsia, diarrhea, salivary hypersecretion, constipation, 
dry mouth, increased appetite, increased weight, fatigue, rash, nasal congestion, upper 
respiratory tract infection, nasopharyngitis, and pharyngolaryngeal pain (see RISPERIDONE 
tablets, Teva Pharmaceuticals, US PI, 2014).
The safety and efficacy of risperidone long-acting injection have been evaluated in clinical 
studies in a total of 2392 patients exposed to 1 or more doses of risperidone for up to 4 years, 
including a total of 332 patients who were treated with 25 or 50 mg risperidone LAI while 
participating in a 12-week, double-blind, placebo-controlled study. The most common ADRs in 
patients with schizophrenia (≥5% of risperidone-treated patients) were headache, parkinsonism, 
dizziness, akathisia, fatigue, constipation, dyspepsia, sedation, weight increased, pain in 
extremity, and dry mouth (see RISPERDAL CONSTA, Janssen Pharmaceuticals, US PI, 2014).
Limited efficacy data for TV-46000 in patients are available. Furthermore, human safety data on 
TV-46000 are also limited; to date, doses up to 225 mg have been tested. However, the safety 
profile is expected to be generally similar to that of risperidone LAI. To date, the only new safety 
signals that were identified in the TV-46000 Phase 1 program were some types of injection site 
reactions such as injection site pain, erythema, induration, pruritus, and swelling. The majority of 
these adverse events were mild to moderate in severity and resolved quickly. To date, there is no 
efficacy or safety data available from the ongoing, blinded Phase 3 Study TV46000-CNS-30072.
1.3.
Known and Potential Benefits and Risks to Patients
1.3.1.
Known and Potential Benefits and Risks of the Test Investigational Medicinal 
Product(s)
Experience with TV-46000 in humans is limited, and therefore, there are only limited data on 
ADRs associated with this formulation. However, the safety profile of the active ingredient, 
risperidone, administered in a different long-acting parenteral formulation, has been well 
characterized. The marketed im risperidone long-acting injection is generally well tolerated. The 
most commonly reported ADRs include insomnia, anxiety, headache, upper respiratory tract 
infection, parkinsonism, and depression. The occurrence of ADRs appears to be dose-related. 
Injection of TV-46000 is expected to result in less pain than the conventional (oil-based) 
antipsychotic im depot injections. Additional information regarding benefits and risks to patients 
can be found in the IB.
Based on the limited data from the clinical program, injection site erythema, injection site 
edema, injection site pain, and injection site nodules appear to be ADRs of TV-46000.


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In summary, the benefit and risk assessment for TV-46000 is favorable following review of the 
available data.
Additional information regarding benefits and risks to patients may be found in the IB.
1.3.2.
Overall Benefit and Risk Assessment for This Study
In completed clinical studies, oral and im administration of risperidone demonstrated superiority 
over placebo in assessments such as Brief Psychiatric Rating Scale, Scale for the Assessment of 
Negative Symptoms, and Positive and Negative Syndrome Scale (PANSS). This superiority was 
generally dose dependent, with oral doses ranging from 2 to 16 mg/day on a once per day or 
twice per day schedule. On a longer term, risperidone treatment resulted in a significantly longer 
time to relapse over a 2-year period compared to treatment with an active comparator.
Intramuscular risperidone was generally well tolerated over the dose range of 12.5 to 50 mg. The 
most common adverse events in clinical studies (≥5% of risperidone-treated patients and with a 
frequency twice that of placebo) were parkinsonism, akathisia, dystonia, tremor, sedation, 
dizziness, anxiety, blurred vision, nausea, vomiting, upper abdominal pain, stomach discomfort, 
dyspepsia, diarrhea, salivary hypersecretion, constipation, dry mouth, increased appetite, 
increased weight, fatigue, rash, nasal congestion, upper respiratory tract infection, 
nasopharyngitis, and pharyngolaryngeal pain. The most common ADRs in clinical studies of 
risperidone LAI in patients with schizophrenia (≥5% of risperidone-treated patients) were 
headache, parkinsonism, dizziness, akathisia, fatigue, constipation, dyspepsia, sedation, weight 
increased, pain in extremity, and dry mouth. 
To date, Teva has evaluated TV-46000 safety data from 99 patients and 53 healthy volunteers at 
doses of 12.5 to 225 mg. Study TV46000-CNS-30072 was only recently initiated and is therefore 
not included in the above total. Limited efficacy data for TV-46000 in patients are available. 
Furthermore, human safety data on TV-46000 are also limited. However, the safety profile is 
expected to be generally similar to that of risperidone LAI. To date, the only new safety signals 
that were identified in the TV-46000 Phase 1 program were some types of injection site 
reactions. They have not significantly impacted TV-46000’s benefit-risk profile nor have they 
presented a significant burden to the patients.
Thus, the safety profile emerging from these data is consistent with other formulations of 
risperidone, with the exception of the identification of some types of injection site reactions.
With regard to the adolescent patient population, nonclinical studies with TV-46000 in young 
and mature animals did not identify a particular concern for treatment of the targeted adolescent 
population aged 13 years and above. 


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2.
STUDY OBJECTIVES AND ENDPOINTS
2.1.
Primary and Secondary Study Objectives and Endpoints
The primary objective and endpoint are presented below. There are no secondary study 
objectives and endpoints.
Objectives
Endpoints
The primary objective of the study 
is to evaluate the long-term safety 
and tolerability of TV-46000 
administered in adult and adolescent 
patients with schizophrenia.
The primary endpoint is the frequency of all adverse events, 
including serious adverse events.
2.1.1.
Justification of Primary Endpoint
The primary endpoint is the frequency of all adverse events, including serious adverse events.
This is compatible with the recommendations of the Food and Drug Administration (FDA), 
which requested during the End-of-Phase 1 interaction that safety data be collected for at least 
100 patients exposed to TV-46000 for a minimum of 12 months.
2.2.
Exploratory Objectives and Endpoints
Exploratory objectives and endpoints are as follows:
Objectives
Endpoints


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Objectives
Endpoints


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Objectives
Endpoints


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Objectives
Endpoints


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3.
STUDY DESIGN
3.1.
General Study Design and Study Schematic Diagram
This is a multicenter, double-blind, parallel-group study to evaluate the long-term safety, 
tolerability, and efficacy of TV-46000 administered q1m or q2m at doses of 50 to 250 mg sc 
(equivalent to 2 to 5 mg/day of oral risperidone) for up to 56 weeks in adult and adolescent 
patients with schizophrenia. As a precautionary measure, adolescent patients will receive doses 
equivalent to 2 to 4 mg/day oral risperidone.
Eligible female and male patients with schizophrenia who did not experience a relapse and 
completed the Phase 3 pivotal efficacy Study TV46000-CNS-30072 (roll-over patients) and new 
patients (who did not participate in Study TV46000-CNS-30072) may enter this long-term study 
if they meet the inclusion/exclusion criteria and provide informed consent or assent, as 
applicable. 
For adolescent patients, it is mandatory that a parent/caregiver accompanies the patient to each 
visit and serves as a reliable informant. It is recommended that a caregiver is identified for each 
adult patient. Local requirements should be followed. The caregiver may be contacted in case of 
loss of contact with the patient or to provide additional information about the patient, if needed. 
Adult patients could be accompanied by caregivers to visits.
A. New Patients: Screening through beginning of Stage 2
For new patients, the study duration will consist of a screening period (up to 4 weeks), a 
conversion/stabilization stage (12 weeks on oral risperidone, Stage 1), a double-blind, 
active-treatment maintenance stage (up to 56 weeks; Stage 2), and a follow-up period (8 weeks).
Screening: These patients will undergo screening procedures/assessments within 4 weeks before 
the start of Stage 1. Adult patients (aged 18-65) should have had a diagnosis of schizophrenia for 
>1 year, and adolescent patients (aged 13-17) should have had a diagnosis of schizophrenia for 
>6 months (diagnosis must be reconfirmed by Structured Clinical Interview for Diagnostic and 
Statistical Manual of Mental Disorders, 5th Edition [DSM-5] [SCID-5]), and have been generally 
responsive to antipsychotics in the past year based on discussions with family members or 
healthcare professionals. Adult patients should also have had ≥1 episode of relapse in the last 
24 months. Patients will provide informed consent or assent, as applicable, at the screening visit, 
before any study-related procedures or assessments are performed.
Stage 1 (12-week oral conversion and stabilization stage): New patients on any antipsychotic 
(other than clozapine) who can benefit from conversion to oral risperidone based on the 
investigator’s judgment will be converted to oral risperidone to stabilize the patients on the 
treatment. Oral risperidone (at a dose of 2 to 5 mg/day, based on clinical judgment) will be given 
for 12 weeks to ensure that the patients can tolerate risperidone and that the doses are adequate to 
treat their positive symptoms. Adolescent patients will receive a maximal dose of 4 mg/day. 
Patients will come to the clinic for 4 visits (weeks -12, -10, -8, and -4) for various assessments 
and dose adjustments (Table 1). Additional visits may be required for dose adjustments. Patients 
will be evaluated using the PANSS, Clinical Global Impression of Severity (CGI-S), Abnormal 
Involuntary Movement Scale (AIMS), Barnes Akathisia Rating Scale (BARS), Simpson-Angus 


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Scale (SAS), Columbia Suicide Severity Rating Scale (C-SSRS), Calgary Depression Scale for 
Schizophrenia (CDSS), Clinical Global Impression-Severity of Suicidality (CGI-SS), and 
Clinical Global Impression-Improvement (CGI-I). Additionally, telephone contact will take 
place at weeks -6 and -2, or more frequently if required in the judgment of the investigator.
Stability (as assessed at the baseline visit) is defined as meeting all of the following criteria for at 
least 4 consecutive weeks prior to the baseline visit:

outpatient status
 
 
Patients who require a stabilization dose below 2 mg/day will not be randomized in the study. As 
a precautionary measure, adolescent patients who will require a stabilization dose of more than 
4 mg/day during the stabilization stage will not be randomized.
If a patient withdraws from the study prior to the randomization (baseline) visit (Visit 6), the 
case report form (CRF) for the patient’s last visit will be marked as “Not Continuing”, and the 
reason for discontinuation will be recorded. No extra testing or procedures will be required in 
addition to the regular visits.
During the baseline visit, new patients who meet the stability criteria will be randomized in a 
1:1 manner to receive TV-46000 q1m or q2m sc injections at the TV-46000 dose equivalent to 
the oral dose on which they were stabilized in Stage 1 of this study and will enter Stage 2 of the 
study (double-blind maintenance stage) described below.
B. Roll-Over Patients: Screening through beginning of Stage 2
For roll-over patients, the study duration will consist of a double-blind, active-treatment
maintenance stage (up to 56 weeks; Stage 2) and a follow-up period (8 weeks).
Roll-over patients will begin this study at the baseline visit and start at Stage 2 of the study 
(double-blind maintenance stage). For these patients, the end-of-treatment (EoT) visit in Study 
TV46000-CNS-30072 will serve as the baseline visit. Some baseline procedures will be 
performed as part of the EoT visit in the TV46000-CNS-30072 study, and the results will be 
transferred to this study's clinical database (see Table 2 and Appendix B, Section 3).
During Stage 2 of this study, patients who were treated with TV-46000 q1m or q2m during 
Study TV46000-CNS-30072 will continue their assigned arm and dose from Study TV46000-
CNS-30072. Patients who were treated with placebo during Study TV46000-CNS-30072 will be 
randomized in a 1:1 manner to receive TV-46000 q1m or q2m sc injections at the TV-46000 
dose equivalent to the oral dose on which they were stabilized in Stage 1 of Study TV46000-
CNS-30072.


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C. New and Roll-Over Patients: Stage 2
After patients are assigned to receive TV-46000 q1m or q2m sc injections during the baseline 
visit, the study will continue on an outpatient basis. The maximal dose of TV-46000 
administered to adult patients will be equivalent to an oral risperidone dose of 5 mg/day, and the 
maximal TV-46000 dose administered to adolescents will be equivalent to 4 mg/day oral 
risperidone. All patients will attend in-clinic visits q1m (ie, the dosing visits) and will undergo 
various procedures and assessments as detailed in Table 2. Throughout the duration of the study, 
telephone contact will take place weekly between clinic visits. 
Patients who complete all scheduled visits will have EoT/early termination (ET) procedures and 
assessments performed at week 56 and follow-up procedures and assessments performed at 
weeks 60 and 64. 
Per definition, an exacerbation in symptoms during Stage 1 (new patients) cannot be defined as a 
relapse event, since relapse events can only occur following stabilization and randomization. 
Patients who started Stage 2 who relapse or meet 1 or more of the withdrawal criteria should be 
invited to perform the ET visit as soon as possible within 4 weeks of the last injection.
Patients who withdraw from the study before completing the 56-week maintenance stage will 
have follow-up procedures and assessments performed at their follow-up visits. During the 
follow-up period, patients will be treated according to the investigator’s judgment.
For new patients (ie, patients not rolling over from the pivotal efficacy study), the total duration 
of patient participation in the study is planned to be up to 80 weeks (including a screening period 
of up to 4 weeks, a 12-week oral conversion/stabilization stage [Stage 1], a 56-week maintenance 
stage [Stage 2], and a follow-up period [8 weeks]). 
For patients rolling over from the pivotal efficacy Study TV46000-CNS-30072, the total duration 
of patient participation in the study is planned to be up to 64 weeks (including up to 56 weeks in 
the maintenance stage [Stage 2] and a follow-up period [8 weeks]).
End of study (EoS) is defined as the date when the last patient in Stage 2 has completed all 
efficacy and safety assessments at the final visit per protocol (Follow-up Visit 2).
The study duration will be approximately 25 months, from Quarter 1 (Q1) 2019 to Quarter 1 
(Q1) 2021.
Study procedures and assessments with their time points are shown in Table 1 and Table 2. The 
study schematic diagram is shown in Figure 1.
For Coronavirus disease 2019 (COVID-19) updates, refer to Appendix N.


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Figure 1:
Overall Study Schematic Diagram


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BL=baseline; EoS=end of study; EoT=end of treatment; ET=early termination; FU=follow-up; PK=pharmacokinetics; plc=placebo; q1m=every month; 
q2m=every 2 months; q4w=every 4 weeks; sc=subcutaneous; V=visit; Wk=week; IMP=investigational medicinal product.


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3.2.
Planned Number of Patients and Countries
Based on regulatory requirements, up to approximately 300 patients are planned to be enrolled in 
Stage 2 of this study in order to collect data on at least 100 patients exposed to TV-46000 for at 
least 1 year.
Assuming that at least 90% of patients in Study TV46000-CNS-30072 roll over into this study, 
then about 225 patients will roll over, and approximately 143 new patients will be screened to 
achieve enrollment of approximately 107 new patients in Stage 1. This is expected to achieve an 
overall number of approximately 300 enrolled patients in Stage 2, including approximately 75 
new patients and approximately 225 roll-over patients. 
In case the assumption about the number of patients rolling over from Study TV46000-CNS-
30072 is found to not be valid at a later stage (ie, at the time of interim analysis), the number of 
new patients may be modified to meet the requirement to follow 100 patients for at least 1 year. 
The study is planned to be conducted in the United States (US) and Bulgaria in approximately 
100 investigational centers (new centers and those that participated in Study TV46000-CNS-
30072). The study is expected to start in Q1 2019 and last until approximately Q1 2021.
Adolescent patients will only be enrolled in the US; any enrolled adolescents will be in addition 
to the aforementioned total.
3.3.
Justification for Study Design and Selection of Population
Long-term use of antipsychotic agents has been shown to be effective in preventing relapse in 
patients with schizophrenia, but carries the risk of side effects (including weight gain, 
hyperglycemia/diabetes, and metabolic syndrome) and must be justified for each new agent or 
new formulation. Therefore, the sponsor is conducting a scientifically valid study that supports 
the use of TV-46000 at the proposed clinical dosage regimen (Study TV46000-CNS-30072). 
This study comprises the safety extension of Study TV46000-CNS-30072, to further evaluate the 
safety, tolerability, and efficacy of TV-46000.
The population for this study consists of adult and adolescent patients with chronic schizophrenia 
and excludes patients with acute disease. Only new patients who have been stabilized on oral 
therapy with risperidone, or stable roll-over patients from Study TV46000-CNS-30072, will be 
enrolled into the double-blind maintenance stage of the study.
The doses of randomized investigational medicinal product (IMP) to be evaluated in this 
double-blind study (50 to 125 mg q1m sc and 100 to 250 mg q2m sc) were selected on the basis 
of Study TV46000-SAD-10055 and Study TV46000-CNS-30072.
Based on the pharmacokinetic performance and the safety profile of TV-46000 in 
Study TV46000-SAD-10055 and the PopPK model-derived simulations, it is expected that 
TV-46000 will provide sufficient coverage throughout 28 days (for q1m) and 56 days (for q2m) 
in 4 doses (50, 75, 100, and 125 mg and 100, 150, 200, and 250 mg, respectively) equivalent to 
2, 3, 4, and 5 mg/day oral risperidone based on the total active moiety (Table 3). The maximal 
TV-46000 dose administered to adolescents will be equivalent to 4 mg/day oral risperidone.
A Phase 3 safety study will allow the establishment of an adequate safety database for long-term 
exposure to TV-46000. Maintaining patients on TV-46000 following their completion of the 


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placebo-controlled Phase 3 pivotal efficacy study or switching patients from placebo to either the 
q1m product or the q2m product will simplify this study design and will provide additional 
safety data for the higher doses (100 to 250 mg).
3.4.
Stopping Rules for the Study
There are no formal rules for ET of this study. During the conduct of the study, serious adverse 
events will be reviewed (Section 7.1.5) as they are reported from the investigational centers to 
identify safety concerns.
The study may be terminated by the sponsor for any reason at any time. For example, the 
sponsor should terminate the study in the event of the following:

new toxicological or pharmacological findings or safety issues that invalidate the 
earlier positive benefit-risk assessment

discontinuation of the development of the IMP
3.5.
Schedule of Study Procedures and Assessments
 
 
 
 
For COVID-19 updates, refer to Appendix N.


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Table 1:
Study Procedures and Assessments (In-Clinic Visits and Telephone Contacts) - For New Patients Only –
Pre-Treatment Period (Screening and Stage 1)
Study Period
Pre-Treatment Perioda
N/A
Screening
Stage 1: Oral Conversion and Stabilization Stageb
Unscheduled Visit
Visit number
V1
V2
V3
V4
V4a
V5
V5a
Time point
Procedures and assessments 
Wk-16
Wk -12
Wk -10
Wk -8
Wk -6
Wk -4c
Wk -2
As deemed 
necessary by the 
investigatord
Allowed time window
+4 weeks
±3 days
N/A
In-clinic visit
X
X
X
X
X
X
Telephone calle,f
X
X
Informed consent (and assent, as applicable)
X
Medical and psychiatric history
X
SCID-5
X
Prior medication history
X
Inclusion and exclusion criteria
X
Clinical laboratory testsg,h
X
X
Virology and thyroid screening testsi
X
Urine drug screen
X
Concomitant medication inquiry
X
X
X
X
X
X
Full physical examination, including weight
Xj
X
Vital sign measurementsk
X
X
X
X
X
X
12-lead ECGl
X
FSH testm
X
Serum β-HCG test for women of childbearing potential
X


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Study Period
Pre-Treatment Perioda
N/A
Screening
Stage 1: Oral Conversion and Stabilization Stageb
Unscheduled Visit
Visit number
V1
V2
V3
V4
V4a
V5
V5a
Time point
Procedures and assessments 
Wk-16
Wk -12
Wk -10
Wk -8
Wk -6
Wk -4c
Wk -2
As deemed 
necessary by the 
investigatord
Allowed time window
+4 weeks
±3 days
N/A
In-clinic visit
X
X
X
X
X
X
Telephone calle,f
X
X
Urine β-HCG test for women of childbearing potentialn
X
X
X
X
Inquiry about pregnancy status (for women of 
childbearing potential)
X
X
PANSS
X
X
X
X
X
X
CGI-S
X
X
X
X
X
CGI-SSo
X
X
X
X
X
CGI-Ip
X
X
X
X
AIMS
X
X
X
X
X
BARS
X
X
X
X
X
SAS
X
X
X
X
X
C-SSRSq
X
X
X
X
X
X
X
X
PSP (for adult patients only)
X
SQLS (for adult patients only)
X
EQ-5D-5L (for adults patients only)
X
CDSS
X
X
X
X
X
Healthcare resource utilization
X
DAI-10 (for adult patients only)
X
Blood samples for plasma drug concentrationr
X
X


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Study Period
Pre-Treatment Perioda
N/A
Screening
Stage 1: Oral Conversion and Stabilization Stageb
Unscheduled Visit
Visit number
V1
V2
V3
V4
V4a
V5
V5a
Time point
Procedures and assessments 
Wk-16
Wk -12
Wk -10
Wk -8
Wk -6
Wk -4c
Wk -2
As deemed 
necessary by the 
investigatord
Allowed time window
+4 weeks
±3 days
N/A
In-clinic visit
X
X
X
X
X
X
Telephone calle,f
X
X
Oral risperidone dispensing (for qd intake)s
X
X
X
X
Dosage review and adjustmentt
X
X
X
X
Adverse event inquiry (including SAE reporting)
X
X
X
X
X
X
X
X
Inquiry regarding alcohol consumption/illicit drug use 
X
X
X
X
X
X
X
X
Brief set of clinical questions to detect psychotic 
symptomsu
X
X
a If a patient withdraws from the study prior to the randomization (baseline) visit (Visit 6), the CRF for the patient’s last visit will be marked as ”Not 
Continuing”, and the reason for discontinuation will be recorded. No extra testing or procedures will be required in addition to the regular visits.
b Visits 3 through 5a should be scheduled relative to Visit 2 (and not relative to screening). For example, Visit 3 should be scheduled 2 weeks (±3 days) after 
Visit 2, regardless of when the screening visit took place.
c Patients whose symptoms have stabilized at this visit will be required to meet the specified stability criteria for at least 4 consecutive weeks, until the baseline 
visit at which they will be assessed.
d Other procedures may be performed at the discretion of the investigator.
e Telephone contact will occur at week -6 and week -2 in the oral conversion and stabilization stage (Stage 1) (or more frequently if required in the judgement of 
the investigator). These contacts will be referred to by the previous visit number and a letter (for example, the telephone contact that takes place 2 weeks after 
Visit 4 will be referred to as “Visit 4a”).
f Each contact will include inquiries about suicidal ideation and behavior (C-SSRS), adverse events, alcohol consumption, and pregnancy status (for women of 
childbearing potential). Patients will also be asked a brief set of clinical questions in order to detect psychotic symptoms (see relevant assessment). 
g Clinical laboratory tests (serum chemistry, hematology, and urinalysis) may also be performed at any time if clinically indicated.
h Glomerular filtration rate (GFR) will be calculated based on plasma creatinine levels, weight, gender, and age using the Cockcroft-Gault equation.
i Includes HIV, HBsAg, hepatitis C antibody, TSH, T3, and T4.
j Height will be measured at the screening visit only.
k Vital sign measurements will include blood pressure [systolic/diastolic], respiratory rate, tympanic temperature, and pulse.


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l At screening, ECG measurements will be done in triplicate. The mean of the 3 measurements will be used to determine study eligibility.
m The FSH test will only be performed for women with no menses for 12 months in order to confirm postmenopausal status.
n Urine β-HCG (dipstick) test will be performed at all visits where oral risperidone is administered prior to study drug administration. A negative result must be 
obtained before study drug can be administered.
o In Stage 1, for new patients, Part 2 of the CGI-SS will be compared to screening.
p CGI-I during Stage 1 will be relative to screening.
q For new patients, the C-SSRS will be administered at screening (baseline/screening version), and the “since last visit” version will be administered at all 
post-screening visits and telephone contacts during the study.
r During the in-clinic visits in Stage 1 (V2 and V5) where the blood samples for pharmacokinetic assessment are taken, samples should be taken within an hour 
prior to dosing, if possible. In any case, the hour of the last dose taken prior to collection of the pharmacokinetic sample will be recorded on the CRF.
s Patients will be advised to take the oral risperidone at approximately the same hour every day (morning or evening, at their convenience). The hour of the last 
dose taken prior to collection of the pharmacokinetic sample will be recorded on the CRF.
t Adolescent patients will receive a maximal dose of 4 mg/day oral risperidone.
u The specific questions asked will be at the discretion of the investigator. A list of suggested questions will be provided to the investigator. Psychiatric adverse 
events or suspicion of psychiatric deterioration prompted by the telephone contact will trigger an invitation of the patient to an unscheduled visit where 
psychiatric scales will be administered to rule out an impending relapse at the discretion of the investigator.
β-HCG=beta human chorionic gonadotropin; AIMS=Abnormal Involuntary Movement Scale; BARS=Barnes Akathisia Rating Scale; CDSS=Calgary Depression 
Scale for Schizophrenia; CGI-I=Clinical Global Impression-Improvement; CGI-S=Clinical Global Impression of Severity; CGI-SS=Clinical Global Impression-
Severity of Suicidality; CRF=case report form; C-SSRS=Columbia Suicide Severity Rating Scale; DAI-10=Drug Attitudes Inventory 10-item version; 
DSM-5=Diagnostic and Statistical Manual of Mental Disorders, 5th Edition; ECG=electrocardiogram; EQ-5D-5L=5-Level EuroQol Five Dimensions 
Questionnaire; FSH=follicle-stimulating hormone; GFR=glomerular filtration rate; HBsAg=hepatitis B surface antigen; HIV=human immunodeficiency virus; 
N/A=not applicable; PANSS=Positive and Negative Syndrome Scale; PSP=Personal and Social Performance Scale; qd=every day; SAE=serious adverse event; 
SAS=Simpson-Angus Scale; SCID-5=Structured Clinical Interview for DSM-5; SQLS=Schizophrenia Quality of Life Scale; T3=triiodothyronine; T4=thyroxine; 
TSH=thyroid-stimulating hormone; Wk=week; V=visit.


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Table 2:
Study Procedures and Assessments (In-Clinic Visits and Telephone Contacts) – For New and Roll-Over Patients 
– Baseline, Double-Blind Maintenance Stage (Stage 2), End of Treatment, and Follow-Up
Study Period
Double-Blind Maintenance Stagea
Follow-Up
N/A
BL
Stage 2: Relapse Prevention Stage
The 24-week series from Visit 7 to Visit 12c repeats (Visit 13-18c, 19-19c), until patient 
completion, relapse, or early termination (Visits 19-19c are identical to Visits 7-7c).
ET/ 
EoT
FU1
FU2/ 
EoS
Unscheduled 
Visit
Visit number
V6
V6a, 
6b, 6c
V7
V7a, 
7b, 7c
V8
V8a, 
8b, 8c
V9
V9a, 
9b, 9c
V10
V10a, 
10b, 
10c
V11
V11a, 
11b, 
11c
V12
V12a, 
12b, 
12c
V20
V21
V22
As deemed 
necessary by 
the 
investigatorb
Time point
Procedures and 
assessments 
Day 1
Wks 1-
3
Wk 4
Wks 
5-7
Wk 8 Wks 9-
11
Wk 
12
Wks 
13-15
Wk 
16
Wks 
17-19
Wk 
20
Wks 
21-23
Wk 
24
Wks 
25-27
Wk 
56
Wk 60 Wk 64
Allowed window
±3 days
N/A
In-clinic visit
X
X
X
X
X
X
X
X
X
X
X
Telephone callc, d
X
X
X
X
X
X
X
Informed consent (and 
assent, as applicable) (for 
roll-over patients only)
X
Inclusion and exclusion 
criteria
Xe
Clinical laboratory testsf, g
Xh
X
X
X
X
X
X
Virology and thyroid 
screening testsi
X
Urine drug screen
Xh
X
Concomitant medication 
inquiry
Xh
X
X
X
X
X
X
X
X
X
X
Full physical examination, 
including weight
Xh j
X
X
X
Vital sign measurementsk
Xh
X
X
X
X
X
X
X
X
X
X
12-lead ECGl
X
X
X
X
Xm
X
X


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Study Period
Double-Blind Maintenance Stagea
Follow-Up
N/A
BL
Stage 2: Relapse Prevention Stage
The 24-week series from Visit 7 to Visit 12c repeats (Visit 13-18c, 19-19c), until patient 
completion, relapse, or early termination (Visits 19-19c are identical to Visits 7-7c).
ET/ 
EoT
FU1
FU2/ 
EoS
Unscheduled 
Visit
Visit number
V6
V6a, 
6b, 6c
V7
V7a, 
7b, 7c
V8
V8a, 
8b, 8c
V9
V9a, 
9b, 9c
V10
V10a, 
10b, 
10c
V11
V11a, 
11b, 
11c
V12
V12a, 
12b, 
12c
V20
V21
V22
As deemed 
necessary by 
the 
investigatorb
Time point
Procedures and 
assessments 
Day 1
Wks 1-
3
Wk 4
Wks 
5-7
Wk 8 Wks 9-
11
Wk 
12
Wks 
13-15
Wk 
16
Wks 
17-19
Wk 
20
Wks 
21-23
Wk 
24
Wks 
25-27
Wk 
56
Wk 60 Wk 64
Allowed window
±3 days
N/A
In-clinic visit
X
X
X
X
X
X
X
X
X
X
X
Telephone callc, d
X
X
X
X
X
X
X
Serum β-HCG test for 
women of childbearing 
potential
X
X
X
Urine β-HCG test for 
women of childbearing 
potentialn
Xh
X
X
X
X
X
X
X
Inquiry about pregnancy 
status (for women of 
childbearing potential)
X
X
X
X
X
X
X
PANSSo
Xh
X
X
X
X
X
X
X
X
X
X
CGI-S
Xh
X
X
X
X
X
X
X
X
X
CGI-SSp
Xh
X
X
X
X
X
X
X
X
X
CGI-Iq
X
X
X
X
X
X
X
X
X
AIMS
Xh
X
X
X
X
X
X
X
X
X
BARS
Xh
X
X
X
X
X
X
X
X
X
SAS
Xh
X
X
X
X
X
X
X
X
X
C-SSRSr
Xh
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X


Uncontrolled Study–Schizophrenia
Clinical Study Protocol with Amendment 01
Study TV46000-CNS-30078
60
Study Period
Double-Blind Maintenance Stagea
Follow-Up
N/A
BL
Stage 2: Relapse Prevention Stage
The 24-week series from Visit 7 to Visit 12c repeats (Visit 13-18c, 19-19c), until patient 
completion, relapse, or early termination (Visits 19-19c are identical to Visits 7-7c).
ET/ 
EoT
FU1
FU2/ 
EoS
Unscheduled 
Visit
Visit number
V6
V6a, 
6b, 6c
V7
V7a, 
7b, 7c
V8
V8a, 
8b, 8c
V9
V9a, 
9b, 9c
V10
V10a, 
10b, 
10c
V11
V11a, 
11b, 
11c
V12
V12a, 
12b, 
12c
V20
V21
V22
As deemed 
necessary by 
the 
investigatorb
Time point
Procedures and 
assessments 
Day 1
Wks 1-
3
Wk 4
Wks 
5-7
Wk 8 Wks 9-
11
Wk 
12
Wks 
13-15
Wk 
16
Wks 
17-19
Wk 
20
Wks 
21-23
Wk 
24
Wks 
25-27
Wk 
56
Wk 60 Wk 64
Allowed window
±3 days
N/A
In-clinic visit
X
X
X
X
X
X
X
X
X
X
X
Telephone callc, d
X
X
X
X
X
X
X
PSP (for adult patients 
only)
Xh
Xs
X
X
X
SQLS (for adult patients 
only)
Xh
Xs
X
X
X
EQ-5D-5L (for adult 
patients only)
Xh
Xs
X
X
X
CDSS
Xh
X
X
X
X
X
X
X
X
X
Healthcare resource 
utilization
Xh
Xs
X
X
X
DAI-10 (for adult patients 
only)
Xh
X
X
Blood samples for 
pharmacogenetic analysis
Xt
Blood samples for 
biomarker analysisu
X
X
X
X
X
X
X
Blood samples for plasma 
drug concentrationv
X
X
X
X
X
X
X
X
X
X
Xw


Uncontrolled Study–Schizophrenia
Clinical Study Protocol with Amendment 01
Study TV46000-CNS-30078
61
Study Period
Double-Blind Maintenance Stagea
Follow-Up
N/A
BL
Stage 2: Relapse Prevention Stage
The 24-week series from Visit 7 to Visit 12c repeats (Visit 13-18c, 19-19c), until patient 
completion, relapse, or early termination (Visits 19-19c are identical to Visits 7-7c).
ET/ 
EoT
FU1
FU2/ 
EoS
Unscheduled 
Visit
Visit number
V6
V6a, 
6b, 6c
V7
V7a, 
7b, 7c
V8
V8a, 
8b, 8c
V9
V9a, 
9b, 9c
V10
V10a, 
10b, 
10c
V11
V11a, 
11b, 
11c
V12
V12a, 
12b, 
12c
V20
V21
V22
As deemed 
necessary by 
the 
investigatorb
Time point
Procedures and 
assessments 
Day 1
Wks 1-
3
Wk 4
Wks 
5-7
Wk 8 Wks 9-
11
Wk 
12
Wks 
13-15
Wk 
16
Wks 
17-19
Wk 
20
Wks 
21-23
Wk 
24
Wks 
25-27
Wk 
56
Wk 60 Wk 64
Allowed window
±3 days
N/A
In-clinic visit
X
X
X
X
X
X
X
X
X
X
X
Telephone callc, d
X
X
X
X
X
X
X
Additional blood samples 
for adolescent 
pharmacokinetic analysis 
(for adolescents only)
Xx
Assessment of stability 
Xy
Randomizationz
X
TV-46000 q1m sc 
administration
Xaa (new 
patients 
only)
X
X
X
X
X
X
Xbb
TV-46000 q2m sc 
administrationcc (to 
maintain the blind, 
patients will be injected 
q4w, but will alternate 
between TV-46000 and 
placebo sc injections)
Xaa (new 
patients 
only)
X
X
X
X
X
X
Xbb
Questions to assess ease 
of study drug 
administration (for new 
patients only)dd
X
X
X


Uncontrolled Study–Schizophrenia
Clinical Study Protocol with Amendment 01
Study TV46000-CNS-30078
62
Study Period
Double-Blind Maintenance Stagea
Follow-Up
N/A
BL
Stage 2: Relapse Prevention Stage
The 24-week series from Visit 7 to Visit 12c repeats (Visit 13-18c, 19-19c), until patient 
completion, relapse, or early termination (Visits 19-19c are identical to Visits 7-7c).
ET/ 
EoT
FU1
FU2/ 
EoS
Unscheduled 
Visit
Visit number
V6
V6a, 
6b, 6c
V7
V7a, 
7b, 7c
V8
V8a, 
8b, 8c
V9
V9a, 
9b, 9c
V10
V10a, 
10b, 
10c
V11
V11a, 
11b, 
11c
V12
V12a, 
12b, 
12c
V20
V21
V22
As deemed 
necessary by 
the 
investigatorb
Time point
Procedures and 
assessments 
Day 1
Wks 1-
3
Wk 4
Wks 
5-7
Wk 8 Wks 9-
11
Wk 
12
Wks 
13-15
Wk 
16
Wks 
17-19
Wk 
20
Wks 
21-23
Wk 
24
Wks 
25-27
Wk 
56
Wk 60 Wk 64
Allowed window
±3 days
N/A
In-clinic visit
X
X
X
X
X
X
X
X
X
X
X
Telephone callc, d
X
X
X
X
X
X
X
Adverse event inquiry 
(including SAE reporting, 
injection site-related 
events including pain)ee
Xh
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Inquiry regarding alcohol 
consumption/illicit drug 
use 
Xh
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Brief set of clinical 
questions to detect 
psychotic symptomsff
X
X
X
X
X
X
X
a The double-blind maintenance stage will be up to 56 weeks in length, with patients continuing until they experience a relapse event (and complete all EoS 
assessments); meet 1 or more of the study discontinuation or withdrawal criteria; or remain relapse-free until study completion. Patients will continue study 
visits and assessments as shown in the table (ie, the same assessments performed at Visits 7 and 8 will be repeated at Visits 9 and 10, respectively, unless 
otherwise specified). The functional measures (PSP, SQLS, and EQ-5D-5L) and the healthcare resource utilization will be performed every 12 weeks (Visits 9, 
12, 15, and 18).
aaNote that the EoT visit in Study TV46000-CNS-30072 will serve as the baseline visit for roll-over patients in this study (ie, roll-over patients receive their last 
injection of IMP at the EoT visit in Study TV46000-CNS-30072 and receive their next injection at week 4 in this study).
b Other procedures may be performed at the discretion of the investigator.
bbApplicable only for the EoT visit (ie, not ET). If in the judgment of the investigator, the patient will not come to 1 or both follow-up visits, then a dose of study 
drug should not be given at this EoT visit.


Uncontrolled Study–Schizophrenia
Clinical Study Protocol with Amendment 01
Study TV46000-CNS-30078
63
c Telephone contact will occur weekly between clinic visits in the double-blind maintenance stage (Stage 2). These contacts will be referred to by the previous 
visit number and a letter (for example, the telephone contacts that take place 1, 2, and 3 weeks after Visit 6 will be referred to as “Visit 6a,” “Visit 6b,” and 
“Visit 6c,” respectively).
ccNew patients randomized to this arm will receive TV-46000 at baseline and q8w thereafter and placebo at week 4 and q8w thereafter (between the TV-46000 
q2m injections) to maintain the blind. Roll-over patients who were assigned to placebo during Study TV46000-CNS-30072 and are randomized to receive TV 
46000 q2m in this study will receive TV 46000 at week 4 and q8w thereafter, and a placebo sc injection at week 8 and q8w thereafter. For roll-over patients 
who were assigned to TV-46000 q2m during Study TV46000-CNS-30072, their injection at week 4 will depend on their injection at the EoT visit of Study 
TV46000 CNS-30072 (ie, if their last injection in Study TV46000-CNS-30072 was placebo, then their Study TV46000-CNS-30078 week 4 injection will be 
TV-46000 and vice versa).
d Each contact will include inquiries about injection site pain, suicidal ideation and behavior (C-SSRS), adverse events, alcohol consumption, and pregnancy 
status (for women of childbearing potential). Patients will also be asked a brief set of clinical questions in order to detect psychotic symptoms (see relevant 
assessment).
ddThis will be completed by the unblinded nurse who administers the study drug to the patients following the first 3 injections (using prefilled syringes) to each 
patient (ie, Visits 6, 7 and 8). In the event that prefilled syringes of TV-46000 become unavailable during the study, the unblinded nurse responsible for study 
drug administration will use vials (instructions on how to use vials can be found in the Pharmacy Manual).
e New patients must meet randomization criteria in addition to other relevant inclusion criteria before randomization. Roll-over patients must meet specific 
inclusion/exclusion criteria (Section 4.1 and Section 4.2).
eeInjection site pain and other injection site reactions will only be assessed during Stage 2 of the study, in which the sc injections are administered. Pain may be 
assessed periodically using the NPRS until resolution.
f Clinical laboratory tests (serum chemistry, hematology, and urinalysis) may also be performed at any time if clinically indicated.
ff The specific questions asked will be at the discretion of the investigator. A list of suggested questions will be provided to the investigator. Psychiatric adverse 
events or suspicion of psychiatric deterioration prompted by the telephone contact will trigger an invitation of the patient to an unscheduled visit where 
psychiatric scales will be administered to rule out an impending relapse at the discretion of the investigator.
g Glomerular filtration rate (GFR) will be calculated based on plasma creatinine levels, weight, gender, and age using the Cockcroft-Gault equation.
h For roll-over patients, this procedure will be performed as part of the TV46000-CNS-30072 EoT visit, and the results will be transferred to this study's clinical 
database.
i For roll-over patients only; includes HIV, HBsAg, hepatitis C antibody, TSH, T3, and T4.
j For adult roll-over patients, height will be obtained from the patient’s record in Study TV46000-CNS-30072. For adolescent roll-over patients, height will be 
measured again at the baseline visit. New patients will have height recorded at screening and therefore do not need to be measured again for height at the 
baseline visit.
k Vital sign measurements will include blood pressure [systolic/diastolic], respiratory rate, tympanic temperature, and pulse.
l At baseline, measurements will be done in triplicate. The mean of the 3 measurements will be used to determine study eligibility. Single measurements will be 
performed at all other in-clinic visits where ECG recordings are taken.
m During the ET/EoT visit, if in the judgment of the investigator the patient will not come to 1 or both of the follow-up visits, an ECG should be performed.
n Urine β-HCG (dipstick) test will be performed at all visits where study drug is administered prior to study drug administration. A negative result must be 
obtained before study drug can be administered.
o The PANSS will be relative to randomization for new patients. For roll-over patients, the PANSS will be relative to randomization in Study TV46000 CNS-
30072.


Uncontrolled Study–Schizophrenia
Clinical Study Protocol with Amendment 01
Study TV46000-CNS-30078
64
p In Stage 2, for new patients, Part 2 of the CGI-SS will be compared to baseline; for roll-over patients, it will be compared to baseline of Study TV46000 CNS 
30072.
q For new patients, CGI-I during Stage 2 will be relative to the baseline visit; for roll-over patients, it will be relative to the patient’s baseline visit in Study 
TV46000-CNS-30072.
r For new patients, the C-SSRS will be administered at screening (baseline/screening version), and the “since last visit” version will be administered at all post 
screening visits and telephone contacts during the study. For roll-over patients, the “since last visit” version will be administered at baseline and all subsequent 
visits and telephone contacts during the study.
s As of Visit 9, inclusive, this assessment will be performed every 12 weeks (Visits 9, 12, 15, and 18), at ET/EoT visit, and at Follow-up Visit 2.
t For new patients, a blood sample for pharmacogenetic analysis will be collected at baseline or any visit thereafter, unless the patient declines testing or local 
regulations prohibit testing. For roll-over patients, if a sample was not collected during Study TV46000-CNS-30072 for any reason, it will be collected at the 
baseline visit or any visit thereafter, unless the patent declines testing or local regulations prohibit testing.
u Blood samples for biomarker analyses will be collected as follows: 6 mL for serum, 6 mL for plasma, and 2.5 mL for PAXgene RNA, unless the patient 
declines testing or local regulations prohibit testing.
v Blood samples for pharmacokinetic assessment should be taken within an hour prior to dosing, where possible and as applicable.
w During Stage 2, unscheduled pharmacokinetic samples will be aimed to be collected in the event of relapse as defined per the study’s relapse criteria, any 
serious adverse event, patient withdrawal, and/or need for potential TV-46000 depot excision. Every effort should be made to obtain the additional 
pharmacokinetic sample at the closest time possible to the occurrence of the event.
x Another pharmacokinetic sample will be collected from adolescent patients at a supplementary in-clinic visit at week 14 (2 weeks after Visit 9). It is highly 
preferable to collect the sample at week 14. However, if this is not possible, it may be collected 2 weeks after another in-clinic visit. Up to 2 additional samples 
may also be collected from adolescent patients at week 15 and week 13 (3 weeks and 1 week post-injection at Visit 9, respectively) at the sponsor’s discretion. 
The additional samples, if taken following another in-clinic visit, will be collected at the same intervals. If more than 1 additional sample is taken, they do not 
need to be collected after the same injection (ie, 1 sample can be taken 3 weeks after Visit X, and another can be taken 1 week after Visit Y). These additional 
pharmacokinetic samples will be taken from new adolescent patients or adolescent roll over patients from whom additional pharmacokinetic blood samples 
were not obtained during Study TV46000-CNS-30072.
y For new patients only. Stability is defined as meeting all of the following criteria for at least 4 consecutive weeks prior to the baseline visit: outpatient status; 
PANSS total score ≤80; minimal presence of specific psychotic symptoms on the PANSS, as measured by a score of ≤4 on each of the following items: 
conceptual disorganization, suspiciousness, hallucinatory behavior, and unusual thought content; CGI-S score ≤4 (moderately ill); and CGI-SS score ≤2 (mildly 
suicidal) on Part 1 and ≤5 (minimally worsened) on Part 2.
z New patients, and roll-over patients who were assigned to the placebo arm in Study TV46000-CNS-30072, will be randomized to receive TV-46000 q1m or 
q2m. Roll-over patients who were randomized to the TV-46000 q1m or q2m treatment arms in Study TV46000-CNS-30072 will continue on the same dosing 
regimen.
β-HCG=beta human chorionic gonadotropin; AIMS=Abnormal Involuntary Movement Scale; BARS=Barnes Akathisia Rating Scale; BL=baseline; 
CDSS=Calgary Depression Scale for Schizophrenia; CGI-I=Clinical Global Impression-Improvement; CGI-S=Clinical Global Impression of Severity; 
CGI-SS=Clinical Global Impression-Severity of Suicidality; C-SSRS=Columbia Suicide Severity Rating Scale; DAI-10=Drug Attitudes Inventory 10-item 
version; ECG=electrocardiogram; EQ-5D-5L=5-Level EuroQol Five Dimensions Questionnaire; EoS=end of study; EoT=end of treatment; ET=early 
termination; FU=follow-up; GFR=glomerular filtration rate; HbsAg=hepatitis B surface antigen; HIV=human immunodeficiency virus; IMP=investigational 
medicinal product; N/A=not applicable; NPRS=Numeric Pain Rating Scale; PANSS=Positive and Negative Syndrome Scale; PSP=Personal and Social 
Performance Scale; q1m=every month; q2m=every 2 months; q8w=every 8 weeks; RNA=ribonucleic acid; SAE=serious adverse event; SAS=Simpson-Angus 
Scale; sc=subcutaneous; SQLS=Schizophrenia Quality of Life Scale; T3=triiodothyronine; T4=thyroxine; TSH=thyroid-stimulating hormone; V=visit; Wk=week.


Uncontrolled Study - Schizophrenia
Clinical Study Protocol with Amendment 01
Study TV46000-CNS-30078
65
4.
SELECTION AND WITHDRAWAL OF PATIENTS
Prospective waivers (exceptions) from study inclusion and exclusion criteria to allow patients to 
be randomized/enrolled are not granted by Teva (Appendix C).
4.1.
Patient Inclusion Criteria
Patients may participate in this study only if they meet all of the following criteria:
4.1.1.
Patients Rolling Over from the Pivotal Efficacy Study TV46000-CNS-30072
a.
The patient must sign and date the informed consent document. For adolescent 
patients, written informed consent will be obtained from each patient’s parent or legal 
guardian, and written assent will be obtained from each patient.
b. The patient must have participated in the pivotal efficacy study (Study 
TV46000-CNS-30072) without experiencing relapse events and without important 
protocol deviations (Appendix C).
c.
If the patient was taking antidepressants or mood stabilizers (including the 
cytochrome P450 [CYP] 2D6 inhibitors fluoxetine, paroxetine, and duloxetine) in 
Study TV46000-CNS-30072, no dose changes or initiation of treatment with these 
medications will be permitted.
d. The patient must be willing and able to comply with study restrictions and willing to 
return to the investigational center for the required visits throughout the duration of 
the study period, including for the follow-up procedures and assessments as specified 
in this protocol.
e.
The patient, in the investigator’s judgment, requires chronic treatment with an 
antipsychotic medication.
f.
The patient, in the investigator’s judgment, can benefit from participation in this 
study.
g. The patient is able to understand the nature of the study and follow protocol 
requirements, including the prescribed dosage regimens (oral and sc administration) 
and non-use of prohibited concomitant medications; can read and understand the 
written word in order to complete patient-reported outcomes measures; and can be 
reliably rated on assessment scales.
h. The patient has had a stable place of residence for the previous 3 months before the 
baseline visit in this study, and changes in residence are not anticipated over the 
course of study participation.
i.
The patient has no significant life events (such as pending loss of housing, family 
status change, long travel abroad, surgery, etc) that could affect study outcomes 
expected throughout the period of study participation.
j.
The patient is a male or female of any ethnic origin, 13 through 65 years of age (note 
the exception for roll-over patients who may have exceeded 65 years of age during 
the course of Study TV46000-CNS-30072; these patients will still be permitted to 
participate in this study).
k. The patient is in adequate health as determined by medical and psychiatric history, 
medical examination, electrocardiogram (ECG), serum chemistry, hematology, 
urinalysis, and serology.


Uncontrolled Study - Schizophrenia
Clinical Study Protocol with Amendment 01
Study TV46000-CNS-30078
66
l.
Women of childbearing potential and sexually active female adolescents must agree 
not to try to become pregnant, and, unless they have exclusively same-sex partners, 
must agree to use a highly effective method of contraception and agree to continue 
use of this method beginning 1 month before the first administration of study drug 
and for the duration of the study and for 120 days after the last injection of study 
drug. Highly effective methods of contraception include the following:

combined estrogen and progestogen hormonal contraception (oral, intravaginal, 
transdermal) associated with inhibition of ovulation; these should be initiated at 
least 1 month before the first dose of IMP.

progestogen-only hormonal contraception (oral, injectable, implantable) 
associated with inhibition of ovulation; these should be initiated at least 1 month 
before the first dose of IMP.

intrauterine device (IUD) and intrauterine hormone-releasing system in place at 
least 2 months before screening

bilateral tubal occlusion

vasectomized partner provided that he is the sole sexual partner and has received 
medical assessment of the surgical process

Sexual abstinence is only considered a highly effective method if defined as 
refraining from heterosexual intercourse in the defined period. The reliability of 
sexual abstinence needs to be evaluated in relation to the duration of the clinical 
study and the preferred and usual lifestyle of the patient.
m. The patient, if adult or adolescent male, is surgically sterile, or, if capable of 
producing offspring, has exclusively same-sex partners or is currently using an 
approved method of birth control and agrees to the continued use of this method for 
the duration of the study (and for 120 days after the last dose of study drug). Male 
patients with sex partners who are women of childbearing potential (see Appendix E)
must use condoms even if surgically sterile. In addition, male patients may not donate 
sperm for the duration of the study and for 120 days after taking the study drug.
4.1.2.
New Patients (Not Rolling Over from the Pivotal Efficacy Study TV46000-CNS-
30072)
a.
[Revision 01] The patient is an adult (age 18-65) and has a diagnosis of schizophrenia 
according to the DSM-5 for >1 year (diagnosis must be reconfirmed by SCID-5) and 
≥1 episode of relapse in the last 24 months, OR the patient is an adolescent (age 13-
17) with a diagnosis of schizophrenia according to the DSM-5 for > 6 months 
(diagnosis must be reconfirmed by SCID-5).
b. The patient has been responsive to an antipsychotic treatment (other than clozapine) 
in the past year based on investigator judgment (and discussions with family 
members, caregivers, or healthcare professionals as applicable).
c.
The patient has provided written informed consent and is competent to do so. For 
adolescent patients, written informed consent will be obtained from each patient’s 
parent or legal guardian, and written assent will be obtained from each patient.


Uncontrolled Study - Schizophrenia
Clinical Study Protocol with Amendment 01
Study TV46000-CNS-30078
67
d. The patient, in the investigator’s judgment, requires chronic treatment with an 
antipsychotic medication.
e.
The patient, in the investigator’s judgment, can benefit from participation in this 
study.
f.
The patient is able to understand the nature of the study and follow protocol 
requirements, including the prescribed dosage regimens (oral and sc administration) 
and non-use of prohibited concomitant medications; can read and understand the 
written word in order to complete patient-reported outcomes measures; and can be 
reliably rated on assessment scales.
g. The patient has a PANSS total score lower than 100 at screening.
h. The patient has had a stable place of residence for the previous 3 months before 
screening, and changes in residence are not anticipated over the course of study 
participation.
i.
The patient has no significant life events (such as pending loss of housing, family 
status change, long travel abroad, surgery, etc) that could affect study outcomes 
expected throughout the period of study participation.
j.
The patient is a male or female of any ethnic origin, 13 through 65 years of age.
k. The patient has a body mass index between 18.0 and 38.0 kg/m2, inclusive. 
l.
The patient is in adequate health as determined by medical and psychiatric history, 
medical examination, ECG, serum chemistry, hematology, urinalysis, and serology.
m. Women of childbearing potential and sexually active female adolescents must agree 
not to try to become pregnant, and, unless they have exclusively same-sex partners, 
must agree to use a highly effective method of contraception and agree to continue 
use of this method beginning 1 month before the first administration of study drug 
and for the duration of the study and for 120 days after the last injection of study 
drug. Highly effective methods of contraception include the following:

combined estrogen and progestogen hormonal contraception (oral, intravaginal, 
transdermal) associated with inhibition of ovulation; these should be initiated at 
least 1 month before the first dose of IMP.

progestogen-only hormonal contraception (oral, injectable, implantable) 
associated with inhibition of ovulation; these should be initiated at least 1 month 
before the first dose of IMP.

IUD and intrauterine hormone-releasing system in place at least 2 months before 
screening

bilateral tubal occlusion

vasectomized partner provided that he is the sole sexual partner and has received 
medical assessment of the surgical process

Sexual abstinence is only considered a highly effective method if defined as 
refraining from heterosexual intercourse in the defined period. The reliability of 
sexual abstinence needs to be evaluated in relation to the duration of the clinical 
study and the preferred and usual lifestyle of the patient.
n. The patient, if adult or adolescent male, is surgically sterile, or, if capable of 
producing offspring, has exclusively same-sex partners or is currently using an 


Uncontrolled Study - Schizophrenia
Clinical Study Protocol with Amendment 01
Study TV46000-CNS-30078
68
approved method of birth control and agrees to the continued use of this method for 
the duration of the study (and for 120 days after the last dose of study drug). Male 
patients with sex partners who are women of childbearing potential (see Appendix E) 
must use condoms even if surgically sterile. In addition, male patients may not donate 
sperm for the duration of the study and for 120 days after taking the study drug.
o. The patient must be willing and able to comply with study restrictions and willing to 
return to the investigational center for the required visits throughout the duration of 
the study period, including for the follow-up procedures and assessments as specified 
in this protocol.
4.1.3.
Randomization Criteria for New Patients
The following criteria are randomization criteria and must be fulfilled at the baseline visit before 
randomization in addition to other relevant inclusion criteria:
a.
The patient has not experienced mental or physical deterioration, which prevents 
participation in the study per investigator judgement.
b. The patient has demonstrated good compliance in following protocol requirements 
during Stage 1 of the study.

If the investigator or the sponsor determines that the patient was not in 
compliance with the study protocol, the case will be evaluated on a case-by-case 
basis, and the investigator and the sponsor will determine whether the patient will 
be randomized in the double-blind period (Stage 2).
c.
The patient has been stabilized per the following criteria for at least 4 consecutive 
weeks prior to the baseline visit:

outpatient status

PANSS total score ≤80

minimal presence of specific psychotic symptoms on the PANSS, as measured by 
a score of ≤4 on each of the following items: conceptual disorganization, 
suspiciousness, hallucinatory behavior, and unusual thought content

CGI-S score ≤4 (moderately ill)

CGI-SS score ≤2 (mildly suicidal) on Part 1 and ≤5 (minimally worsened) on 
Part 2
4.2.
Patient Exclusion Criteria
Patients may not participate in this study if they meet any of the following criteria:
4.2.1.
Patients Rolling Over from the Pivotal Efficacy Study TV46000-CNS-30072
a.
The patient has a finding in the baseline 12-lead ECG that is considered clinically 
significant in the judgment of the investigator.
b. Poor compliance with study procedures (in the opinion of the investigator or sponsor) 
during the pivotal efficacy Study TV46000-CNS-30072. This should be discussed on 
a case-by-case basis.


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Clinical Study Protocol with Amendment 01
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69
4.2.2.
New Patients (Not Rolling Over from the Pivotal Efficacy Study TV46000-CNS-
30072) and Roll-Over Patients
a.
The patient has a current clinically significant DSM-5 diagnosis other than 
schizophrenia, including schizoaffective disorder, major depressive disorder, bipolar 
disorder, delirium, dementia, or amnestic or other cognitive disorders, or borderline, 
paranoid, histrionic, schizotypal, schizoid, or antisocial personality disorder.
b. The patient is currently on clozapine or has received electroconvulsive therapy in the 
last 12 months.
c.
The patient has a history of epilepsy or seizures, neuroleptic malignant syndrome, 
tardive dyskinesia, or other medical condition that would expose the patient to undue 
risk.
d. The patient has a positive serology for human immunodeficiency virus (HIV)-1, 
HIV-2, hepatitis B surface antigen, and/or hepatitis C. If serology is positive for 
hepatitis C but the ribonucleic acid test is negative and the patient has no history of 
liver disease, enrollment will be considered following discussion between the 
investigator and the medical monitor as needed.
e.
The patient has current or a history of known hypersensitivity to risperidone or any of 
the excipients of TV-46000 or the oral formulation of risperidone used in the 
stabilization phase.
f.
The patient has a substance use disorder, including alcohol and benzodiazepines but 
excluding nicotine and caffeine.
g. The patient has a significant risk of violent behavior based on the patient’s medical 
history or the investigator’s judgement. 
h. The patient has a significant risk of committing suicide based on the patient’s medical 
history or the investigator’s judgement and/or the C-SSRS (lifetime). Patients with a 
C-SSRS (current) positive response to suicidal ideation items 3, 4, or 5 are not 
eligible.
i.
The patient has a clinically significant deviation from normal in the physical 
examination.
j.
The patient has clinically significant findings in biochemistry, hematology, ECG, or 
urinalysis results.
k. If the patient has a prolonged QTcF interval (defined as a QTcF interval of 
>450 msec for males and >470 msec for females) at screening or baseline, calculated 
as the mean of the triplicate ECG measurements, eligibility will be decided on a 
case-by-case basis following discussion between the investigator and the sponsor.
l.
The patient has any clinically significant uncontrolled medical condition (treated or 
untreated). The investigator may discuss with the medical monitor as needed.
m. The patient is a pregnant or lactating female.
n. The patient has any disorder that may interfere with drug absorption, distribution, 
metabolism, or excretion (including gastrointestinal surgery).
o. The patient has any other disease or condition that, in the opinion of the investigator, 
would make participation not in the best interest of the patient or that could prevent, 
limit, or confound the protocol-specified assessments. 
p. The patient has used an investigational drug other than TV-46000 within 3 months 
prior to screening or has participated in a non-drug clinical trial within 30 days prior 
to screening.


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q. The patient is using or consuming medications prohibited in this study.
r.
Vulnerable patients (eg, people kept in detention).
4.3.
Withdrawal Criteria and Procedures for the Patient
4.3.1.
General Withdrawal Criteria
Patients are expected to participate in the study for its entire duration and to perform the 
scheduled visits and procedures.
Each patient is free to withdraw from the study or discontinue treatment with IMP at any time, 
without prejudice to their continued care, but every effort should be undertaken to determine the 
reason for discontinuation. 
Every effort should be made to ensure that the patients comply with study visits and procedures 
as detailed in the protocol. Patients must be withdrawn from the study if any of the following 
events occur:
1. The patient withdraws consent or requests discontinuation from the IMP or withdrawal 
from the study for any reason.
2. The patient develops an illness that would interfere with his or her continued 
participation.
3. The patient is noncompliant with the study procedures and assessments or with 
administration of IMPs in the opinion of the investigator.
4. The patient takes prohibited concomitant medications as defined in this protocol.
5. A female patient has a confirmation of pregnancy during the study from a positive 
pregnancy test.
6. The sponsor requests withdrawal of the patient.
7. The patient experiences an adverse event or other medical condition which indicates to 
the investigator that continued participation is not in the best interest of the patient.
Patients should be treated with standard of care after withdrawal from or termination of the study 
as appropriate.
See Appendix F for information regarding how the study will define and address lost to 
follow-up patients to help limit the amount and impact of missing data.
If the reason for withdrawal from the study or discontinuation from IMP is an adverse event 
and/or clinically significant abnormal laboratory test result, monitoring will be continued as 
applicable (eg, until the event has resolved or stabilized, until the patient is referred to the care of 
a healthcare professional, or until a determination of a cause unrelated to the IMP or study 
procedure is made). The specific event or test result (including repeated test results, as 
applicable) must be recorded both on the source documentation and in the CRF; both the adverse 
events page and the relevant page of the CRF will be completed at that time.
The investigator must inform the study contact person as soon as possible of each patient who is 
being considered for withdrawal due to adverse events. Additional reports must be provided 
when requested.


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If a patient is withdrawn from the study for multiple reasons that include also adverse events, the 
relevant page of the CRF should indicate that the withdrawal was related to an adverse event. An 
exception to this requirement will be the occurrence of an adverse event that in the opinion of the 
investigator is not severe enough to warrant discontinuation but that requires the use of a 
prohibited medication, thereby requiring discontinuation of the patient. In such a case, the reason 
for discontinuation would be “need to take a prohibited medication,” not the adverse event.
In the case of patients lost to follow-up, attempts to contact the patient must be made and 
documented in the patient’s medical records and transcribed to the CRF.
All assessments should be performed according to the protocol on the last day the patient takes 
IMP, or as soon as possible thereafter.
4.3.2.
Study-Specific Patient Withdrawal Criteria and Procedures
Patients must be withdrawn from the study if any of the following events occur:
1. The patient withdraws consent to continue in the study for any reason. Every effort 
should be undertaken to identify the reason for discontinuation.
2. The patient develops a serious or intolerable adverse event that necessitates 
discontinuation at the discretion of the investigator.
3. The investigator believes that continued participation is not in the best interest of the 
patient.
4. The investigator believes that the patient has not adhered to the study procedures or 
restrictions. A protocol deviation occurs that, in the opinion of the investigator, warrants 
discontinuation from the study.
5. The patient requires concomitant medication that may interfere with the 
pharmacokinetics of the study drug.
6. The patient relapses, as defined by the study’s relapse criteria.
7. The patient demonstrates a significant clinical deterioration that cannot be managed with 
rescue medication, as judged by the investigator based on any relevant history or 
observation made by the investigative site, including rating scales.
8. A patient has a mean increase of ≥30 msec from baseline in triplicate QTcF (interval 
corrected for heart rate using Fridericia’s formula) values at any visit, pending discussion 
between the sponsor and the investigator.
9. The patient exhibits an event of possible drug-induced liver injury that requires 
immediate study treatment cessation and is defined as follows:
a.
alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >8× the 
upper limit of normal (ULN)
b. ALT or AST >5×ULN for more than 2 weeks
c.
ALT or AST >3×ULN and total bilirubin level >2×ULN or international 
normalized ratio >1.5


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d. ALT or AST >3×ULN with the appearance of fatigue, nausea, vomiting, right 
upper quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%)
Patients should be treated with standard of care after withdrawal from or termination of the study 
as appropriate.
4.3.3.
Pharmacokinetic Sampling in Case of Patient Withdrawal
Note: Withdrawal under the above criteria will be discussed by the investigator and the sponsor. 
For patients who withdraw from the study, every effort will be made to follow safety after 
withdrawal, including pharmacokinetic sampling when applicable, unless consent is withdrawn.
For pharmacokinetics, the sample date and time will be recorded both on the source 
documentation and the CRF.
If a patient is withdrawn from the study or there is occurrence of a serious adverse event that in 
the judgement of the investigator would be best managed by immediate cessation of treatment, 
the possibility to excise the IMP depot should be discussed with the sponsor to draw on learnings 
of this procedure gained during pre-clinical studies. In this case, 2 consecutive pharmacokinetic 
samples will be obtained: 1 immediately before the excision procedure and 1 several hours after 
the procedure and prior to patient discharge. Additional pharmacokinetic samples may be 
obtained if judged to be required by the sponsor. The sample date and time as well as the date 
and time of the excision procedure will be recorded both on the source documentation and the 
CRF.
4.4.
Replacement of Patients
The sponsor intends to follow up on a meaningful number of patients with an adequate exposure 
to TV-46000 and has committed to follow 100 patients for at least 1 year, who can be either 
patients rolling over from Study TV46000-CNS-30072 or new patients. The assumptions about 
the number of new patients to be enrolled into this study are based on the proportion of new 
patients who will not be eligible for randomization at the end of Stage 1 and the overall number 
and timing of withdrawals of the study patients enrolled during Stage 2. The sponsor will follow 
the recruitment and completion rates periodically against the original assumptions and warrants 
the right to increase the proportion of new patients in this study in case the assumptions are not 
met.
4.5.
Rescreening
A patient who is screened but not enrolled, eg, because enrollment inclusion and exclusion 
criteria were not met or enrollment did not occur within the specified window, may be 
considered for screening again if, eg, there is a change in the patient’s medical condition or a 
modification of study inclusion and exclusion criteria.
Patients may have individual parameters retested at the discretion of both the investigator and the 
sponsor.
Patients may be rescreened once if the repeated values for the laboratory, vital sign, or ECG 
screening criteria are within acceptable limits as judged by the investigator or if repeated values 
show normalization of the out-of-range values, but their initial screening period has expired.


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If the patient is rescreened, an informed consent form (ICF) or assent form, as applicable, will 
need to be re-signed.
4.6.
Screening Failure
Screening failures are defined as participants who consent to participate in the clinical study but 
are not subsequently enrolled in the study. For these patients, minimal information must be 
obtained, including but not limited to demography, screening failure details, eligibility criteria, 
and any serious adverse events.


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5.
TREATMENTS
5.1.
Investigational Medicinal Products Used in the Study
IMPs are defined as the test IMP and placebo IMP.
5.1.1.
Test Investigational Medicinal Product
TV-46000 will be supplied as a ready-to-use, extended-release injectable product in a single-use 
2-mL vial or as a 1 mL Luer lock prefilled syringe containing 50, 75, 100, 125, 150, 200, or 250 
mg of risperidone. 
 
 
 
 
 
 
 
 
For COVID-19 updates, refer to Appendix N.
 
5.1.1.1.
Starting Dose and Dose Levels
For new patients, TV-46000 will be administered in the abdomen (except as indicated below) by 
sc injection, at intervals of q1m or q2m, at a dose equivalent to the oral risperidone (2 to 
5 mg/day) on which they were stabilized in Stage 1, per the conversion table below (Table 3) and 
per their assigned treatment arm. The maximal dose administered will be equivalent to an oral 
risperidone dose of 5 mg/day (adolescent patients will receive a maximal dose equivalent to oral 
risperidone 4 mg/day). As a precautionary measure, adolescent patients who will require a 
stabilization dose of more than 4 mg/day (oral risperidone) during the stabilization stage will not 
be randomized. Patients who would require a stabilization dose below 2 mg/day will not be 
randomized in the study.
Roll-over patients who were randomized to the q1m or q2m treatment arms in Study 
TV46000-CNS-30072 will continue to receive TV-46000 at the same frequency and dose. 
Patients randomized to the placebo arm in Study TV46000-CNS-30072 will be re-randomized to 
either the q1m or q2m arms and will receive TV-46000 at the dose equivalent to the oral dose on 
which they were stabilized in Stage 1 of Study TV46000-CNS-30072. 


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Several investigational centers may be selected by the sponsor (based on the sponsor’s 
considerations, and the centers’ capabilities and prior clinical experience with injectable 
medication) for injection of study drug into the back of the upper arm instead of the abdomen for 
all or some of the enrolled patients at these sites (approximately 20% of the study patient 
population).
The injection site that is chosen for an individual patient should remain consistent throughout the 
study. If the chosen site is the arm, the injection will be administered in an alternating manner 
between the right and the left arm. If the chosen site is the abdomen, the injection will be 
administered in an alternating manner to the right and to the left of the umbilicus. Further details 
will be provided in the Pharmacy Manual.
Table 3:
Conversion Table between Oral Risperidone and TV-46000 Doses
Corresponding 
TV-46000 Dose
Oral Risperidone Dose
2 mg/day
3 mg/day
4 mg/day
5 mg/day (Adults Only)
at q1m
50 mg
75 mg
100 mg
125 mg
at q2m
100 mg
150 mg
200 mg
250 mg
q1m=every month; q2m=every 2 months.
5.1.1.2.
Dose Modification and Dose Stratification
The dose of test IMP will not be modified for a given patient during the study.
5.1.2.
Placebo Investigational Medicinal Product
TV-46000 Placebo is available as an extended-release injectable product 
 
 
 
 
 
 
 
 
 
Additional details about sc injection administration can be found in the Pharmacy Manual.
For COVID-19 updates, refer to Appendix N.
Table 4:
Investigational Medicinal Products Used in the Study
 
 
 


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Note: For COVID-19 updates, refer to Appendix N.
 
5.2.
Preparation, Handling, Labeling, Storage, and Accountability for 
IMPs
5.2.1.
Storage and Security
The investigator or designee must confirm appropriate temperature conditions have been 
maintained for all medicinal products received and any discrepancies must be reported and 
resolved before their use.
The IMPs (TV-46000 and TV-46000 Placebo) must be stored according to the storage conditions 
specified on the label and must be securely locked 
 
 and kept in the outer carton until use.
For COVID-19 updates, refer to Appendix N.
5.2.2.
Labeling
Supplies of IMPs will be labeled according to the current International Council for 
Harmonisation (ICH) guidelines on Good Clinical Practice (GCP) and Good Manufacturing 
Practice and will include any locally required statements. If necessary, labels will be translated 
into the local language.
5.2.3.
Accountability
Each IMP shipment will include a packing slip listing the contents of the shipment and any 
applicable forms.
The investigator is responsible for ensuring that deliveries of IMPs and other study materials 
from the sponsor are correctly received, recorded, handled, and stored safely and properly in 
accordance with the Code of Federal Regulations (CFR) or national and local regulations, and 
are used in accordance with this protocol.
Only patients enrolled in the study may receive IMPs, and only authorized staff at each 
investigational center may supply or administer IMPs. All IMPs must be stored in a secure, 
environmentally controlled, and monitored (manual or automated) area in accordance with the 
labeled storage conditions or appropriate instructions with access limited to the investigator and 
authorized staff at each investigational center.
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for IMP accountability, reconciliation, and record maintenance (ie, receipt, 
reconciliation, and final disposition records).
A record of IMP accountability (ie, IMP and other study materials received, used, retained, 
returned, or destroyed) must be prepared and signed by the principal investigator or designee, 
with an account given for any discrepancies. All test or placebo IMP supplies (used, partially 
used, and unused) will be returned to the sponsor or its designee according to local and national 
regulations and the site’s standard operating procedures (SOPs), following written authorization 
from the sponsor. 


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The sponsor’s or designee’s monitor will review all relevant drug-related information for 
accountability purposes prior to any drug destruction. Documented evidence of destruction 
should be made available to the sponsor and/or its designees. The investigator, pharmacist, or 
drug administrator must verify that no TV-46000 drug supplies remain in the study centers’ 
possession at the end of the study.
Further guidance and information are provided in the Pharmacy Manual.
For COVID-19 updates, refer to Appendix N.
5.3.
Justification for Investigational Medicinal Products
5.3.1.
Justification for Dose of Test Investigational Medicinal Product
The doses of randomized IMP to be evaluated in this double-blind study (50 to 125 mg q1m sc 
and 100 to 250 mg q2m sc) were selected on the basis of Study TV46000-SAD-10055 
(see Section 1.2.2.1). 
 
 
 
 
 
 
 
 
 
Based on the pharmacokinetic performance and the safety profile of TV-46000 in 
Study TV46000-SAD-10055 and the PopPK model-derived simulations, it is expected that 
TV-46000 will provide sufficient coverage throughout 28 days (for q1m) and 56 days (for q2m) 
in 4 doses (50, 75, 100, and 125 mg and 100, 150, 200, and 250 mg, respectively) equivalent to 
2, 3, 4, and 5 mg/day oral risperidone based on the total active moiety (Table 3). The maximal 
TV-46000 dose administered to adolescents will be equivalent to 4 mg/day oral risperidone.
5.3.2.
Justification for Use of Placebo Investigational Medicinal Product
TV-46000 Placebo is administered in this study to patients in the TV-46000 q2m treatment group 
in order to maintain the blind. There is no placebo arm in this study.
5.4.
Other Medicinal Products/Non-Investigational Medicinal Products
Oral risperidone used for stabilization (Table 5) will be a commercial product supplied either via 
a hybrid approach (by the study center and centrally) or a completely centralized manner to 
allow 1 process for all sites and system integration. The brand name of the oral risperidone 
supplied will be recorded on the source documentation.
Note that oral risperidone is mandated for use in this study (for new patients); however, for the 
purposes of this study, it is not considered an IMP.


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Table 5:
Other Medicinal Products Used in the Study
Medicinal product name
Stabilization
Trade name and INN, if applicable, or 
company-assigned number
Risperidone
Formulation
Tablets, oral solution, or orally disintegrating 
tabletsa
Unit dose strengths/dosage levels
Multiple strengths commercially available
Route of administration
Oral; self-administered by patient
Dosing instructions
2 to 5 mg/day
Packaging
Various (commercial product)
Manufacturer
Various (commercial product)
a The brand name of the oral risperidone supplied will be recorded on the source documentation.
INN=international nonproprietary name.
5.5.
Treatment after the End of the Study
In cases where the patient is withdrawn from this study, no further treatment is planned by the 
sponsor after the patient completes their participation in this study. In addition, continued access 
to IMP will not be provided to study participants once the study ends. Investigators should advise 
the study participants to return to the care of their primary physicians. Patients may be treated in 
the meantime per investigator judgment and instruction as applicable.
5.6.
Restrictions
Patients will be required to comply with the following restrictions:
5.6.1.
Activity
There are no specific restrictions in this study regarding normal daily activities, unless otherwise 
advised by the investigator.
5.6.2.
Specific Beverages
Patients should not consume excessive amounts of alcoholic beverages, defined as more than 
2 units per day (1 unit = 1/2 pint [8 ounces] of beer, 1 small glass [5 ounces] of wine, or 1 
measure of spirits), during the course of the study, including the follow-up period. Patients 
should be advised regarding potential risk of drowsiness, dizziness, and other side effects of 
alcohol on risperidone treatment.
5.6.3.
Blood Donation
Patients may not donate blood from 30 days prior to the first IMP administration until 6 months 
after the last IMP administration.


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5.7.
Prior and Concomitant Medication or Therapy
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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5.8.
Procedures for Monitoring Patient Compliance
 
 
 
 
 
 
If the investigator or the sponsor determines that the patient is not in compliance with the study 
protocol, the investigator and the sponsor should determine whether the patient should be 
withdrawn from the study.


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5.9.
Randomization and Blinding
To avoid unblinding, all patients enrolled in Study TV46000-CNS-30078 will be assigned to a 
treatment group via the Interactive Response Technology (IRT) at their baseline visit according 
to the following specifications: 

New patients will be randomized via the IRT to receive sc injections of either 
TV-46000 q1m or TV-46000 q2m in a 1:1 ratio. Randomization will be stratified by 
the dose of oral risperidone on which the patient was stabilized during Stage 1 (2/3, 4, 
or 5 mg/day). The dose of TV-46000 will be equivalent to the 2 to 5 mg/day dose of 
oral risperidone on which the patient was stabilized in Stage 1. As a precautionary 
measure, adolescent patients who will require a stabilization dose of more than 4 
mg/day during the stabilization stage will not be randomized. Patients who are 
randomized to TV-46000 q1m will receive an sc injection of TV-46000 at baseline 
and every 4 weeks (q4w) thereafter. To ensure blinding, patients who are randomized 
to TV-46000 q2m will receive an sc injection of TV-46000 at baseline and every 
8 weeks (q8w) thereafter and an sc injection of placebo 4 weeks after baseline and 
q8w thereafter.

Roll-over patients who were assigned to TV-46000 q1m during Study 
TV46000-CNS-30072 will be assigned via the IRT to continue the same dosing 
frequency and same dose as in Study TV46000-CNS-30072. Note that the EoT visit 
in Study TV46000-CNS-30072 will serve as the baseline visit for roll-over patients in 
this study (ie, roll-over patients receive their last injection of IMP at the EoT visit in 
Study TV46000-CNS-30072 and receive their next injection at week 4 in this study).
They will receive an sc injection of TV-46000 at the EoT visit in Study 
TV46000-CNS-30072 and q4w thereafter (ie, weeks 4, 8 and so on in this study).

Roll-over patients who were assigned to TV-46000 q2m during Study 
TV46000-CNS-30072 will be assigned via the IRT to continue the same dosing 
frequency and same dose as in Study TV46000-CNS-30072. Note that the EoT visit 
in Study TV46000-CNS-30072 will serve as the baseline visit for roll-over patients in 
this study (ie, roll-over patients receive their last injection of IMP at the EoT visit in 
Study TV46000-CNS-30072 and receive their next injection at week 4 in this study).
To maintain the blind, they will be injected q4w, but will alternate between 
TV-46000 sc and placebo injections. Their injection at week 4 will depend on their 
injection at the EoT visit of Study TV46000-CNS-30072 (ie, if their last injection in 
Study TV46000-CNS-30072 was placebo, then their Study TV46000-CNS-30078 
week 4 injection will be TV-46000 and vice versa).

Roll-over patients who were assigned to placebo during Study 
TV46000-CNS-30072 will be randomized via the IRT to receive sc injections of 
either TV-46000 q1m or TV-46000 q2m in a 1:1 ratio. Randomization will be 
stratified by the dose of oral risperidone on which the patient was stabilized during 
Stage 1 (2/3, 4, or 5 mg/day). The dose of TV-46000 will be equivalent to the 2 to 
5 mg/day dose of oral risperidone (adolescent TV-46000 doses will be equivalent to 2 
to 4 mg/day oral risperidone) on which the patient was stabilized in Stage 1 of Study 
TV46000-CNS-30072. Note that the EoT visit in Study TV46000-CNS-30072 will 


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serve as the baseline visit for roll-over patients in this study (ie, roll-over patients 
receive their last injection of IMP at the EoT visit in Study TV46000-CNS-30072 and 
receive their next injection at week 4 in this study). Patients who are randomized to 
TV-46000 q1m will receive an sc injection of TV-46000 at week 4 in this study and 
q4w thereafter. To ensure blinding, patients who are randomized to TV-46000 q2m 
will receive an sc injection of TV-46000 at week 4 in this study and q8w thereafter, 
and an sc injection of placebo at week 8 and q8w thereafter.
Patients and investigators will remain blinded to the identity of the treatment administered to 
each patient. Due to the differences between TV-46000 and placebo and the alternation between 
placebo and TV-46000 for the TV-46000 q2m arm, an unblinded nurse, who is not associated 
with rating the patient (including assessment of the injection site if needed) and is independent 
from the study team, will be required at each site to administer the drug. 
 
 
 
 
 
The sponsor’s clinical personnel (and delegates) involved in the study will not be blinded to the 
identity and dosing regimens of the IMPs received by the new patients during the course of this 
study. 
 
 
 
 
New patients and roll-over patients in the placebo group of Study TV46000-CNS-30072 will be 
randomly assigned to treatment groups by means of a computer-generated randomization list. 
The specifications for randomization will be under the responsibility and oversight of Teva 
Global Statistics.
In the event of an emergency, it will be possible to determine to which treatment group and dose 
the patient has been allocated by accessing the Randomization and Trial Supply Management 
(RTSM) system. All investigational centers will be provided with details of how to access the 
system for code breaking at the start of the study. The medical monitor or equivalent should be 


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notified following unblinding. Any unblinding of the IMP performed by the investigator must be 
recorded in the source documents.
The randomization list will be assigned to the relevant treatment groups through a qualified 
service provider, eg, via the RTSM system. The generation of the randomization list and 
management of the RTSM system will be done by a qualified service provider under the 
oversight of the responsible function at Teva.
The unblinded nurse at the investigational center who will dispense the IMPs will know the IMP 
assignments for each patient. In addition, up to 2 other individuals from the investigational center 
may know the IMP assignments to provide quality assurance and oversight in their preparation 
and administration, as necessary. These individuals will not be involved in the conduct of any 
study procedures or assessments of any adverse events.
For COVID-19 updates, refer to Appendix N.
5.10.
Maintenance of Randomization and Blinding
5.10.1.
Maintenance of Randomization
Patient randomization codes will be maintained in a secure location at the service provider 
contracted to generate the codes.
5.10.2.
Blinding and Unblinding
Pharmacokinetic data will be assessed during the study. 
For information about investigational site personnel who may be aware of IMP assignments, see 
Section 5.9. These individuals will not be involved in the conduct of any study procedures or 
assessments of any adverse events.
In cases of a serious adverse event or a pregnancy, or in cases when knowledge of the IMP 
assignment is needed to make treatment decisions, the investigator may unblind the patient’s 
IMP assignment as deemed necessary, mainly in emergency situations. Individual randomization 
codes, indicating the IMP assignment for each randomized patient, will be available to the 
investigator(s) or pharmacist(s) at the investigational center via the RTSM, both via telephone 
and internet. Breaking of the treatment code can always be performed by the investigator without 
prior approval by the sponsor; however, the sponsor should be notified following the breaking of 
the treatment code. 
When a blind is broken, the patient will be withdrawn from the study and the event will be
recorded on the CRF. The circumstances leading to the breaking of the code should be fully 
documented in the investigator’s study files and in the patient’s source documentation. 
Assignment of IMP should not be recorded in any study documents or source document.
5.10.3.
Data Monitoring Committee
There will be no Data Monitoring Committee/Data and Safety Monitoring Board in this study.


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5.11.
Total Blood Volume
 
 
 
 
 
 
 
 
 


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6.
ASSESSMENT OF EFFICACY
For each assessment, where applicable, every effort should be made to retain the same rater for 
each patient throughout the course of the study, except under exceptional circumstances.
For COVID-19 updates, refer to Appendix N.
6.1.
Assessments of Efficacy
6.1.1.
Clinical Global Impression–Improvement (CGI-I)
The CGI-I scale permits a global evaluation of the patient’s overall improvement in symptoms. 
The CGI-I scale rates the patient’s improvement relative to his or her symptoms on a 7-point 
scale ranging from 1 (very much improved) to 7 (very much worse) (Guy 1976a).
The CGI-I will be administered by the investigator/trained rater at all in-clinic visits during the 
study (except for the screening and baseline visits). For new patients, CGI-I during Stage 1 will 
be relative to screening; CGI-I during Stage 2 will be relative to the baseline visit. For roll-over 
patients, the CGI-I during Stage 2 will be relative to the patient’s baseline visit in Study 
TV46000-CNS-30072.
6.1.2.
Positive and Negative Syndrome Scale (PANSS)
The PANSS (Kay 1987) is a 30-item instrument used in patients with schizophrenia to identify 
the presence and severity of psychopathology symptoms, the relationship of these symptoms to 
one another, and the global psychopathology. Each item is scored on a 7-point scale ranging 
from 1 (absent) to 7 (extreme). The positive symptom scale includes 7 items with a maximum 
score of 49; the negative symptom scale includes 7 items with a maximum score of 49; and the 
general psychopathology scale includes 16 items with a maximum score of 112.
The PANSS will be administered by the investigator at screening and all visits during the study. 
 
 
6.2.
Other Assessments
6.2.1.
Structured Clinical Interview for DSM-5 (SCID-5)
The SCID-5 is a semi-structured interview guide for making DSM-5 diagnoses. It will be 
administered at screening (for new patients only) by a clinician or trained mental health 
professional who is familiar with the DSM-5 classification and diagnostic criteria.
The SCID-5 can be used to ensure that the major DSM-5 diagnoses are systematically evaluated 
and that all the study patients have symptoms that meet the DSM-5 criteria for inclusion and 
exclusion, and to characterize a study population in terms of current and previous psychiatric 
diagnoses (First 2015).


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6.2.2.
Quality of Life Scales
The quality of life scales used in this study will include the 2 measures described below.
6.2.2.1.
Schizophrenia Quality of Life Scale (SQLS)
The Schizophrenia Quality of Life Scale (SQLS) will be administered to adult patients only at 
the time points specified in Table 1 and Table 2, and will be used to capture quality of life. The 
33-item measure yields 3 subscale scores: psychosocial, motivation/energy, and symptoms/side 
effects (Wilkinson 2000). Higher scores on the scales indicate worse quality of life.
6.2.2.2.
5-Level EuroQol Five Dimensions Questionnaire (EQ-5D-5L)
The 5-Level EuroQol Five Dimensions Questionnaire (EQ-5D-5L) will be administered to adult 
patients only at the time points specified in Table 1 and Table 2, and is a standardized 
questionnaire that assesses overall state of health. The EQ-5D-5L consists of 2 parts. In Part 1, 
patients rate their health state in 5 domains (mobility, self-care, usual activities, pain/discomfort, 
and mood) using a scale of 1 to 5, where 1 = no problems, 2 = slight problems, 3 = moderate 
problems, 4 = severe problems, and 5 = extreme problems. In Part 2, patients rate their health 
state on a 100-mm visual analog scale; a rating of 0 represents the worst imaginable health state, 
and a rating of 100 represents the best imaginable health state (EuroQol Group 1990, Rabin 
2001).
6.2.3.
Drug Attitudes Inventory 10-item Version (DAI-10)
The Drug Attitudes Inventory 10-item Version (DAI-10) will be administered to adult patients 
only at the time points specified in Table 1 and Table 2, and measures subjective responses and 
attitudes toward maintenance of antipsychotic drug therapy that may affect compliance. There 
are 2 versions: the DAI-10 and the DAI-30, which correlate very closely (r=0.93). Only the 
shorter DAI-10 will be used in this study. The DAI-10 consists of 10 items covering 3 domains 
(subjective positive, subjective negative, and attitude toward medication), although only a single 
composite score is computed (Hogan 1983, Nielsen 2012). A positive total score indicates a 
compliant response and a negative total score indicates a non-compliant response.
6.2.4.
Personal and Social Performance Scale (PSP)
The Personal and Social Performance Scale (PSP) will be administered to adult patients only at 
the time points specified in Table 1 and Table 2, and is a clinician-rated instrument that measures 
personal and social functioning in patients with schizophrenia (Morosini 2000). The PSP is a 
100-point single-item rating scale, divided into 10 equal intervals. The score is based on the 
assessment of patient’s functioning in 4 categories: 1) socially useful activities, 2) personal and 
social relationships, 3) self-care, and 4) disturbing and aggressive behaviors. Higher scores 
represent better personal and social functioning, with ratings from 91 to 100 indicating more than 
adequate functioning, while scores under 30 indicate functioning so poor that intensive 
supervision is required.
6.2.5.
Healthcare Resource Utilization
Healthcare resource utilization will be assessed for hospitalizations, emergency room (ER) visits, 
and outpatient visits (ie, not including protocol-mandated outpatient visits) at the time points 


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specified in Table 1 and Table 2. Hospitalizations will be assessed as the percentage of patients 
with hospitalizations over the past 4 weeks, the associated length of stay, and the number of 
hospitalizations among patients who were hospitalized. In addition, the percentage of patients 
with ER visits and their number of ER visits over the past 4 weeks and the percentage of patients 
with outpatient visits and their number of outpatient visits over the past 4 weeks will be 
evaluated at all study visits.
This should be completed by the site investigator/coordinator through patient interviews. 
Verification against medical records should be performed whenever possible. The family 
member or caregiver may also need to provide input.
6.2.6.
Clinical Global Impression of Severity (CGI-S)
The CGI-S scale was developed to rate the severity of a patient’s condition on a 7-point scale 
ranging from 1 (normal, not at all ill) to 7 (among the most extremely ill patients) (Guy 1976a). 
The CGI-S will be administered by the investigator/trained rater at all in-clinic visits.


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7.
ASSESSMENT OF SAFETY
In this study, safety will be assessed by qualified study personnel by evaluating the reported 
adverse events, clinical laboratory test results, vital sign measurements, ECG findings, physical 
examination findings (including body weight measurements), use of concomitant medication, 
and local injection site tolerance. Additional assessments of safety of specific interest to the use 
of medicinal products in schizophrenia include assessments of suicidality, depression, and 
abnormal movements (eg, tardive dyskinesia, akathisia, and parkinsonism).
For COVID-19 updates, refer to Appendix N.
7.1.
Adverse Events
7.1.1.
Definition of an Adverse Event
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 physical sign, symptom, or 
laboratory parameter that develops or worsens in severity during the course of this study, or 
significant worsening of the disease under study, or of any concurrent disease, whether or not 
considered related to the IMP. A new condition or the worsening of a pre-existing condition will 
be considered an adverse event. Stable chronic conditions (such as arthritis) that are present 
before study entry and do not worsen during this study will not be considered adverse events.
Accordingly, an adverse event can include any of the following:

intercurrent illnesses

physical injuries

events possibly related to concomitant medication

significant worsening (change in nature, severity, or frequency) of the disease under 
study or other pre-existing conditions

drug interactions

events occurring during diagnostic procedures or during any washout phase of this
study

laboratory or diagnostic test abnormalities that result in the withdrawal of the patient 
from the study, are associated with clinical signs and symptoms or a serious adverse 
event, require medical treatment or further diagnostic work-up, or are considered by 
the investigator to be clinically significant
(Note: Abnormal laboratory or diagnostic test results at the screening visit that 
preclude a patient from entering the study or receiving study treatment are not 
considered adverse events.)


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Worsening of the disease under study, schizophrenia, will be assessed using PANSS and should 
be recorded as an adverse event only if the presentation or outcome is more severe than would 
normally be expected from the normal course of the disease in a particular patient.
 
 
7.1.2.
Recording and Reporting of Adverse Events
For recording of adverse event, the study period is defined for each patient as the time period 
from signature of the ICF or assent form, as applicable, to the end of the follow-up period. The 
follow-up period of recording of adverse events is defined as 120 days after the last dose of IMP. 
The period for reporting treatment-emergent adverse events is defined as the period after the first 
dose of IMP in this study is administered and until 120 days after the last dose of IMP.
All adverse events that occur during the defined study period must be recorded both on the 
source documentation and the CRF, regardless of the severity of the event or judged relationship 
to the IMP. For serious adverse events, the serious adverse event form must be completed, and 
the serious adverse event must be reported immediately (Section 7.1.5.3.1). The investigator 
does not need to actively monitor patients for adverse events after the defined period.
At each contact with the patient, the investigator or designee must question the patient about 
adverse events by asking an open-ended question such as “Have you had any unusual symptoms 
or medical problems since the last visit? If yes, please describe.” All reported or observed signs 
and symptoms will be recorded individually, except when considered manifestations of a 
medical condition or disease state. A precise diagnosis will be recorded whenever possible. 
When such a diagnosis is made, all related signs, symptoms, and any test findings will be 
recorded collectively as a single diagnosis on the CRF and, if it is a serious adverse event, on the 
serious adverse event form.
The clinical course of each adverse event will be monitored at suitable intervals until resolved, 
stabilized, or returned to baseline; or until the patient is referred for continued care to a 
healthcare professional; or until a determination of a cause unrelated to the IMP or study 
procedure is made.
The onset and end dates, duration (in cases of adverse event duration of less than 24 hours), 
action taken regarding IMP, treatment administered, and outcome for each adverse event must be 
recorded both on the source documentation and the CRF.
The relationship of each adverse event to the IMP and study procedures and the severity and 
seriousness of each adverse event, as judged by the investigator, must be recorded as described 
below.
Further details are given in the Serious Adverse Event Management Plan (SMP).
7.1.3.
Severity of an Adverse Event
The severity of each adverse event must be recorded as one of the following:
Mild:
No limitation of usual activities


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Moderate: Some limitation of usual activities
Severe:
Inability to carry out usual activities
7.1.4.
Relationship of an Adverse Event to the Investigational Medicinal Product
The relationship of an adverse event to the IMP is characterized in Table 6.
Table 6:
The Relationship of an Adverse Event to the Investigational Medicinal 
Product
Term
Definition
Clarification
No reasonable 
possibility
(not related)
This category applies to adverse 
events that, after careful 
consideration, are clearly due to 
extraneous causes (disease, 
environment, etc) or to adverse 
events that, after careful medical 
consideration at the time they are 
evaluated, are judged to be unrelated 
to the IMP.
The relationship of an adverse event may be considered 
“no reasonable possibility” if it is clearly due to 
extraneous causes or if at least 2 of the following apply:

It does not follow a reasonable temporal sequence 
from the administration of the IMP.

It could readily have been produced by the patient’s 
clinical state, environmental or toxic factors, or other 
modes of therapy administered to the patient.

It does not follow a known pattern of response to the 
IMP.

It does not reappear or worsen when the IMP is 
re-administered.
Reasonable 
possibility
(related)
This category applies to adverse 
events for which, after careful 
medical consideration at the time 
they are evaluated, a connection with 
the administration of IMP cannot be 
ruled out with certainty.
The relationship of an adverse event may be considered 
“reasonable possibility” if at least 2 of the following 
apply:

It follows a reasonable temporal sequence from 
administration of the IMP.

It cannot be reasonably explained by the known 
characteristics of the patient’s clinical state, 
environmental or toxic factors, or other modes of 
therapy administered to the patient.

It disappears or decreases on cessation or reduction in 
dose. There are important exceptions when an 
adverse event does not disappear after 
discontinuation of the IMP, yet an IMP relationship 
clearly exists.

It follows a known pattern of response to the IMP.
IMP=investigational medicinal product.
7.1.5.
Serious Adverse Events
For recording of serious adverse events, the study period is defined for each patient as the time 
period from signature of the ICF or assent form, as applicable, to the end of the follow-up period. 
Serious adverse events occurring in a patient after the end of the follow-up period should be 
reported to the sponsor if the investigator becomes aware of them, following the procedures 
described in Section 7.1.5.3.1.
 
 
. 


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7.1.5.1.
Definition of a Serious Adverse Event
A serious adverse event is an adverse event occurring at any dose that results in any of the 
following outcomes or actions:

results in death

is life-threatening adverse event (ie, the patient 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 
were more severe

requires inpatient hospitalization or prolongation of existing hospitalization, which 
means that hospital inpatient admission or prolongation of hospital stay were required 
for treatment of an adverse event, or that they occurred as a consequence of the event
Hospitalizations scheduled before the patient signed the ICF or assent form, as 
applicable, will not be considered serious adverse events, unless there was worsening 
of the pre-existing condition during the patient’s participation in this study.

results in persistent or significant disability/incapacity (refers to a substantial 
disruption of one’s ability to conduct normal life functions)

is a congenital anomaly/birth defect

an important medical event that may not result in death, be life-threatening, or require 
hospitalization, but may jeopardize the patient and may require medical intervention 
to prevent one of the outcomes listed in this definition
Examples of such events are intensive treatment in an ER or at home for allergic 
bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; 
or the development of drug dependency or drug abuse. Note: Any suspected 
transmission of an infectious agent via a medicinal product is considered an important 
medical event.
All occurrences of possible drug-induced liver injury that meet Hy’s law criteria, defined as all
of the below, must be reported by the investigator to the sponsor as a serious adverse event:

ALT or AST increase of >3× ULN

total bilirubin increase of >2× ULN

absence of initial findings of cholestasis (ie, no substantial increase of alkaline 
phosphatase)
An adverse event that does not meet any of the criteria for seriousness listed above will be 
regarded as a nonserious adverse event.
7.1.5.2.
Expectedness
A serious adverse event that is not included in the Adverse Reaction section of the relevant 
reference safety information (RSI) by its specificity, severity, outcome, or frequency is 
considered an unexpected adverse event. The RSI for this study is the RSI section of the current 
version of the IB for TV-46000. For the purpose of suspected unexpected serious adverse 


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reaction (SUSAR) reporting, the version of the RSI at the time of occurrence of the SUSAR 
applies.
The sponsor’s Global Patient Safety and Pharmacovigilance (GPSP) team will determine the 
expectedness for all serious adverse events.
7.1.5.3.
Reporting a Serious Adverse Event
7.1.5.3.1. Investigator Responsibility
To satisfy regulatory requirements, all serious adverse events that occur during the study, 
regardless of judged relationship to administration of the IMP, must be reported to the sponsor 
by the investigator. The event must be reported within 24 hours of when the investigator learns 
about it. Completing the serious adverse event form and reporting the event must not be delayed, 
even if not all the information is available. The investigator does not need to actively monitor 
patients for adverse events once this study has ended.
Serious adverse events occurring to a patient after the last administration of IMP of that patient 
has ended should be reported to the sponsor if the investigator becomes aware of them.
The serious adverse event form should be sent to the local safety officer (LSO) or designee (a 
contract research organization [CRO] in a country without a sponsor LSO) (contact information 
is in the Clinical Study Personnel Contact Information section); the LSO will forward the report 
to the sponsor’s GPSP.
The following information should be provided to record the event accurately and completely:

study number

investigator and investigational center identification

patient number

onset date and detailed description of adverse event including seriousness criteria

investigator’s assessment of the relationship of the adverse event to the IMP (no 
reasonable possibility, reasonable possibility)

the date of awareness about the event
Additional information includes the following:

age and sex of patient

date of first dose of IMP

date of last administered dose of IMP

action taken

outcome, if known

severity

explanation of assessment of relatedness


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
concomitant medication (including doses, routes of administration, and regimens) and 
treatment of the event

pertinent laboratory or other diagnostic test data

medical history

results of dechallenge/rechallenge, if known

for an adverse event resulting in death

cause of death (whether or not the death was related to IMP)

autopsy findings (if available)
Each report of a serious adverse event will be reviewed and evaluated by the investigator and the 
sponsor to assess the nature of the event and the relationship of the event to the IMP, study 
procedures, and to underlying disease.
 
 
 
Additional information (follow-up) about any serious adverse event unavailable at the initial 
reporting should be forwarded by the investigator within 24 hours of when it becomes known to 
the same address as the initial report.
For all countries, the sponsor’s GPSP will distribute the Council for International Organizations 
of Medical Sciences form/Extensible Markup Language file to the LSO/CRO for submission to 
the competent authorities (CAs), Independent Ethics Committee/Institutional Review Boards 
(IEC/IRBs), and investigators, according to regulations. The investigator must ensure that the 
IEC/IRB is also informed of the event, in accordance with national and local regulations.
7.1.5.3.2. Sponsor Responsibility
If a serious unexpected adverse event is believed to be related to the IMP or study procedures, 
the sponsor will take appropriate steps to notify all investigators participating in sponsored 
clinical studies of IMP and the appropriate CAs (and IEC/IRB, as appropriate).
In addition to notifying the investigators and CAs (and IEC/IRB, as appropriate), other action 
may be required, including the following:

altering existing research by modifying the protocol

discontinuing or suspending the study

modifying the existing consent form and informing all study participants of new 
findings

modifying listings of expected toxicities to include adverse events newly identified as 
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7.1.6.
Protocol-Defined Adverse Events of Special Interest
No protocol-defined adverse events of special interest were identified for this study.
7.1.7.
Protocol Deviations Because of an Adverse Event
If a patient experiences an adverse event or medical emergency, deviations from the protocol 
may be allowed on a case-by-case basis. To ensure patient safety, after the event has stabilized or 
treatment has been administered (or both), the investigator or other physician in attendance must 
contact the physician identified in the Clinical Study Personnel Contact Information section of 
this protocol as soon as possible to discuss the situation. The investigator, in consultation with 
the sponsor, will decide whether the patient should continue to participate in the study.
7.2.
Pregnancy
Any female patient becoming pregnant during the study will discontinue IMP.
All pregnancies of women participating in the study and female partners of men participating in 
the study, if applicable, that occur during the study, or within at least 120 days after the last dose 
of study drug, are to be reported immediately to the individual identified in the Clinical Study 
Personnel Contact Information section of this protocol, and the investigator must provide the 
sponsor (LSO/CRO) with the completed pregnancy form. The process for reporting a pregnancy 
is the same as that for reporting a serious adverse event but using the pregnancy form 
(Section 7.1.5.3).
The investigator is not required to report patients who are found to be pregnant between 
screening and baseline, provided no protocol-related procedures have been applied.
All female patients (or female partners of men participating in the study) who become pregnant 
will be monitored for the outcome of the pregnancy (including spontaneous, elective, or 
voluntary abortion). If the pregnancy continues to term, the outcome (health of the infant up to 
8 weeks of age), including details of birth and presence or absence of any birth defects, 
congenital abnormalities, or maternal and newborn complications, will be reported to the 
sponsor. Any complication of pregnancy during the study and any complication of pregnancy 
that the investigator becomes aware of after withdrawal from the study will be reported as an 
adverse event or a serious adverse event, as appropriate.
Since there is lack of data on human teratogenicity, genotoxicity, fetotoxicity, or spermatoxicity 
for this IMP, female partners of men participating in the study who become pregnant will be 
asked to sign an ICF or assent form, as applicable.
If the pregnancy in the woman participating in the study and/or the female partners of men 
participating in the study does not continue to term, one of the following actions will be taken:

For a spontaneous abortion, report as a serious adverse event.

For an elective abortion due to developmental anomalies, report as a serious adverse 
event.

For an elective abortion not due to developmental anomalies, report on the pregnancy 
form; do not report as an adverse event.


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7.3.
Medication Error and Special Situations Related to the 
Investigational Medicinal Products
Any administration of IMP that is not in accordance with the study protocol should be reported 
as a deviation in the patient’s source documents, regardless of whether or not an adverse event 
occurs as a result.
The following are types of medication errors and special situations:
1. Medication error: Any unintentional error in the prescribing, dispensing, or
administration of a medicinal product while in the control of the healthcare professional, 
patient, or consumer.
2. Overdose: Administration of a quantity of a medicinal product given per administration 
or cumulatively which is above the maximum recommended dose according to the 
authorized product information. Clinical judgment should always be applied. Any dose of 
IMP (whether the test IMP, reference IMP, or placebo IMP), whether taken intentionally 
or unintentionally, in excess of that prescribed must be immediately reported to the 
sponsor.
3. Misuse: Situations where the IMP is intentionally and inappropriately used not in 
accordance with the authorized product information.
4. Abuse: Persistent or sporadic, intentional excessive use of IMP which is accompanied by
harmful physical or psychological effects.
5. Off-label use: Situations where an IMP is intentionally used for a medical purpose not in 
accordance with the authorized product information.
6. Occupational exposure: Exposure to an IMP, as a result of one’s professional or non-
professional occupation.
7. Breastfeeding: Suspected adverse reactions which occur in infants following exposure to 
a medicinal product from breast milk.
7.4.
Clinical Laboratory Tests
All clinical laboratory test results outside the reference range will be judged by the investigator 
as belonging to one of the following categories:

abnormal and not clinically significant

abnormal and clinically significant
A laboratory test result that is judged by the investigator as clinically significant will be recorded 
both on the source documentation and the CRF as an adverse event and monitored as described 
in Section 7.1.2. An event may include a laboratory or diagnostic test abnormality (once 
confirmed by repeated testing) that results in the withdrawal of the patient from the study, the 
temporary or permanent withdrawal of the IMP or medical treatment, or further diagnostic 
work-up per investigator’s judgement. (Note: Abnormal laboratory or diagnostic test results at 
the screening visit that preclude a patient from entering the study or receiving IMP are not 
considered adverse events.)


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For COVID-19 updates, refer to Appendix N.
Table 7:
Clinical Laboratory Tests
 
 
 
 
 
 
 
 
Table 7.


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7.5.
Physical Examinations
Full physical examinations, including height (to be obtained at the screening visit for new 
patients and at the baseline visit for adolescent roll-over patients) and weight, will be performed 
at the time points detailed in Table 1 and Table 2. The full physical examination will consist of 


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examining the following body systems: cardiovascular, respiratory, abdominal, skin, 
neurological, and musculoskeletal systems. The physical examination will also include 
examination of general appearance, including head, eyes, ears, nose, and throat; chest; abdomen; 
skin; lymph nodes; and extremities. Body weight and tympanic temperature will be measured at 
each visit. Systolic and diastolic blood pressure and pulse rate will be measured with the patient 
in a seated position. Any physical examination finding that is judged by the investigator as 
clinically significant (except at the screening visit [new patients]) will be considered an adverse 
event, recorded on the CRF, and monitored as described in Section 7.1.2.
7.6.
Vital Signs
Vital signs (blood pressure [systolic/diastolic], respiratory rate, tympanic temperature, and pulse)
will be measured at the time points detailed in Table 1 and Table 2. All vital sign results outside 
the reference ranges will be judged by the investigator as belonging to one of the following 
categories:

abnormal and not clinically significant

abnormal and clinically significant
Before blood pressure and pulse are measured, the patient must rest in a supine or seated position 
for at least 5 minutes. (The same position and arm should be used each time vital signs are 
measured for a given patient.) For any abnormal vital sign value, the measurement should be 
repeated as soon as possible. Any vital sign value that is judged by the investigator as clinically 
significant will be recorded both on the source documentation and on the CRF as an adverse 
event and will be monitored as described in Section 7.1.2.
For COVID-19 updates, refer to Appendix N.
7.7.
Electrocardiography
A standard 12-lead ECG will be recorded at the time points detailed in Table 1 and Table 2. 
Triplicate measurements will be performed at screening and baseline, and single measurements 
will be performed at all other in-clinic visits where ECG recordings are taken. A qualified 
physician at a central diagnostic center will interpret the ECG.
All ECG results outside the reference ranges will be judged by the investigator as belonging to 
one of the following categories:

abnormal and not clinically significant 

abnormal and clinically significant
Any ECG finding that is judged by the investigator as clinically significant (except at the 
screening visit [new patients]) will be considered an adverse event, recorded on the source 
documentation and in the CRF, and monitored as described in Section 7.1.2.
For COVID-19 updates, refer to Appendix N.


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7.8.
Assessment of Local Tolerability and Pain
In cases where an adverse event related to an injection site reaction is reported, an assessment of 
the sc injection site (ie, local tolerability [skin at injection site]) will be made. The presence and 
severity of erythema, swelling, induration, and pain at the injection site may be assessed using 
the scales below as applicable. 
7.8.1.
Erythema and Edema Assessment
Scoring of erythema and edema will be done using 5-point scales:
Erythema:

None = 0

Very slight = 1

Well defined = 2

Moderate to severe = 3

Severe = 4
Edema:

None = 0

Very slight = 1

Slight = 2

Moderate = 3

Severe = 4
7.8.2.
Induration and Nodule Assessment
The presence and size (length and width) of any palpable induration/nodule at the injection site 
will be assessed and recorded. Scoring of nodules will be done using a 4-point scale:

No induration/nodule = 0

Discernible induration/small nodule <0.5 cm = 1

Marked induration/medium size nodule of 0.5 to 1 cm = 2

Severe induration/significant size nodule >1 cm = 3
7.8.3.
Injection Pain Intensity Assessment
In cases where an adverse event related to an injection site reaction is reported, the intensity of 
injection pain will be assessed by patients using an 11-point Numeric Pain Rating Scale (0 [no 
pain] to 10 [worst pain]) (Williamson 2005). Pain measurement will be evaluated during visits 
and telephone calls until resolution. The exact timing will be captured in the source 
documentation.


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7.9.
Assessment of Suicidality
Risperidone is considered to be central nervous system-active. In addition, there is increased risk 
of suicide attempts in patients with schizophrenia or bipolar disorder. The sponsor considers it 
important to monitor for such events before and during this clinical study.
Risperidone is considered to be an atypical antipsychotic medicinal product. Although 
risperidone or other similar medicinal products in this class are not known to be associated with 
an increased risk of suicidal thinking or behavior when given to patients with schizophrenia, the 
sponsor considers it important to monitor for such events before and during this clinical study.
The study population should be monitored appropriately and observed closely for suicidal 
ideation and behavior or any other unusual changes in behavior. Consideration should be given 
to discontinuing the test IMP in participants who experience signs of suicidal ideation or 
behavior.
Families and caregivers of participants being treated with test IMP 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 and treatment-emergent suicidal ideation 
and behavior will be assessed during the study using the C-SSRS and CGI-SS scales.
7.9.1.
Columbia Suicide Severity Rating Scale (C-SSRS)
The C-SSRS is a semi-structured interview that captures the occurrence, severity, and frequency 
of suicide-related thoughts and behaviors (Posner 2011). There are required items that address 
suicidal ideation and potential additional items related to intensity of ideation and suicidal 
behavior if there are any positive responses to a required item. The C-SSRS uses dichotomous 
scales (ie, yes or no), Likert scales, and text or narrative to further describe the thoughts or 
behaviors.
The minimum requirements determined by the scale author, Dr. Kelly Posner Gerstanhaber, MD, 
state that anyone can administer the C-SSRS for clinical trials, regardless of education level, as 
long as the administrator views the C-SSRS training video and gets a training certificate. Thus, 
the C-SSRS interview and rating will be performed by raters with appropriate prior clinical trial 
experience with C-SSRS administration, who meet the minimum requirements outlined by the 
scale author, after review and approval by the Teva clinical project physician or designee.
For new patients, the C-SSRS will be administered at screening (baseline/screening version), and 
the “since last visit” version will be administered at all post-screening visits and telephone 
contacts during the study.
For roll-over patients, the “since last visit” version will be administered at baseline and all 
subsequent visits and telephone contacts during the study.
7.9.2.
Clinical Global Impression-Severity of Suicidality (CGI-SS)
The CGI-SS scale provides an overall clinician-rated assessment of the risk of suicidality 
(Lindenmayer 2003). The CGI-SS consists of a 5-point scale in Part 1 ranging from 1 (not at all 


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suicidal) to 5 (attempted suicide) and a 7-point scale in Part 2 ranging from 1 (very much 
improved) to 7 (very much worse).
The CGI-SS will be assessed at screening (for new patients) and all in-clinic visits during the 
study. In Stage 1, for new patients, Part 2 of the CGI-SS will be compared to screening. In 
Stage 2, for new patients, Part 2 of the CGI-SS will be compared to baseline; for roll-over 
patients, it will be compared to baseline of Study TV46000-CNS-30072.
7.10.
Study-Specific Assessments of Safety
7.10.1.
Abnormal Involuntary Movement Scale (AIMS)
The AIMS will be performed at the time points specified in Table 1 and Table 2. The AIMS 
scores the occurrence of tardive dyskinesia in patients receiving neuroleptic medications 
(Guy 1976b). The AIMS is a 14-item scale that includes assessments of orofacial movements, 
extremity and truncal dyskinesia, examiner’s judgment of global severity, subjective measures of 
awareness of movements and distress, and a yes/no assessment of problems concerning teeth 
and/or dentures. Higher scores indicate greater severity of the condition.
7.10.2.
Barnes Akathisia Rating Scale (BARS)
The BARS will be performed at the time points specified in Table 1 and Table 2. The BARS is 
an instrument that assesses the severity of drug-induced akathisia (Barnes 1989). The BARS 
includes 3 items for rating objective restless movements, subjective restlessness, and any 
subjective distress associated with akathisia that are scored on a 4-point scale of 0 to 3 and 
summed yielding a total scored ranging from 0 to 9. The BARS also includes a global clinical 
assessment of severity scored on a scale of 0 to 5. Higher scores are indicative of greater severity 
of akathisia.
7.10.3.
Simpson-Angus Scale (SAS)
The SAS will be performed at the time points specified in Table 1 and Table 2. The SAS is a 
10-item instrument for the assessment of neuroleptic-induced parkinsonism (Simpson 1970). The 
items on the scale include measurements of hypokinesia, rigidity, glabellar reflex, tremor, and 
salivation. Each item is rated on a 5-point scale (0 to 4), with a higher score indicating greater 
severity of symptoms. The mean score is calculated by adding the individual item scores and 
dividing by 10.
7.10.4.
Calgary Depression Scale for Schizophrenia (CDSS)
The CDSS will be performed at the time points specified in Table 1 and Table 2. The CDSS is 
specifically designed to assess the level of depression separate from the positive, negative, and 
EPS in schizophrenia (Addington 1993). This clinician-administered instrument consists of 
9 items, each rated on a 4-point scale from 0 (absent) to 3 (severe). 


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7.11.
Other Assessments
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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8.
ASSESSMENT OF PHARMACOKINETICS/ 
PHARMACODYNAMICS/BIOMARKERS/ 
PHARMACOGENOMICS
8.1.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
For COVID-19 updates, refer to Appendix N.


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8.2.
 
8.3.
Assessment of Exploratory Biomarkers
8.4.
Pharmacogenetics
 
 
 
 
 
 


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9.
STATISTICS
This section describes the statistical analysis as foreseen at the time of planning the study. The 
changes, additions, and further details about the analyses will be described in the statistical 
analysis plan. After finalization of the statistical analysis plan, any additional analyses or 
changes to analyses that may be required will be fully disclosed in the clinical study report 
(CSR).
Note that for new patients, baseline or screening data from the current study (after signing the 
ICF or assent form, as applicable) will be used. For roll-over patients, unless otherwise specified, 
data from Study TV46000-CNS-30072 will be used as baseline.
9.1.
Sample Size and Power Considerations
This study is safety-oriented in nature; therefore, no formal hypothesis testing is planned. Based 
on regulatory requirements, up to approximately 300 patients are planned to be enrolled in 
Stage 2 of this study in order to collect data on at least 100 patients exposed to TV-46000 for at 
least 1 year. Adolescent patients will only be enrolled in the US; any enrolled adolescents will be 
in addition to the aforementioned total.
9.2.
Analysis Sets
9.2.1.
Intent-to-Treat Analysis Set
The intent-to-treat (ITT) analysis set will include all randomized patients who were randomized 
either in Study TV46000-CNS-30072 or in Study TV46000-CNS-30078.
In the ITT analysis set, treatment will be assigned based on the TV-46000 treatment to which the 
patients were randomized in this study, regardless of which treatment they actually received.
The ITT analysis set will include all randomized patients, including new patients who did not 
take any IMP. 
9.2.2.
Safety Analysis Set
The safety analysis set will include all patients who receive at least 1 dose of TV-46000 during 
this study. In the safety analysis set, treatment will be assigned based on the treatment the 
patients actually received, regardless of the treatment to which they were randomized, unless 
otherwise specified. 
9.2.3.
Per-Protocol Analysis Set
The per-protocol analysis set will include all patients in the safety analysis set who have no 
important protocol deviations. In this analysis set, treatment will be assigned based on the 
treatment the patients actually received. 
9.2.4.
Pharmacokinetics Analysis Set
The pharmacokinetics analysis set will include all patients from the safety analysis set who also 
have ≥1 plasma concentration measurement.


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9.2.5.
Enrolled Patients Set
The enrolled patients set will include all new patients who have met study eligibility 
requirements for Stage 1 and received at least one dose of oral risperidone in Stage 1 and all roll-
over patients from Study TV46000-CNS-30072.
9.2.6.
Additional Analysis Sets
Additional analysis sets will be defined in the statistical analysis plan. 
9.3.
Data Handling Conventions
For all variables, only the observed data from the patients will be used in the statistical analyses 
(ie, there is no plan to estimate missing data, unless otherwise specified). Ad hoc imputation for 
safety presentation may be conducted and will be detailed in the statistical analysis plan.
9.4.
Study Population
The safety analysis set (Section 9.2.2) will be used for study population summaries and efficacy 
endpoints unless otherwise specified. Summary tables will be presented by treatment group and 
for all patients and by source of patients (new patients and roll-over patients). Select summary 
tables will be presented using the ITT analysis set.
9.4.1.
Patient Disposition
The numbers and percentages of new patients screened and enrolled in Stage 1 of this study; new
patients who were enrolled in Stage 1 of this study but were not randomized for the double-blind 
maintenance stage (Stage 2) and their reason for not being randomized; all (new and roll-over) 
patients who were assigned treatment; all patients who were assigned treatment but not treated; 
all patients in the ITT, safety, and pharmacokinetics analysis sets; all patients who completed the 
study; and all patients who withdrew from the study will be summarized. Data from patients who 
withdrew from the study will also be summarized by reason for withdrawal using descriptive 
statistics.
9.4.2.
Demographic and Baseline Characteristics
Patient demographic and baseline characteristics, including medical history, prior medications 
and therapies, and ECG findings, will be summarized using descriptive statistics. For continuous 
variables, descriptive statistics (n, mean, standard deviation, median, minimum, and maximum) 
will be provided. For categorical variables, patient counts and percentages will be provided. 
Categories for missing data will be presented if necessary.
The ITT analysis set and the safety analysis set will be used for the summary, as applicable.
9.5.
Efficacy Analysis
Efficacy analysis will be descriptive and will be described in the statistical analysis plan.
9.5.1.
Primary Endpoint
As this is a safety-oriented study, there is no primary efficacy endpoint for this study 
 


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9.5.2.
Exploratory Endpoints
9.5.3.
Planned Method of Analysis
. Summaries 
will be presented by treatment group and by source of patients (new patients and roll-over 
patients).
9.5.3.1.
Primary Efficacy Analysis
There is no primary efficacy analysis for this study.
9.5.3.2.
Sensitivity Analysis
No sensitivity analyses are planned.
9.5.3.3.
Exploratory Efficacy Analysis
For COVID-19 updates, refer to Appendix N.
9.6.
Multiple Comparisons and Multiplicity
No adjustments will be made for the preplanned multiple comparisons/endpoints.
9.7.
Safety Analysis
Safety analyses will be performed on the safety analysis set (Section 9.2.2). 
Safety assessments and time points are provided in Table 1 and Table 2.
All adverse events will be coded using the Medical Dictionary for Regulatory Activities. Each 
patient will be counted only once in each preferred term or system organ class category for the 
analyses of safety. Summaries will be presented for all adverse events (overall and by severity), 
including adverse events determined by the investigator to be related to the test IMP (ie, 
reasonable possibility [see Section 7.1.4], defined as related or with missing relationship), 
serious adverse events, and adverse events causing withdrawal from the study. Summaries will 
be presented by source of patients (new patients and roll-over patients) and by treatment group as 
well as total. Summaries will include both incidence and person-time incidence (number of 
events divided by the total exposure to drug). A summary table of adverse events that includes 
adverse events from Study TV46000-CNS-30072 for roll-over patients will be presented as well. 
Patient listings of serious adverse events and adverse events leading to withdrawal will be 
presented.
Changes in laboratory, ECG, and vital sign measurement data will be summarized descriptively. 
All values will be compared with predefined criteria to identify potentially clinically significant 
values or changes, and such values will be listed.
The use of concomitant medications will be summarized by therapeutic class using descriptive 
statistics.


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Descriptive statistics for allowed rescue medications (Section 5.7) will be presented by treatment 
group.
Safety outcomes, including changes from baseline in EPS scale scores (BARS, AIMS, and SAS) 
and CDSS during Stage 2, will be presented using descriptive statistics by treatment group. 
The incidence of treatment-emergent adverse events related to EPS will be summarized by the 
following event categories: akathisia, dyskinesia, dystonia, parkinsonism, and tremor. The
C-SSRS and CGI-SS will be used to assess the risk of suicide events during the study. 
Descriptive statistics will be presented by treatment group.
If any patient dies during the study, a listing of deaths will be provided, and all relevant 
information will be discussed in the patient narrative included in the CSR.
Selected safety data will also be presented by site of injection (abdomen versus arm) and by age 
group (adolescents [ages 13 through 17] and adults [18 years of age or older]), as applicable. 
For continuous variables, descriptive statistics (n, mean, standard deviation, median, minimum, 
and maximum) will be provided for actual values and changes from baseline to each time point. 
For categorical variables, patient counts and percentages will be provided.
Safety data collected in Stage 1 will also be summarized using descriptive statistics for new 
patients.
9.8.
Tolerability Analysis
In cases where an adverse event related to an injection site reaction is reported, an assessment of 
the sc injection site (ie, local tolerability [skin at injection site]) will be made. The presence and 
severity of erythema, swelling, induration, and pain at the injection site may be assessed and 
summarized using descriptive statistics.
9.9.
Pharmacokinetic Analysis
Pharmacokinetic analysis will be descriptive and will be described in the statistical analysis plan.
9.10.
Pharmacodynamic Analysis
Not applicable.
9.11.
Pharmacokinetic/Pharmacodynamic Analysis
The results of the pharmacokinetic/pharmacodynamic analysis (if relevant data permit) will be 
presented in a separate report.
9.12.
Biomarker and Pharmacogenetics Analysis
Genetic variation in CYP2D6, and corresponding metabolizer status, will be assessed using 
descriptive statistics for an association with pharmacokinetic endpoints.
Biomarker and pharmacogenetics analysis plans and results will be reported separately from the 
main study results.


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9.13.
Planned Interim Analysis
There will be a planned data cut with statistical output produced before the New Drug 
Application submission.
9.14.
Reporting Deviations from the Statistical Plan
Deviations from the statistical plan, along with the reasons for the deviations, will be described 
in protocol amendments, the statistical analysis plan, the CSR, or any combination of these, as 
appropriate, and in accordance with applicable national, local, and regional requirements and 
regulations.


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10.
QUALITY CONTROL AND QUALITY ASSURANCE
Refer to Appendix C for information regarding quality control and quality assurance. This 
includes information about protocol amendments, deviations, responsibilities of the investigator 
to study personnel, study monitoring, and audit and inspection.
For COVID-19 updates, refer to Appendix N.
Refer to Appendix K for the definition of a clinical product complaint and investigator 
responsibilities in the management of a clinical product complaint.
11.
COMPLIANCE STATEMENT
This study will be conducted in full accordance with the ICH Harmonised Tripartite Guideline, 
Guideline for GCP E6 and any applicable national and local laws and regulations (eg, Title 21 
Code of Federal Regulations [21CFR] Parts 11, 50, 54, 56, 312, and 314, Directive 2001/20/EC 
of the European Parliament and of the Council on the approximation of the laws, regulations, and 
administrative provisions of the Member States relating to the implementation of GCP in the 
conduct of clinical trials on medicinal products for human use). Any episode of noncompliance 
will be documented.
The investigator is responsible for performing the clinical study in accordance with this protocol 
and the applicable GCP guidelines referenced above for collecting, recording, and reporting the 
data accurately and properly. Agreement of the investigator to conduct and administer this 
clinical study in accordance with the protocol will be documented in separate clinical study 
agreements with the sponsor and other forms as required by national CAs in the country where 
each investigational center is located.
The investigator is responsible for ensuring the privacy, health, and welfare of the patients during 
and after the clinical study and must ensure that trained personnel are immediately available in 
the event of a medical emergency. The investigator and the involved clinical study personnel 
must be familiar with the background and requirements of the study and with the properties of 
the IMPs as described in the IB or PI.
The principal investigator at each investigational center has the overall responsibility for the 
conduct and administration of the clinical study at that investigational center and for contacts 
with study management, with the IEC/IRB, and with CAs.
See Appendix D for the ethics expectations of informed consent or assent, CAs and IEC/IRB, 
confidentiality regarding study patients, and requirements for registration of the clinical study.
12.
DATA MANAGEMENT AND RECORD KEEPING
See Appendix L for information regarding data management and record keeping. This includes 
direct access to source data and documents, data collection, data quality control, and archiving of 
CRFs and source documents.


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13.
FINANCING AND INSURANCE
A separate clinical study agreement, including a study budget, will be signed between each 
principal investigator and the sponsor (or the CRO designated by the sponsor) before the IMP is 
delivered.
The patients in this clinical study are insured in accordance with applicable legal provisions. The 
policy coverage is subject to the full policy terms, conditions, extensions, and exclusions. 
Excluded from the insurance coverage are damages to health and worsening of previous existing 
disease that would have occurred or continued if the patient had not taken part in the clinical 
study.
The policy of Clinical Trials Insurance will be provided to the investigational centers by the 
sponsor.
For covered clinical studies (see 21CFR54), the investigator will provide the sponsor with 
financial information required to complete the FDA 3454 form. Each investigator will notify the 
sponsor of any relevant changes during the conduct of the study and for 1 year after the study has 
been completed.
14.
PUBLICATION POLICY
See Appendix M for information regarding the publication policy.


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15.
REFERENCES
Addington D, Addington J, Maticka-Tyndale E. Assessing depression in schizophrenia: the 
Calgary Depression Scale. Br J Psychiatry Suppl 1993 Dec;(22):39-44.
Asarnow R, Brown W, Strandburg R. Children with a schizophrenic disorder: neurobehavioral 
studies. Eur Arch Psychiatry Clin Neurosci 1995;245:70-9.
Barnes TR, Curson DA. Long-term depot antipsychotics. A risk-benefit assessment. Drug Saf 
1994;10:464-79.
Barnes TR. A rating scale for drug-induced akathisia. Br J Psychiatry 1989 May;154:672-6.
Birnbaum M, Sharif Z. Medication adherence in schizophrenia: patient perspectives and the 
clinical utility of paliperidone ER. Patient Prefer Adherence 2008;2:233-40.
Bo S, Haahr UH. Early-onset psychosis and child and adolescent schizophrenia. Scandinavian J 
Child Adolescent Psychiatry and Psychology 2016;4(1):1-3.
EuroQol Group. EuroQol-a new facility for the measurement of health-related quality of life. 
Health Policy 1990;16:199-208.
First MB, Williams JBW, Karg RS, Spitzer RL. Structured Clinical Interview for DSM-5 
Disorders, Clinical Trials Version (SCID-5-CT). Arlington, VA. American Psychiatric 
Association, 2015.
Guy W. ECDEU Assessment Manual for Psychopharmacology (revised). Rockville (Maryland): 
US Department of Health, Education, and Welfare; Public Health service; Alcohol, Drug Abuse, 
and Mental Health Administration; National Institute of Mental Health, Psychopharmacology 
Research Branch, 1976a;218-22. 
Guy WA. Abnormal Involuntary Movement Scale (AIMS). In: ECDEU Assessment Manual for 
Psychopharmacology. Washington, D.C; 1976b:534-7.
Hogan TP, Awad AG, Eastwood R. A self-report scale predictive of drug compliance in 
schizophrenics: reliability and discriminative validity. Psychological Medicine 1983;13(1):177-
83.
Hollis C. Adult outcomes of child- and adolescent-onset schizophrenia: diagnostic stability and 
predictive validity. Am J Psychiatry 2000;157(10):1652-9. 
Hughes DA. Estimation of the impact of non-compliance on pharmacokinetics: an analysis of the 
influence of dosing regimens. British J Clin Pharm 2007;65:871-8.
Kay SR, Fiszbeln A, Opler LA. The positive and negative syndrome scale (PANSS) for 
schizophrenia. Schizophrenia Bull 1987;13(2):261-76.
Keith SJ, Kane JM. Partial compliance and patient consequences in schizophrenia: our patients 
can do better. J Clin Psychiatry 2003;64:1308-15.
Lindenmayer JP, Czobor P, Alphs L, Nathan AM, Anand R, Islam Z, et al. InterSePT Study 
Group. The InterSePT scale for suicidal thinking reliability and validity. Schizophr Res 
2003;63:161-70. 


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Lytle S, McVoy M, Sajatovic M. Long-acting injectable antipsychotics in children and 
adolescents. J Child Adolesc Psychopharmacol 2017;27(1):2-9. 
Morosini PL, Magliano L, Brambilla L, Ugolini S, Pioli R. Development, reliability and 
acceptability of a new version of the DSM-IV Social and Occupational Functioning Assessment 
Scale (SOFAS) to assess routine social functioning. Acta Psychiatr Scand 2000 Apr;101(4):323-
9.
New York State Office of Mental Health. Schizophrenia. June 2011. 16 pages.
Nielsen RE, Lindstrom E, Nielsen J, Levander S. DAI-10 is as good as DAI-30 in schizophrenia. 
Eur Neuropsychopharmacol 2012;22(10):747-50.
Perkovic MN, Erjavec GN, Strac DS, Uzun S, Kozumplik O, Pivac N. Theranostic Biomarkers 
for Schizophrenia. Int J Mol Sci 2017;18(4).pii:E733.
Posner K, Brown GK, Stanley B, Brent DA, Yershova KV, Oquendo MA, et al. The Columbia-
Suicide Severity Rating Scale: initial validity and internal consistency findings from three 
multisite studies with adolescents and adults. Am J Psychiatry 2011;168(12):1266-77.
Rabin R, de Charro F. EQ-5D: a measure of health status from the EuroQol Group. Ann Med 
2001 Jul;33(5):337-43.
Rainer MK. Risperidone long-acting injection: a review of its long term safety and efficacy. 
Neuropsychiatr Dis Treat 2008;4(5):919-27.
Rapoport J, Addington A, Frangou S. The neurodevelopmental model of schizophrenia: what can 
very early onset cases tell us? Curr Psychiatry Rep 2005;7:81-2.
RISPERDAL CONSTA (risperidone) LONG ACTING INJECTION. US Prescribing 
Information. Janssen Pharmaceuticals, Inc., 2014.
RISPERIDONE tablets USP for oral use. US Prescribing Information. Teva Pharmaceuticals 
USA, Inc., 2014.
Simpson GM, Angus JWS. A rating scale for extrapyramidal side effects. Acta Psychiatr Scand 
1970;212:11-9.
Stefan M, Travis M. An atlas of schizophrenia. London: The Parthenon Publishing Group, 2002.
Subotnik KL, Casaus LR, Ventura J, Luo JS, Hellemann GS, Gretchen-Doorly D, et al. Long-
acting injectable risperidone for relapse prevention and control of breakthrough symptoms after a 
recent first episode of schizophrenia. A randomized clinical trial. JAMA Psychiatry 
2015;72(8):822-9.
Walburn J, Gray R, Gournay K, Quraishi S, David AS. Systematic review of patient and nurse 
attitudes to depot antipsychotic medication. Br J Psychiatry 2001;179:300-7.
Weinberger D, Harrison PJ (Eds.) Schizophrenia. 3rd ed. Hoboken, NJ: Wiley-Blackwell;2011. 
Wilkinson G, Hesdon B, Wild D, Cookson R, Farina C, Sharma V, et al. Self-report quality of 
life measure for people with schizophrenia: the SQLS. Br J Psychiatry 2000;177:42-6.
Williamson A, Hoggart B. Pain: A review of three commonly used pain rating scales. J Clin 
Nurs 2005;14(7):798-804.


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16.
SUMMARY OF CHANGES
16.1.
Global Amendment 01 (Dated 03 June 2020) 
The primary reason for this amendment is to clarify various aspects related to study conduct. For 
example, to avoid duplication and reduce patient burden, many of the baseline procedures and 
assessments outlined in this protocol related to the roll-over patients, will be performed in the 
end-of-treatment (EoT) visit of the TV46000-CNS-30072 study, and the results will be 
transferred to this study's clinical database. The volume of collected blood samples was corrected 
accordingly. Other modifications include the biomarker sample collection (which is now 
optional) and gender was removed as a stratification factor for randomization of new patients and 
roll-over patients previously assigned to placebo. In addition, various clarifications were made, 
eg, blinding of personnel to the IMP treatment assignments in the TV46000-CNS-30072 and 
TV46000-CNS-30078 studies (especially with regard to those also involved in the conduct of the 
TV46000-CNS-30072 study).
Also, since pin-pointing the onset of schizophrenia in adolescents is difficult, the time since the 
diagnosis of schizophrenia in the inclusion criterion for adolescents (aged 13-17) was reduced to 
6 months to better align with the DSM-5 criteria, and the requirement for relapse in the last 24 
months was removed due to the short time since diagnosis.
Administrative issues were added or corrected (eg, study name, sponsor address, personnel 
changes, etc), and other issues tracked during the course of the study were revised as applicable. 
The 2 existing administrative letters (dated 22 July 2019 and 09 February 2020) that have not yet 
been incorporated into a protocol amendment, were implemented in this one.
Additionally, COVID-19 pandemic-related operational updates were added to the study as a new 
appendix (Appendix N). Administrative changes have been applied, including updating the Table 
of Contents.
All major changes to the protocol body are listed below in the table, and are reflected in the 
synopsis, as applicable. Table 2 (Study Procedures and Assessments) has also been revised to 
reflect the changes described below. 
Minor grammatical and editorial changes (typos, punctuation, etc) have been made to the 
protocol (and protocol synopsis, as appropriate).


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Original text with changes shown
New wording
Reason/Justification for 
change
TITLE PAGE 
NDA number: Not applicable 213586
NDA number: 213586
New Drug Application 
number assigned.
[Other sections affected by 
this change: Investigator 
Agreement and 
Coordinating Investigator 
Agreement]
See New wording column.
(The SHINE Study – Safety in Humans of TV-46000 sc 
INjection Evaluation)
Addition of study name to 
protocol.
[Other section affected by 
this change: Investigator 
Agreement and 
Coordinating Investigator 
Agreement]
Teva Branded Pharmaceutical Products R&D, Inc.
41 Moores Road 145 Brandywine Parkway
Frazer, Pennsylvania 19355 West Chester, Pennsylvania 19380
United States of America
Teva Branded Pharmaceutical Products R&D, Inc.
145 Brandywine Parkway
West Chester, Pennsylvania 19380
United States of America
Per Administrative Letter 
02, new address following 
relocation of sponsor 
offices.
COORDINATING INVESTIGATOR AGREEMENT
See New wording column.
Executed signature pages are maintained within the Trial Master 
File.
Clarification.
LIST OF ABBREVIATIONS
See New wording column
Added:
COVID-19 = Coronavirus disease 2019
TC = telephone call/teleconference
VC = videoconference 
Newly-introduced 
abbreviations
1. INTRODUCTION AND BACKGROUND
1.1. Introduction
...
TV-46000 incorporates risperidone and 2 copolymers, 
specifically poly(D,L-lactide)-co-poly(ethylene glycol)-co-
...
TV-46000 incorporates risperidone and 2 copolymers, 
specifically poly(D,L-lactide)-co-poly(ethylene glycol)-co-
Clarification and 
simplification.


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Original text with changes shown
New wording
Reason/Justification for 
change
poly(D,L-lactide) and methoxy-poly(ethylene glycol)-co-
poly(D,L-lactide), dissolved in DMSO. Exposure to aqueous 
environments causes the formulation to gel. Therefore, after sc 
administration, the q1m and q2m products form a depot under 
the skin due to the insolubility of the copolymers in an aqueous 
environment. The copolymers are designed to degrade by 
hydrolysis, ultimately leading to the resorption of the depot at 
the injection site. The depot is expected to be fully degraded 
following the complete release of the drug substance.
...
poly(D,L-lactide) and methoxy-poly(ethylene glycol)-co-
poly(D,L-lactide), dissolved in DMSO. Therefore, after sc 
administration, the q1m and q2m products form a depot under 
the skin. The depot is expected to be fully degraded following 
the complete release of the drug substance.
...
3. STUDY DESIGN
3.1. General Study Design and Study Schematic Diagram
Screening: These patients will undergo screening 
procedures/assessments within 4 weeks before the start of 
Stage 1. They Adult patients (aged 18-65) should have had a 
diagnosis of schizophrenia for >1 year, and adolescent patients 
(aged 13-17) should have had a diagnosis of schizophrenia for 
>6 months (diagnosis must be reconfirmed by Structured 
Clinical Interview for Diagnostic and Statistical Manual of 
Mental Disorders, 5th Edition [DSM-5] [SCID-5]), and have 
been generally responsive to antipsychotics in the past year 
based on discussions with family members or healthcare 
professionals. Patients Adult patients should also have had 
≥1 episode of relapse in the last 24 months. Patients will 
provide informed consent or assent, as applicable, at the 
screening visit, before any study-related procedures or 
assessments are performed.
Screening: These patients will undergo screening 
procedures/assessments within 4 weeks before the start of 
Stage 1. Adult patients (aged 18-65) should have had a 
diagnosis of schizophrenia for >1 year, and adolescent patients 
(aged 13-17) should have had a diagnosis of schizophrenia for 
>6 months (diagnosis must be reconfirmed by Structured 
Clinical Interview for Diagnostic and Statistical Manual of 
Mental Disorders, 5th Edition [DSM-5] [SCID-5]), and have 
been generally responsive to antipsychotics in the past year 
based on discussions with family members or healthcare 
professionals. Adult patients should also have had ≥1 episode of 
relapse in the last 24 months. Patients will provide informed 
consent or assent, as applicable, at the screening visit, before 
any study-related procedures or assessments are performed.
Clarification following 
revision of adolescent 
inclusion criterion.
Roll-over patients will begin this study at the baseline visit and 
start at Stage 2 of the study (double-blind maintenance stage). 
For these patients, the end-of-treatment (EoT) visit in Study 
TV46000-CNS-30072 will serve as the baseline visit. Some 
baseline procedures will be performed as part of the EoT visit in 
the TV46000-CNS-30072 study, and the results will be 
transferred to this study's clinical database (see Table 2 and 
Appendix B, Section 3).
Roll-over patients will begin this study at the baseline visit and 
start at Stage 2 of the study (double-blind maintenance stage). 
For these patients, the end-of-treatment (EoT) visit in Study 
TV46000-CNS-30072 will serve as the baseline visit. Some 
baseline procedures will be performed as part of the EoT visit in 
the TV46000-CNS-30072 study, and the results will be 
transferred to this study's clinical database (see Table 2 and 
Appendix B, Section 3).
Clarification.
Cross-references to 
relevant protocol sections 
added.
The study duration will be approximately 2225 months, from 
The study duration will be approximately 25 months, from 
Correction due to updated 


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Reason/Justification for 
change
Quarter 1 (Q1) 2019 to Quarter 4 Quarter 1 (Q4 Q1) 2020 2021.
Quarter 1 (Q1) 2019 to Quarter 1 (Q1) 2021.
timeline projections.
3.2. Planned Number of Patients and Countries
The study is planned to be conducted in the United States (US), 
Canada, and Bulgaria, and France (and possibly other countries 
as well) in approximately 100 investigational centers (new 
centers and those that participated in Study TV46000-CNS-
30072). The study is expected to start in Q1 2019 and last until 
approximately Q4 2020 Q1 2021.
The study is planned to be conducted in the United States (US) 
and Bulgaria in approximately 100 investigational centers (new 
centers and those that participated in Study TV46000-CNS-
30072). The study is expected to start in Q1 2019 and last until 
approximately Q1 2021.
Updated study countries 
and timelines.
3.5. Schedule of Study Procedures and Assessments
Table 2: Study Procedures and Assessments (In-Clinic Visits and Telephone Contacts) – For New and Roll-Over Patients – Baseline, Double-Blind 
Maintenance Stage (Stage 2), End of Treatment, and Follow-Up
See New wording column.
h. For roll-over patients, this procedure will be performed as 
part of the TV46000-CNS-30072 EoT visit, and the results will 
be transferred to this study's clinical database. 
Newly-added footnote for 
clarification.
Subsequent footnotes were 
re-labeled.
See New wording column.
The footnote was added for clarification to the X denoting the 
30078 baseline visit for the following procedures:

clinical laboratory tests (serum chemistry, hematology, 
and urinalysis)

urine drug screen

inquiry of concomitant medication

full physical examination 

vital sign measurements

urine β-HCG tests (for women of childbearing 
potential)

PANSS

CGI-S

CGI-SS

AIMS

BARS

SAS

C-SSRS

PSP (for adult patients only)
To avoid duplication and 
reduce patient burden, 
some procedures for roll-
over patients will be 
performed as part of the 
EoT visit in the TV46000-
CNS-30072 study.


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change

SQLS (for adult patients only)

EQ-5D-5L (for adult patients only)

CDSS

healthcare resource utilization

DAI-10 (for adult patients only)

inquiry about adverse events (including serious adverse 
event reporting and injection site-related events 
including pain)

inquiry about alcohol consumption and illicit drug use 
since previous visit
s. t. For new patients, a blood sample for pharmacogenetic 
analysis will be collected at baseline or any visit thereafter, 
unless the patient declines testing or local regulations prohibit 
testing. For roll-over patients, if a sample was not collected 
during Study TV46000-CNS-30072 for any reason, it will be 
collected at the baseline visit or any visit thereafter, unless the 
patent declines testing or local regulations prohibit testing.
t. For new patients, a blood sample for pharmacogenetic 
analysis will be collected at baseline or any visit thereafter, 
unless the patient declines testing or local regulations prohibit 
testing. For roll-over patients, if a sample was not collected 
during Study TV46000-CNS-30072 for any reason, it will be 
collected at the baseline visit or any visit thereafter, unless the 
patent declines testing or local regulations prohibit testing.
PGx sample collection is 
now optional and not 
mandatory.
Other sections affected by 
this change: Appendix B.
t. u. Blood samples for biomarker analyses will be collected as 
follows: 6 mL for serum, 6 mL for plasma, and 2.5 mL for 
PAXgene RNA, unless the patient declines testing or local 
regulations prohibit testing.
u. Blood samples for biomarker analyses will be collected as 
follows: 6 mL for serum, 6 mL for plasma, and 2.5 mL for 
PAXgene RNA, unless the patient declines testing or local 
regulations prohibit testing.
Biomarker sample 
collection is now optional 
and not mandatory.
4. SELECTION AND WITHDRAWAL OF PATIENTS
4.1.2. New Patients (Not Rolling Over from the Pivotal Efficacy Study TV46000-CNS-30072)
a. [Revision 01] The patient is an adult (age 18-65) and has a 
diagnosis of schizophrenia according to the DSM-5 for >1 year 
(diagnosis must be reconfirmed by SCID-5) and ≥1 episode of 
relapse in the last 24 months, OR the patient is an adolescent 
(age 13-17) with a diagnosis of schizophrenia according to the 
DSM-5 for > 6 months (diagnosis must be reconfirmed by 
SCID-5).
a. [Revision 01] The patient is an adult (age 18-65) and has a 
diagnosis of schizophrenia according to the DSM-5 for >1 year 
(diagnosis must be reconfirmed by SCID-5) and ≥1 episode of 
relapse in the last 24 months, OR the patient is an adolescent 
(age 13-17) with a diagnosis of schizophrenia according to the 
DSM-5 for > 6 months (diagnosis must be reconfirmed by 
SCID-5). 
Adolescent inclusion 
criterion was revised to 
better align with the DSM-
5, and the requirement for 
relapse was removed due 
the short time since 
diagnosis.
5. TREATMENTS
5.7. Prior and Concomitant Medication or Therapy 
In general, aAntidepressants, antipsychotics (other than study 
drug), and mood stabilizers will not be permitted as concomitant 
medications. However, some antidepressants and mood 
In general, antidepressants, antipsychotics (other than study 
drug), and mood stabilizers will not be permitted as concomitant 
medications. However, some antidepressants and mood 
Clarification that 
exceptions are
allowed for some 


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change
stabilizers (including the CYP2D6 inhibitors fluoxetine, 
paroxetine, and duloxetine) will be permitted if the patient is on 
a stable dose for at least 3 months prior to screening.
stabilizers (including the CYP2D6 inhibitors fluoxetine, 
paroxetine, and duloxetine) will be permitted if the patient is on 
a stable dose for at least 3 months prior to screening.
antidepressants
under the conditions listed.
5.9. Randomization and Blinding
New patients will be randomized via the IRT to receive sc 
injections of either TV-46000 q1m or TV-46000 q2m in a 1:1 
ratio. Randomization will be stratified by gender (male or 
female) and the dose of oral risperidone on which the patient 
was stabilized during Stage 1 (2/3, 4, or 5 mg/day).
New patients will be randomized via the IRT to receive sc 
injections of either TV-46000 q1m or TV-46000 q2m in a 1:1 
ratio. Randomization will be stratified by the dose of oral 
risperidone on which the patient was stabilized during Stage 1 
(2/3, 4, or 5 mg/day).
Gender was removed as a 
stratification factor for 
randomization.
Roll-over patients who were assigned to placebo during 
Study TV46000-CNS-30072 will be randomized via the IRT to 
receive sc injections of either TV-46000 q1m or TV-46000 q2m 
in a 1:1 ratio. Randomization will be stratified by gender (male 
or female) and the dose of oral risperidone on which the patient 
was stabilized during Stage 1 (2/3, 4, or 5 mg/day).
Roll-over patients who were assigned to placebo during 
Study TV46000-CNS-30072 will be randomized via the IRT to 
receive sc injections of either TV-46000 q1m or TV-46000 q2m 
in a 1:1 ratio. Randomization will be stratified by the dose of 
oral risperidone on which the patient was stabilized during 
Stage 1 (2/3, 4, or 5 mg/day).
Gender was removed as a 
stratification factor for 
randomization.
…
The sponsor’s clinical personnel (and delegates) involved in the 
study will not be blinded to the identity and dosing regimens of 
the IMPs received by the new patients in Study TV46000 CNS
30072 and during the course of this study.
Since the roll-over of patients from Study TV46000-CNS-
30072 into this study is expected to occur prior to Study 
TV46000-CNS-30072 database lock, the sponsor’s clinical 
personnel (and delegates) involved in the TV46000-CNS-30072 
study will be blinded to the identity of their IMP treatment 
assignments in the TV46000-CNS-30072 and TV46000-CNS-
30078 studies, until the TV46000-CNS-30072 database is 
locked for final analysis and the IMP assignment is known. 
However, certain personnel (ie, site unblinded pharmacist/nurse, 
IRT study staff, and Clinical Supply Chain) who have been 
unblinded since the beginning of the TV46000-CNS-30072 
study, will remain unblinded during the roll-over transition 
period until the database of Study TV46000-CNS-30072 is 
locked.
…
…
The sponsor’s clinical personnel (and delegates) involved in the 
study will not be blinded to the identity and dosing regimens of 
the IMPs received by the new patients during the course of this 
study.
Since the roll-over of patients from Study TV46000-CNS-30072 
into this study is expected to occur prior to Study TV46000-
CNS-30072 database lock, the sponsor’s clinical personnel (and 
delegates) involved in the TV46000-CNS-30072 study will be 
blinded to the identity of their IMP treatment assignments in the 
TV46000-CNS-30072 and TV46000-CNS-30078 studies, until 
the TV46000-CNS-30072 database is locked for final analysis 
and the IMP assignment is known. However, certain personnel 
(ie, site unblinded pharmacist/nurse, IRT study staff, and 
Clinical Supply Chain) who have been unblinded since the 
beginning of the TV46000-CNS-30072 study, will remain 
unblinded during the roll-over transition period until the 
database of Study TV46000-CNS-30072 is locked.
…
Correction per Admin 
Letter 02 (dated Feb 
2020).
Clarification regarding 
unblinding of study 
personnel in the TV46000-
CNS-30072 and TV46000-
CNS-30078 studies.


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change
5.11. Total Blood Volume (Other sections affected by this change: Appendix H)
The total blood volume to be collected for each patient in this 
study is variable, since the duration of participation will be up to 
either approximately 80 weeks in duration (for new patients) or 
64 weeks in duration (for roll-over patients). The maximum 
total blood volume to be collected in this study is approximately 
320 mL for each new patient and approximately 298 277 mL for 
each roll-over patient (including the ET/EoT visit and assuming 
that the patient completes the follow-up visits).
Up to 3 additional samples will be collected from adolescent 
patients for pharmacokinetic analysis (see Section 8.1). These 
additional pharmacokinetic samples will be taken from new 
adolescent patients or adolescent roll-over patients from whom 
additional pharmacokinetic blood samples were not obtained 
during Study TV46000-CNS-30072. Therefore, the maximum 
total blood volume to be collected is approximately 332 mL for 
each new adolescent patient and approximately 310 289 mL for 
each roll-over adolescent patient.
The total blood volume to be collected for each patient in this 
study is variable, since the duration of participation will be up to 
either approximately 80 weeks in duration (for new patients) or 
64 weeks in duration (for roll-over patients). The maximum 
total blood volume to be collected in this study is approximately 
320 mL for each new patient and approximately 277 mL for 
each roll-over patient (including the ET/EoT visit and assuming 
that the patient completes the follow-up visits).
Up to 3 additional samples will be collected from adolescent 
patients for pharmacokinetic analysis (see Section 8.1). These 
additional pharmacokinetic samples will be taken from new 
adolescent patients or adolescent roll-over patients from whom 
additional pharmacokinetic blood samples were not obtained 
during Study TV46000-CNS-30072. Therefore, the maximum 
total blood volume to be collected is approximately 332 mL for 
each new adolescent patient and approximately 289 mL for each 
roll-over adolescent patient.
Correction of blood 
volume for roll-over 
patients since, to avoid 
duplication, some 
procedures will be 
performed as part of the 
EoT visit in the TV46000-
CNS-30072 study.
6. ASSESSMENT OF EFFICACY
6.1.1. Clinical Global Impression - Improvement
The CGI-I will be administered by the investigator/trained rater 
at all in-clinic visits during the study (except for the screening 
and baseline visits).
The CGI-I will be administered by the investigator/trained rater 
at all in-clinic visits during the study (except for the screening 
and baseline visits).
Clarification.
7. ASSESSMENT OF SAFETY
7.4.2.2. Human Chorionic Gonadotropin Tests
A serum beta human chorionic gonadotropin (β-HCG) test will 
be performed for all women of child bearing potential at 
screening (new patients only), baseline, and the follow-up visits 
(see Table 1 and Table 2). At baseline, both a serum and a urine 
β-HCG test will be performed for new and roll-over patients. 
...
A serum beta human chorionic gonadotropin (β-HCG) test will
be performed for all women of child bearing potential at 
screening (new patients only), baseline, and the follow-up visits 
(see Table 1 and Table 2). At baseline, both a serum and a urine 
β-HCG test will be performed for new and roll-over patients. 
...
Clarification.
7.11. Other Assessments
The unblinded nurses who administer study drug to patients will 
The unblinded nurses who administer study drug to patients will 
Clarification.


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Reason/Justification for 
change
complete the following set of questions after drug 
administration (for new patients only) in order to assess the ease 
of administration when using the prefilled syringes. For each 
patient, this set of questions (Table 8) will be completed only 
for the first 3 injections. 
The responses will only be captured in the site’s source 
documentation, not in the clinical database.
...
complete the following set of questions after drug 
administration (for new patients only) in order to assess the ease 
of administration when using the prefilled syringes. For each 
patient, this set of questions (Table 8) will be completed only 
for the first 3 injections. 
The responses will only be captured in the site’s source 
documentation, not in the clinical database.
...
8. ASSESSMENT OF PHARMACOKINETICS/PHARMACODYNAMICS/BIOMARKERS/PHARMACOGENOMICS
8.3. Assessment of Exploratory Biomarkers
8.4. Pharmacogenetics 
...
For roll-over patients, if a sample was not collected during 
Study TV46000-CNS-30072 for any reason, it will be collected 
at the baseline visit or any visit thereafter, unless the patient 
declines testing or local regulations prohibit testing.
...
For roll-over patients, if a sample was not collected during 
Study TV46000-CNS-30072 for any reason, it will be collected 
at the baseline visit or any visit thereafter, unless the patient 
declines testing or local regulations prohibit testing.
Collection of PGx samples 
is now optional for new 
and roll-over patients.
9. STATISTICS
9.2.5. Enrolled Patients Set
See New wording column.
9.2.5. Enrolled Patients Set
The enrolled patients set will include all new patients who have 
met study eligibility requirements for Stage 1 and received at 
least one dose of oral risperidone in Stage 1 and all roll-over 
patients from Study TV46000-CNS-30072.
This definition was added 
for consistency with the 
TV46000-CNS-30072 
protocol.
APPENDIX A. CLINICAL LABORATORIES AND OTHER DEPARTMENTS AND INSTITUTIONS
Sponsor’s Authorized Representative
 
Specialty Clinical Development
Sponsor’s Authorized Representative
 
Specialty Clinical Development
Updated to reflect change 
of responsibilities at Teva.
Other sections affected by 
this change: Sponsor 


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Reason/Justification for 
change
Teva Branded Pharmaceutical Products R&D, Inc.
Tel: +
Cell: +
Email: 
Teva Branded Pharmaceutical Products R&D, Inc.
Tel: +
Cell: +
Email: 
Protocol Approval page.
Sponsor’s Medical Expert/Contact Point designated by the 
Sponsor for Further Information on the Study
Teva Branded Pharmaceutical Products R&D, Inc.
Tel: +
Cell: +
Email: 
Sponsor’s Medical Expert/Contact Point designated by the 
Sponsor for Further Information on the Study
Teva Branded Pharmaceutical Products R&D, Inc.
Tel: +
Cell: +
Email: 
Updated to reflect change 
of responsibilities at Teva. 
Medical Monitors:
ICON PLC
Mobile: 
Email: 
Back up: Lead Medical Monitor (MM) and Regional MM 
for Bulgaria:
ICON PLC
Tel:+
Mobile: 
 
E-Mail: 
Regional MM for US:
ICON PLC
External Tel: 
Mobile: 
Email: 
MM General E-Mail: STUDY-MA-DL-0075-0112-
MedicalReview@iconplc.com
Medical Monitors:
Lead Medical Monitor (MM) and Regional MM for 
Bulgaria:
ICON PLC
Tel:+
Mobile: +
 
E-Mail: 
Regional MM for US:
ICON PLC
External Tel
Mobile: 
Email: 
MM General E-Mail: STUDY-MA-DL-0075-0112-
MedicalReview@iconplc.com
Updated due to change of 
responsibilities.
General email added.


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Reason/Justification for 
change
Rater Training for Clinical Scales and Utilization Measures
Bracket Signant Health (formerly Bracket)
575 E. Swedesford Road, Ste 200
Wayne, PA 19087 
United States
Rater Training for Clinical Scales and Utilization Measures
Signant Health (formerly Bracket)
575 E. Swedesford Road, Ste 200
Wayne, PA 19087
United States
Update of vendor name 
following the merge 
between Bracket and
CRF Health. Other contact 
information remains 
unchanged.
Bioassay and Pharmacokinetic Sample Analysis
Please refer to the study Trial Master File.
Teva Pharmaceutical Works P. Ltd. Co. (TPW)
Bioanalytical Laboratory
Pallagi St. 13
Debrecen 4042
Hungary
Bioassay and Pharmacokinetic Sample Analysis
Teva Pharmaceutical Works P. Ltd. Co. (TPW)
Bioanalytical Laboratory
Pallagi St. 13
Debrecen 4042
Hungary
Updated with the details of 
the laboratory that will 
perform the analysis.
APPENDIX B. STUDY PROCEDURES AND ASSESSMENTS BY VISIT
The following procedures will be performed at Visit 6 for new 
and roll-over patients, unless otherwise specified. 
Note: For roll-over patients, the procedures marked with an 
asterisk (*) will be performed as part of the EoT visit in the 
TV46000-CNS-30072 study, and the results will be transferred 
to this study's clinical database.
The following procedures will be performed at Visit 6 for new 
and roll-over patients, unless otherwise specified. 
Note: For roll-over patients, the procedures marked with an 
asterisk (*) will be performed as part of the EoT visit in the 
TV46000-CNS-30072 study, and the results will be transferred 
to this study's clinical database.
To avoid duplication and 
to reduce patient burden, 
some procedures will be
performed as part of the 
EoT visit in the TV46000-
CNS-30072 study.
See new wording column
The following procedures were marked with an asterisk:

clinical laboratory tests (serum chemistry, hematology, 
and urinalysis)

urine drug screen

inquiry of concomitant medication

full physical examination (including weight; height to 
be measured for adolescent roll-over patients only)

vital sign measurements

urine β-HCG tests (for women of childbearing 
potential)

PANSS

CGI-S

CGI-SS

AIMS

BARS

SAS
Clarification.


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Reason/Justification for 
change

C-SSRS

PSP (for adult patients only)

SQLS (for adult patients only)

EQ-5D-5L (for adult patients only)

CDSS

healthcare resource utilization

DAI-10 (for adult patients only)

inquiry about adverse events (including serious adverse 
event reporting and injection site-related events 
including pain)

inquiry about alcohol consumption and illicit drug use 
since previous visit

blood samples for biomarker analysis - unless the 
patient declines testing or local regulations prohibit 
testing

blood samples for biomarker analysis - unless the 
patient declines testing or local regulations prohibit 
testing
Biomarker sample 
collection is now optional 
and not mandatory.
Updated for all relevant 
time points in the 
appendix.
See New wording column.
Unscheduled Visits:
...
In addition, to reduce patient burden and to avoid unnecessary 
data collection, the investigator will have discretion in 
determining whether the aforementioned procedures (which are 
currently marked in Table 1 and Table 2 as mandatory) actually
need to be performed during the unscheduled visit in the case 
that:
(i) the unscheduled visit is one of multiple in-clinic visits, that 
are deemed necessary in close proximity (2 or more visits within 
1 week), and
(ii) when the visit is for administrative purposes (eg, 
reconsenting) or clinical reasons (eg, repeat laboratory sample 
collection for reasons unrelated to an adverse event or
impending/current relapse), and not due to a potential relapse or 
a change in the patient's medical status per clinical judgement.
Notwithstanding, it is hereby emphasized that the above refers 
only to unscheduled visits, and not to any other scheduled in-
Clarification regarding 
procedures to be 
performed during 
unscheduled visits, per 
Letter of Clarification 01.


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Reason/Justification for 
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clinic visits or telephone contacts.
APPENDIX G. LIST OF PROHIBITED MEDICATIONS (Other sections affected by this change: Section 5.7)
...
In addition to those listed above, medications that may be 
expected to significantly interfere with the metabolism or 
excretion of risperidone and/or 9-OH risperidone, may be 
associated with a significant drug interaction with risperidone, 
or may pose a significant risk to patients’ participation in the 
study (eg, chloroquine, which is a QTc prolongator) are 
prohibited.
...
In addition to those listed above, medications that may be 
expected to significantly interfere with the metabolism or 
excretion of risperidone and/or 9-OH risperidone, may be 
associated with a significant drug interaction with risperidone, 
or may pose a significant risk to patients’ participation in the 
study (eg, chloroquine, which is a QTc prolongator) are 
prohibited.
Clarification due to 
COVID-19 pandemic.
APPENDIX H. TOTAL BLOOD VOLUME
See New wording column.
Table of Maximum Total Blood Volumes for Roll-Over Patients 
has been revised to reflect the changes described below:

The number of clinical laboratory samples was updated 
from 10 to 9, and the total blood volume for these 
samples was updated from 70 mL to 63 mL;

The number of biomarkers samples was updated from 
10 to 9, and the total blood volume for these samples 
was updated from 145 mL to 130.5 mL;

Total number of samples in the study was updated 
from 42 to 40;

Maximum total blood volume collected in the study for 
adults patients was updated from 298 mL to 277mL;

Maximum total blood volume collected in the study for
adolescents was updated from 310 mL to 289 mL;
Correction of blood 
volume for roll-over 
patients since, to avoid 
duplication, some 
procedures will be 
performed as part of the 
EoT visit in the 30072 
study.
d. Biomarker blood samples will be collected as follows: 6 mL 
each for plasma and serum, and 2.5 mL for RNA (PAXgene), 
unless the patient declines testing or local regulations prohibit 
testing.
d. Biomarker blood samples will be collected as follows: 6 mL 
each for plasma and serum, and 2.5 mL for RNA (PAXgene), 
unless the patient declines testing or local regulations prohibit 
testing.
Collection of biomarker 
samples is now optional 
for new and roll-over 
patients.
APPENDIX I. EXPLORATORY BIOMARKERS SAMPLES


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APPENDIX J. PHARMACOGENETIC ASSESSMENTS
For new patients, a blood sample for pharmacogenetic analysis 
will be collected at baseline or any visit thereafter, unless the 
patient declines testing or local regulations prohibit testing. For 
roll-over patients, if a sample was not collected during Study 
TV46000-CNS-30072 for any reason, it will be collected at the 
baseline visit or any visit thereafter, unless the patient declines 
testing or local regulations prohibit testing.
For new patients, a blood sample for pharmacogenetic analysis 
will be collected at baseline or any visit thereafter, unless the 
patient declines testing or local regulations prohibit testing. For 
roll-over patients, if a sample was not collected during Study 
TV46000-CNS-30072 for any reason, it will be collected at the 
baseline visit or any visit thereafter, unless the patient declines 
testing or local regulations prohibit testing.
Collection of PGx samples 
is now optional for new 
and roll-over patients.
APPENDIX N. MANAGEMENT OF STUDY ACTIVITIES DURING COVID-19
New appendix and text.
Additional text too numerous to include in this table; refer to 
Appendix N of this protocol.
Created to manage study 
conduct during the 
COVID-19 pandemic.
Section 3.1. General Study Design and Study Schematic Diagram; Section 3.5. Schedule of Study Procedures and Assessments; Section 5.1.1. Test 
Investigational Medicinal Product; Section 5.1.2. Placebo Investigational Medicinal Product; Table 4. Investigational Medicinal Products Used in the 
Study; Section 5.2.1. Storage and Security; Section 5.2.3. Accountability; Section 5.9. Randomization and Blinding; Section 6. Assessment of Efficacy; 
Section 7. Assessment of Safety; Section 7.4. Clinical Laboratory Tests; Section 7.6. Vital Signs; Section 7.7. Electrocardiography; Section 8.1. 
Pharmacokinetic Assessment; Section 9.5.3.3. Exploratory Efficacy Analysis; Section 10. Quality Control and Quality Assurance; Appendix C. Quality 
Control and Quality Assurance; Appendix F. Lost to Follow-Up 
See New wording column.
For COVID-19 updates, refer to Appendix N.
Updated sections to cross-
reference the addition of 
Appendix N.


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16.2.
Administrative Letter 02 (Dated 09 February 2020)


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16.3.
Letter of Clarification 01 (Dated 22 July 2019)


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APPENDIX A. CLINICAL LABORATORIES AND OTHER 
DEPARTMENTS AND INSTITUTIONS
Sponsor’s Authorized Representative
 
Teva Branded Pharmaceutical Products R&D, Inc.
Legal Representative of the Sponsor in the 
European Union
 
 
 
Sponsor’s Medical Expert/Contact Point 
Designated by the Sponsor for Further 
Information on the Study
 
Teva Branded Pharmaceutical Products R&D, Inc.
Coordinating Investigator
 
Medical Monitors
Lead Medical Monitor (MM) and Regional 
MM for Bulgaria:
Regional MM for US:
MM General E-Mail:


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Sponsor’s Representative of Global Patient 
Safety and Pharmacovigilance
For serious adverse events:
Send by email to the local safety officer/contract 
research organization. The email address will be 
provided in the serious adverse event report form. 
In the event of difficulty transmitting the form, 
contact the sponsor’s study personnel identified 
above for further instruction.
 
Teva Pharmaceutical Industries, Ltd.
Contract Research Organization
ICON Clinical Research LLC
2100 Pennbrook Parkway
North Wales, PA 19454
United States
Central Clinical Laboratory
ICON Clinical Research Ltd
South County Business Park
Leopardstown,
Dublin 18
D18 X5R3
Ireland
Rater Training for Clinical Scales and 
Utilization Measures
Signant Health (formerly Bracket)
575 E. Swedesford Road, Ste 200
Wayne, PA 19087 
United States
Electronic Data Capture
ICON Clinical Research LLC
2100 Pennbrook Parkway
North Wales, PA 19454
United States
Central Electrocardiogram Evaluation
eResearch Technology, Inc
1818 Market Street #1000
Philadelphia, PA, 19103
United States
Interactive Response Technology
ICON Clinical Research LLC
2100 Pennbrook Parkway
North Wales, PA 19454
United States
Bioassay and Pharmacokinetic Sample 
Analysis
Teva Pharmaceutical Works P. Ltd. Co. (TPW)
Bioanalytical Laboratory
Pallagi St. 13
Debrecen 4042
Hungary


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APPENDIX B. STUDY PROCEDURES AND ASSESSMENTS BY VISIT
1. Procedures for Screening (Visit 1, Week -16+4 weeks) – New Patients Only
The screening visit (Visit 1) will take place within 4 weeks of Stage 1 (Visit 2, Week -12). 
The following procedures will be performed at Visit 1:

obtain written informed consent (and assent, as applicable) before any study-related 
procedures are performed

review medical and psychiatric history

Structured Clinical Interview for Diagnostic and Statistical Manual of Mental 
Disorders, 5th Edition (SCID-5)

review prior medication history

review inclusion and exclusion criteria

clinical laboratory tests (ie, serum chemistry, hematology, and urinalysis)

virology and thyroid screening tests

urine drug screen

inquiry about concomitant medication

full physical examination (including height and weight)

vital sign measurements

12-lead electrocardiogram (ECG) (in triplicate)

follicle-stimulating hormone test (for women with no menses for 12 months)

serum beta human chorionic gonadotropin (β-HCG) pregnancy test (for women of 
childbearing potential)

Positive and Negative Syndrome Scale (PANSS)

Clinical Global Impression of Severity (CGI-S) 

Clinical Global Impression-Severity of Suicidality (CGI-SS)

Abnormal Involuntary Movement Scale (AIMS)

Barnes Akathisia Rating Scale (BARS) 

Simpson-Angus Scale (SAS)

Columbia Suicide Severity Rating Scale (C-SSRS)

Personal and Social Performance Scale (PSP) (for adult patients only)

Schizophrenia Quality of Life Scale (SQLS) (for adult patients only)

5-Level EuroQol Five Dimensions Questionnaire (EQ-5D-5L) (for adult patients 
only)


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
Calgary Depression Scale for Schizophrenia (CDSS) 

healthcare resource utilization

Drug Attitudes Inventory 10-item version (DAI-10) (for adult patients only)

inquiry about adverse events (including serious adverse event reporting)

inquiry about alcohol consumption and illicit drug use
2. Procedures Before Administration of Investigational Medicinal Product 
(Stage 1: Oral Conversion and Stabilization Stage) – New Patients Only
a. Stage 1: Oral Conversion and Stabilization (Visit 2, Week -12±3 days; Visit 3, 
Week -10±3 days; Visit 4, Week -8±3 days; and Visit 5, Week -4±3 days)
The following procedures will be performed at Visits 2, 3, 4, and 5 (unless otherwise 
specified):

clinical laboratory tests (serum chemistry, hematology, and urinalysis) – at Visit 4 
only

inquiry of concomitant medication

full physical examination, including weight - at Visit 2 only

vital sign measurements

urine β-HCG test (for women of childbearing potential)

PANSS

CGI-S

CGI-SS

Clinical Global Impression–Improvement (CGI-I) 

AIMS 

BARS

SAS

C-SSRS

CDSS 

blood samples for plasma drug concentration - if possible, should be taken within an 
hour prior to dosing – at Visit 2 and Visit 5 only

oral risperidone dispensing (for qd intake)

dosage review and adjustment

inquiry about adverse events (including serious adverse event reporting)

inquiry about alcohol consumption and illicit drug use since previous visit


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b. Stage 1: Oral Conversion and Stabilization (Telephone Contacts [Visit 4a, 
Week -6±3 days and Visit 5a, Week -2±3 days])
The following procedures and assessments will be performed at Visits 4a and 5a (telephone 
contacts):

inquiry about pregnancy status (for women of childbearing potential) 

C-SSRS

adverse event inquiry (including serious adverse event reporting)

inquiry about alcohol consumption and illicit drug use since previous visit

brief set of clinical questions to detect psychotic symptoms – the specific questions 
asked will be at the discretion of the investigator.
Psychiatric adverse events or suspicion of psychiatric deterioration prompted by the 
telephone contact will trigger an invitation of the patient to an unscheduled visit where 
psychiatric scales will be administered to rule out an impending relapse at the discretion of 
the investigator.
3. Procedures During Double-blind Maintenance Stage Administration of 
Investigational Medicinal Product (Baseline [Visit 6, Day 1 ±3 days])
The following procedures will be performed at Visit 6 for new and roll-over patients, unless 
otherwise specified. 
Note: For roll-over patients, the procedures marked with an asterisk (*) will be performed 
as part of the EoT visit in the TV46000-CNS-30072 study, and the results will be transferred 
to this study's clinical database.

obtain written informed consent (and assent, as applicable) before any study-related 
procedures are performed (roll-over patients only)

review inclusion and exclusion criteria (including randomization-specific criteria for 
new patients) 

clinical laboratory tests (serum chemistry, hematology, and urinalysis)*

virology and thyroid screening tests (roll-over patients only)

urine drug screen*

inquiry of concomitant medication*

full physical examination (including weight; height to be measured for adolescent 
roll-over patients only)*

vital sign measurements*

12-lead ECG (in triplicate)

serum β-HCG tests (for women of childbearing potential)

urine β-HCG tests (for women of childbearing potential)* 

PANSS*


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
CGI-S*

CGI-SS*

AIMS*  

BARS*  

SAS*

C-SSRS*

PSP (for adult patients only)*

SQLS (for adult patients only)*

EQ-5D-5L (for adult patients only)*

CDSS*  

healthcare resource utilization*

DAI-10 (for adult patients only)*

blood samples for pharmacogenetic analysis (new patients and roll-over patients 
for whom a sample was not collected in Study TV46000-CNS-30072) - unless the 
patient declines testing or local regulations prohibit testing.

blood samples for biomarker analysis - unless the patient declines testing or local 
regulations prohibit testing

blood samples for plasma drug concentration - if possible, should be taken within an 
hour prior to dosing

assessment of stability (based on the defined criteria) (new patients only)

randomization (new patients and roll-over patients who were assigned to placebo 
in Study TV46000-CNS-30072)

TV-46000 every month (q1m) administration– for patients in that treatment group 
(new patients only)

TV-46000 every 2 months (q2m) administration – for patients in that treatment group 
(new patients only)

questions to assess ease of study drug administration – to be performed only when 
using prefilled syringes (assessed following the first 3 injections for each patient) 
(new patients only)

inquiry about adverse events (including serious adverse event reporting and injection 
site-related events including pain)*

inquiry about alcohol consumption and illicit drug use since previous visit*
4. Procedures During Double-blind Maintenance Stage Administration of 
Investigational Medicinal Product (Stage 2: Relapse Prevention)


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Note: The 24-week series from Visit 7 to Visit 12c repeats (Visit 13-18c, 19-19c), 
until patient completion, relapse, or early termination (Visits 19-19c are identical to 
Visits 7-7c).
a. Stage 2: Relapse Prevention (Telephone Contacts [Visit 6a, Week 1±3 days; 
Visit 6b, Week 2±3 days; and Visit 6c, Week 3±3 days; and so forth after each 
in-clinic visit in Stage 2 until the ET/EoT visit])
Note: Telephone contact will occur weekly between in-clinic visits during the double-blind 
maintenance stage (Stage 2) (see Table 2). These contacts will be referred to by the previous 
visit number and a letter (for example, the telephone contacts that take place 1, 2, and 
3 weeks after Visit 6 will be referred to as “Visit 6a,” “Visit 6b,” and “Visit 6c,” 
respectively). 
The following procedures and assessments will be performed at all telephone contacts 
between the in-clinic visits:

inquiry about pregnancy status (for women of childbearing potential) 

C-SSRS

adverse event inquiry (including serious adverse event reporting and injection 
site-related events including pain)

inquiry about alcohol consumption and illicit drug use since previous visit

brief set of clinical questions to detect psychotic symptoms – the specific questions 
asked will be at the discretion of the investigator.
Psychiatric adverse events or suspicion of psychiatric deterioration prompted by the 
telephone contact will trigger an invitation of the patient to an unscheduled visit where 
psychiatric scales will be administered to rule out an impending relapse at the discretion of 
the investigator.
b. Stage 2: Relapse Prevention (Visit 7, Week 4±3 days; Visit 9, Week 12±3 days; 
Visit 11, Week 20±3 days)
The following procedures and assessments will be performed at Visits 7, 9, and 11:

inquiry of concomitant medication

vital sign measurements

urine β-HCG test (for women of childbearing potential)

PANSS 

CGI-S

CGI-SS

CGI-I 

AIMS 

BARS 


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
SAS

C-SSRS

PSP (for adult patients only) – Visit 9 only

SQLS (for adult patients only) - Visit 9 only

EQ-5D-5L (for adult patients only) - Visit 9 only

CDSS

healthcare resource utilization – Visit 9 only

blood samples for plasma drug concentration - if possible, should be taken within an 
hour prior to dosing 
 
 
 
 
 

vital sign measurements

12-lead ECG

urine β-HCG test (for women of childbearing potential)

PANSS

CGI-S

CGI-SS

CGI-I 

AIMS 

BARS 


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
SAS

C-SSRS

PSP (for adult patients only) – Visit 12 only

SQLS (for adult patients only) - Visit 12 only

EQ-5D-5L (for adult patients only) - Visit 12 only

CDSS

healthcare resource utilization – Visit 12 only

blood samples for biomarker analysis - unless the patient declines testing or local 
regulations prohibit testing

blood samples for plasma drug concentration - if possible, should be taken within an 
hour prior to dosing

TV-46000 q1m administration – for patients in that treatment group

TV-46000 q2m administration – for patients in that treatment group (to maintain the 
blind, patients will be injected q4w, but will alternate between TV-46000 sc and 
placebo injections)

questions to assess ease of study drug administration – to be performed only when 
using prefilled syringes (assessed following the first 3 injections for each patient) 
(new patients only) – Visit 8 only

adverse event inquiry (including serious adverse event reporting and injection 
site-related events including pain)

inquiry about alcohol consumption and illicit drug use since previous visit
Note: Another pharmacokinetic sample will be collected from adolescent patients only at a 
supplementary in-clinic visit at week 14 (2 weeks after Visit 9 [week 12]). It is highly 
preferable to collect the sample at week 14. However, if this is not possible, it may be 
collected 2 weeks after another in-clinic visit. Up to 2 additional samples may also be 
collected from adolescent patients at week 15 and week 13 (3 weeks and 1 week 
post-injection at Visit 9, respectively) at the sponsor’s discretion. The additional samples, if 
taken following another in-clinic visit, will be collected at the same intervals. If more than 1 
additional sample is taken, they do not need to be collected after the same injection (ie, 1 
sample can be taken 3 weeks after Visit X, and another can be taken 1 week after Visit Y). 
These additional pharmacokinetic samples will be taken from new adolescent patients or 
adolescent roll-over patients from whom additional pharmacokinetic blood samples were not 
obtained during Study TV46000-CNS-30072.
d. Stage 2: Early Termination (ET) Visit/End-of-Treatment Visit (EoT) (Visit 20, 
Week 56±3 days)
The following procedures and assessments will be performed at the ET/EoT visit:

clinical laboratory tests (serum chemistry, hematology, and urinalysis)


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
urine drug screen 

inquiry of concomitant medication

full physical examination, including weight 

vital sign measurements

urine β-HCG test (for women of childbearing potential)

PANSS 

CGI-S

CGI-SS

CGI-I

AIMS 

BARS 

SAS

C-SSRS

PSP (for adult patients only)

SQLS (for adult patients only)

EQ-5D-5L (for adult patients only)

CDSS 

healthcare resource utilization

DAI-10 (for adult patients only)

blood samples for biomarker analysis - unless the patient declines testing or local 
regulations prohibit testing

blood samples for plasma drug concentration - if possible, should be taken within an 
hour prior to dosing

TV-46000 q1m administration – for patients in that treatment group (this is 
applicable only for the EoT visit, not the ET visit)

TV-46000 q2m administration – for patients in that treatment group (to maintain the 
blind, patients will be injected q4w, but will alternate between TV-46000 sc and 
placebo injections) (this is applicable only for the EoT visit, not the ET visit)

adverse event inquiry (including serious adverse event reporting, injection site-related 
events including pain)

inquiry about alcohol consumption and illicit drug use since previous visit
Note: If per the investigator's judgement, the patient is at risk of not appearing at one or both 
of the follow-up visits, the investigator may perform an ECG at this visit. Likewise, if in the 


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judgment of the investigator, the patient will not come to 1 or both follow-up visits, then a 
dose of study drug should not be given at this EoT visit.
5. Follow-up (Visit 21, Week 60±3 days; Visit 22, Week 64±3 days)
The following procedures and assessments will be performed at Follow-up Visit 1 (Visit 21) 
and Follow-up Visit 2 (Visit 22):

clinical laboratory tests (serum chemistry, hematology, and urinalysis)

inquiry of concomitant medication

full physical examination (including weight)

vital sign measurements

12-lead ECG

serum β-HCG tests (for women of childbearing potential)

PANSS

CGI-S

CGI-SS

CGI-I 

AIMS 

BARS 

SAS

C-SSRS

PSP (for adult patients only) – Follow-up Visit 2 only

SQLS (for adult patients only) - Follow-up Visit 2 only

EQ-5D-5L (for adult patients only) - Follow-up Visit 2 only

CDSS 

healthcare resource utilization – Follow-up Visit 2 only

DAI-10 (for adult patients only) - Follow-up Visit 2 only

blood samples for biomarker analysis - unless the patient declines testing or local 
regulations prohibit testing

blood samples for plasma drug concentration

adverse event inquiry (including serious adverse event reporting, injection site-related 
events including pain)

inquiry about alcohol consumption and illicit drug use since previous visit
6. Unscheduled Visits


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An unscheduled visit may be performed at any time during the study as deemed necessary by 
the investigator (eg, in cases of psychiatric adverse events or suspicion of psychiatric 
deterioration). The date and reason for the unscheduled visit will be recorded on the CRF as 
well as any other data obtained from procedures and assessments.
Procedures performed during unscheduled visits will include the following:

inquiry of concomitant medication

vital sign measurements

PANSS

C-SSRS

blood samples for plasma drug concentration

adverse event inquiry (including serious adverse event reporting and injection 
site-related events including pain)

inquiry about alcohol consumption and illicit drug use since previous visit
Other procedures may be performed at the discretion of the investigator.
In addition, to reduce patient burden and to avoid unnecessary data collection, the investigator 
will have discretion in determining whether the aforementioned procedures (which are currently 
marked in Table 1 and Table 2 as mandatory) actually need to be performed during the 
unscheduled visit in the case that:
(i) the unscheduled visit is one of multiple in-clinic visits, that are deemed necessary in close 
proximity (2 or more visits within 1 week), and
(ii) when the visit is for administrative purposes (eg, reconsenting) or clinical reasons (eg, 
repeat laboratory sample collection for reasons unrelated to an adverse event or
impending/current relapse), and not due to a potential relapse or a change in the patient's 
medical status per clinical judgement.
Notwithstanding, it is hereby emphasized that the above refers only to unscheduled visits, and 
not to any other scheduled in-clinic visits or telephone contacts.
During Stage 2, unscheduled pharmacokinetic samples will be aimed to be collected in the event 
of relapse as defined per the study’s relapse criteria, any serious adverse event, patient 
withdrawal, and/or need for potential TV-46000 depot excision. Every effort should be made to 
obtain the additional pharmacokinetic sample at the closest time possible to the occurrence of the 
event.


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APPENDIX C. QUALITY CONTROL AND QUALITY ASSURANCE
Protocol Amendments and Protocol Deviations
Protocol Amendments
No changes from the final approved (signed) protocol will be initiated without the prior written 
approval or favorable opinion of a written amendment by the Independent Ethics 
Committee/Institutional Review Board (IEC/IRB) and national and local competent authorities 
(CAs), as applicable, except when necessary to address immediate safety concerns to the patients 
or when the change involves only nonsubstantial logistics or administration. The principal 
investigator at each investigational center, the coordinating investigator (if applicable), and the 
sponsor will sign the protocol amendment.
Important Protocol Deviations
Any deviation from the protocol that affects, to a significant degree, (a) the safety, physical, or 
mental integrity of the patients in the study and/or (b) the scientific value of the study will be 
considered an important protocol deviation. Important protocol deviations may include 
non-adherence on the part of the patient, the investigator, or the sponsor to protocol-specific 
inclusion and exclusion criteria, primary objective variable criteria, or GCP guidelines; 
noncompliance to IMP administration; use of prohibited medications. Important protocol 
deviations will be identified and recorded in the patient’s source. All important protocol 
deviations will be reported to the responsible IEC/IRB, as required.
When an important protocol deviation is reported, the sponsor will determine whether to 
withdraw the patient from the study or permit the patient to continue in the study, with 
documented approval from the medical expert. The decision will be based on ensuring the safety 
of the patient and preserving the integrity of the study.
Changes in the inclusion and exclusion criteria of the protocol are not prospectively granted by 
the sponsor. If investigational center personnel learn that a patient who did not meet protocol 
inclusion and exclusion criteria was entered in a study, they must immediately inform the 
sponsor of the important protocol deviation. If such patient has already completed the study or 
has withdrawn early, no action will be taken but the deviation will be recorded.
For COVID-19 updates, refer to Appendix N.
Information to Study Personnel
The investigator is responsible for giving information about the study to all personnel members 
involved in the study or in any element of patient management, both before starting the study and 
during the course of the study (eg, when new personnel become involved). The investigator must 
ensure that all study personnel are qualified by education, experience, and training to perform 
their specific task. These study personnel members must be listed on the investigational center 
authorization form, which includes a clear description of each personnel member’s 
responsibilities. This list must be updated throughout the study, as necessary.
The study monitor is responsible for explaining the protocol to all study personnel, including the 
investigator, and for ensuring they comply with the protocol.


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Study Monitoring
To ensure compliance with GCP guidelines, the study monitor or representative is responsible 
for ensuring that patients have signed the informed consent form or assent form, as applicable, 
and the study is conducted according to applicable Standard Operating Procedures (SOPs), the 
protocol, and other written instructions and regulatory guidelines.
The study monitor is the primary association between the sponsor and the investigator. The main 
responsibilities of the study monitor(s) are to visit the investigator before, during, and after the 
study to ensure adherence to the protocol, that all data are correctly and completely recorded and 
reported, and that informed consent or assent, as applicable, is obtained and recorded for all 
patients before they participate in the study and when changes to the consent form are warranted, 
in accordance with IEC/IRB approvals.
The study monitor(s) will contact the investigator and visit the investigational center according 
to the monitoring plan. The study monitor will be permitted to review and verify the various 
records (case report forms and other pertinent source data records, including specific electronic 
source document relating to the study) to verify adherence to the protocol and to ensure the 
completeness, consistency, and accuracy of the data being recorded.
As part of the supervision of study progress, other sponsor personnel may, on request, 
accompany the study monitor on visits to the investigational center. The investigator and 
assisting personnel must agree to cooperate with the study monitor to resolve any problems, 
errors, or possible misunderstandings concerning the findings detected during the course of these 
monitoring visits or provided in follow-up written communication.
For COVID-19 updates, refer to Appendix N.
Audit and Inspection
The sponsor may audit the investigational center to evaluate study conduct and compliance with 
protocols, SOPs, GCP guidelines, and applicable regulatory requirements. The sponsor’s Global 
Clinical Quality Assurance, independent of Global Specialty Development, is responsible for 
determining the need for (and timing of) an investigational center audit.
The investigator must accept that CAs and sponsor representatives may conduct inspections and 
audits to verify compliance with GCP guidelines.


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APPENDIX D. ETHICS
Informed Consent and Assent
The investigator, or a qualified person designated by the investigator, should fully inform the 
patient (and the parent/legally acceptable representative, as applicable) of all pertinent aspects of 
the study, including the written information approved by the Independent Ethics 
Committee/Institutional Review Board (IEC/IRB). All written and oral information about the 
study will be provided in a language as nontechnical as practical to be understood by the patient 
and the parent/legally acceptable representative, as applicable. The patient and the parent/legally 
acceptable representative, as applicable, should be given ample time and opportunity to inquire 
about details of the study and to decide whether or not to participate in the study. The above 
should be detailed in the source documents.
Written informed consent will be obtained from each patient before any study-specific 
procedures or assessments are done and after the aims, methods, anticipated benefits, and 
potential hazards are explained. The patient’s willingness to participate in the study will be 
documented in the informed consent form (ICF), which will be signed and personally dated by 
the patient and by the person who conducted the informed consent discussion. The investigator 
will keep the original ICFs, and copies will be given to the patients. It will also be explained to 
the patients that the patient is free to refuse participation in the study and free to withdraw from 
the study at any time without prejudice to future treatment.
For adolescent patients, a personally signed and dated ICF will be provided by the parent/legally 
acceptable representative, and a signed and dated assent form will be provided by each patient 
before any study-specific procedures or assessments are done and after the aims, methods, 
anticipated benefits, and potential hazards are explained according to IEC/IRB requirements. The 
forms will be signed and dated also by the person who conducted the informed consent 
discussion. The investigator will keep the original informed consent and assent forms, and copies 
will be given to the patients (and the parent/legally acceptable representative). It will also be 
explained to the patients (and the parent/legally acceptable representative) that they are free to 
refuse participation in the study and free to withdraw from the study at any time without 
prejudice to future treatment.
Competent Authorities and Independent Ethics Committees/Institutional Review Boards
Before this study starts, the protocol will be submitted to the national competent authority (CA) 
and to the respective IEC/IRB for review. As required, the study will not start at a given 
investigational center before the IEC/IRB and CA (as applicable) for the investigational center 
give written approval or a favorable opinion.
Confidentiality Regarding Study Patients
The investigator must ensure that the privacy of the patients, including their identity and all 
personal medical information, will be maintained at all times. In case report forms (CRFs) and 
other documents or image material submitted to the sponsor, patients will be identified not by 
their names, but by an identification number.


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Personal medical information may be reviewed for the purpose of patient safety or for verifying 
data in the source and the CRF. This review may be conducted by the study monitor, properly 
authorized persons on behalf of the sponsor, Global Quality Assurance, or CAs. Personal 
medical information will always be treated as confidential.
Registration of the Clinical Study
In compliance with national and local regulations and in accordance with Teva standard 
procedures, this clinical study will be registered on trials registry websites.


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APPENDIX E.
BIRTH CONTROL METHODS AND PREGNANCY 
TESTING
Contraception recommendations and pregnancy testing should encompass all investigational 
medicinal products (IMPs) as well as non-IMPs, eg, background therapy, and the measures to be 
followed should be based on the medicinal product with the highest risk.
Assessment of likelihood of possible interaction between IMP or concomitant medications and 
hormonal contraception should be conducted. Hormonal contraception may be susceptible to 
interaction with the IMP, which may reduce the efficacy of the contraception method, eg, 
cytochrome P450 4A inducers. In cases of suspected interaction, hormonal contraceptive alone 
may not be sufficient. In the absence of clinical pharmacokinetic interaction study data in IMPs 
with demonstrated or suspected human teratogenicity/fetotoxicity, recommendation for use of 
hormonal contraceptives should be thoroughly justified by the sponsor. Additional contraceptive 
methods, including supplementary barrier methods, may be considered.
Women/girls of childbearing potential are defined as:

not surgically (documented hysterectomy, bilateral oophorectomy, or bilateral 
salpingectomy) or congenitally sterile

not postmenopausal
Postmenopausal women are defined as:

one year postmenopausal (no menses for 12 months without an alternative medical
cause plus an increased concentration of follicle stimulating hormone of more than 
35 U/L) in women not using hormonal contraception or hormonal replacement 
therapy
Recommendations for application of birth control methods:

IMP with possible human teratogenicity/fetotoxicity

Highly effective method of contraception

Contraception during treatment and until the end of relevant systemic exposure

Additional pregnancy testing to be considered; as a minimum, at the end of 
relevant systemic exposure

In each case of delayed menstrual period (over 1 month between menstruations), 
confirmation of absence of pregnancy is strongly recommended. This 
recommendation also applies to women of childbearing potential with infrequent 
or irregular menstrual cycles.
Description of highly effective birth control methods:
Highly effective birth control methods are methods that can achieve a failure rate of less than 1% 
per year when used consistently and correctly, are considered. Such methods include the 
following:


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
Combined estrogen and progestogen hormonal contraception (oral, intravaginal, and 
transdermal) associated with inhibition of ovulation; these should be initiated at least 
7 days (for IMPs without suspected teratogenicity/genotoxicity) and 1 month (for 
IMPs potentially teratogenic/genotoxic) before the first dose of IMP.

Progestogen-only hormonal contraception (oral, injectable, and implantable) 
associated with inhibition of ovulation; these should be initiated at least 7 days (for 
IMPs without suspected teratogenicity/genotoxicity) and 1 month (for IMPs 
potentially teratogenic/genotoxic) before the first dose of IMP.

Intrauterine device and intrauterine hormone-releasing system need to be in place at 
least 2 months before screening.

Bilateral tubal occlusion

Vasectomized partner, provided he is the sole sexual partner and has received medical 
assessment of the surgical process

Sexual abstinence is only considered a highly effective method if defined as 
refraining from heterosexual intercourse in the defined period. The reliability of 
sexual abstinence needs to be evaluated in relation to the duration of the clinical study 
and the preferred and usual lifestyle of the patient.

Periodic abstinence (eg, calendar, ovulation, symptothermal, and post-ovulation 
methods), declaration of abstinence for the duration of a study, and withdrawal are 
not acceptable methods of contraception (according to Medicines and Healthcare 
Products Regulatory Agency).
Male contraception
Male patients must always use a condom.
Vasectomy:
Use of contraceptive methods applies also to vasectomized men because of the risk associated 
with transfer of a drug via seminal fluid.
Pregnancy tests in women of childbearing potential:
Consider additional pregnancy testing, but at least at the end of relevant systemic exposure, in 
case of possible human teratogenicity/fetotoxicity. This refers to IMPs for which human data on 
pregnancies is limited or not available, there is no suspicion of human teratogenicity based on 
class effects or genotoxic potential, and nonclinical reproductive toxicity studies of relevance for 
early human pregnancy show positive findings that do not generate a strong suspicion of human 
teratogenicity/fetotoxicity.
Pregnant female partners of male study participants:
Male study participants must use condoms during intercourse if their female partners are 
pregnant.


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APPENDIX F.
LOST TO FOLLOW-UP
A patient will be considered lost to follow-up if he/she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the investigational center.
The following actions must be taken if a patient fails to return to the investigational center for a 
required study visit:

The investigational center must attempt to contact the patient and/or caregiver and 
reschedule the missed visit as soon as possible and counsel the patient on the 
importance of maintaining the assigned visit schedule and ascertain whether or not 
the patient wishes to and/or should continue in the study.

In cases in which the patient is deemed lost to follow-up, the investigator or designee 
must make every effort to regain contact with the patient and/or caregiver (where 
possible, 3 telephone calls and, if necessary, a certified letter to the patient’s last 
known mailing address or local equivalent methods). These contact attempts should 
be documented in the patient’s medical records and transcribed to the CRF.

Should the patient and/or caregiver continue to be unreachable, he/she will be 
considered to have withdrawn from the study with a primary reason of “lost to 
follow-up.”
For COVID-19 updates, refer to Appendix N.


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APPENDIX G. LIST OF PROHIBITED MEDICATIONS
List of Prohibited Medications Affecting Cytochrome P450
A partial list of prohibited drugs that are either strong/moderate inhibitors of cytochrome P450 
(CYP) 2D6 or strong inducers of CYP3A4 and/or P-glycoprotein is presented below:
List of Prohibited Medications Affecting Cytochrome P450
Therapeutic class
Strong and moderate CYP2D6 
inhibitorsa
Strong CYP3A4 and/or 
P-gp inducersb
Anti-arrhythmics
Quinidine, dronedarone
Antidepressantsc
Fluoxetine, paroxetine, 
duloxetine
Kinase inhibitors
Dacomitinib
Recreational drugs/ 
psychostimulants
Ecstasy
Calcimimetic agents
Cinacalcet
Protease inhibitors
Tipranavir/ritonavir
Antifungals
Terbinafine
Monoamine oxidase inhibitors
Moclobemide
Beta 3-adrenoreceptor agonists
Mirabegron
Fusion inhibitors
AMD070
Glucosylceramide synthase 
inhibitors
Eliglustat
Anti-emetics
Rolapitant
Antibiotics
Rifampin, rifabutin
Antineoplastics
Mitotane
Antilipemics
Avasimibe
Anticonvulsants
Phenytoin, carbamazepine, 
phenobarbital
Anti-androgens
Enzalutamide
Dopamine-Norepinephrine 
reuptake inhibitors
Bupropion
Others
Lumacaftor
Herbal medications
St John’s Wort 
a The use of strong or moderate inhibitors of CYP2D6 is prohibited within 14 days or 5 half-lives (whichever occurs 
last) prior to first oral risperidone dose and throughout the study.
b The use of strong inducers of CYP3A4 and/or P-glycoprotein is prohibited within 30 days prior to first oral 
risperidone dose and throughout the study.


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c These antidepressants are permitted if the patient was on a stable dose for at least 3 months prior to screening (no 
dose changes or initiation of treatment with these medications will be permitted during the study).
CYP=cytochrome P450; P-gp=P-glycoprotein.
Moreover, the use of the following medications is prohibited throughout the study:

risperidone (except when given according to the study protocol)

antipsychotics other than the study treatments

except during the conversion and stabilization stage (Stage 1) and only if required 
for conversion from a previous antipsychotic to oral risperidone

dopamine reuptake inhibitors or prescription psychostimulants within 30 days prior to 
first oral risperidone dose

opiates or opiate-containing analgesics within 14 days prior to first oral risperidone 
dose
In addition to those listed above, medications that may be expected to significantly interfere with 
the metabolism or excretion of risperidone and/or 9-OH risperidone, may be associated with a 
significant drug interaction with risperidone, or may pose a significant risk to patients’ 
participation in the study (eg, chloroquine, which is a QTc prolongator) are prohibited.


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APPENDIX H. TOTAL BLOOD VOLUME
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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APPENDIX I.
EXPLORATORY BIOMARKERS SAMPLES
 
 
 
 
 
 
 
 
 
 


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APPENDIX J.
PHARMACOGENETIC ASSESSMENTS
A blood sample (6 mL) for pharmacogenetic assessment will be collected from all patients who 
signed the informed consent or assent form, as applicable, for pharmacogenetic assessments at 
the time point detailed in Table 2. 
For new patients, a blood sample for pharmacogenetic analysis will be collected at baseline or 
any visit thereafter, unless the patient declines testing or local regulations prohibit testing. For 
roll-over patients, if a sample was not collected during Study TV46000-CNS-30072 for any 
reason, it will be collected at the baseline visit or any visit thereafter, unless the patient declines 
testing or local regulations prohibit testing.
 
A blood sample for DNA extraction will be collected at baseline, or any visit thereafter, in one 
6.0 mL tripotassium ethylenediaminetetraacetic acid (K3EDTA) vacutainer plastic tubes.
Blood samples for DNA extraction will be stored at approximately –70°C (if –70°C storage is
not possible at the site, store at –20°C) before shipment.
Details on processes for collection, labeling, and shipment of these samples can be found in the 
procedural manual.
Samples will be stored for a period of up to 15 years from the last patient last visit in the main
study and then will be destroyed.


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APPENDIX K. PRODUCT COMPLAINTS
Clinical Product Complaints
A clinical product complaint is defined as a problem or potential problem with the physical 
quality or characteristics of clinical investigational medicinal product (IMP) supplies or clinical 
device supplies used in a clinical research study sponsored by Teva. Examples of a product 
complaint include but are not limited to the following:

suspected contamination

questionable stability (eg, color change, flaking, crumbling, etc)

defective components

missing or extra units (eg, primary container is received at the investigational center 
with more or less than the designated number of units inside)

incorrect packaging, or incorrect or missing labeling/labels

unexpected or unanticipated taste or odor, or both

device not working correctly or appears defective in some manner
Each investigational center will be responsible for reporting a possible clinical product complaint 
by completing the product complaint form provided by Teva and emailing it to 
clinical.productcomplaints@tevapharm.com within 48 hours of becoming aware of the issue.
For complaints involving a device or other retrievable item, it is required that the device (or 
item) be sent back to the sponsor for investigative testing whenever possible. For complaints 
involving an IMP, all relevant samples (eg, the remainder of the patient’s IMP supply) should be 
sent back to the sponsor for investigative testing whenever possible.
1. Product Complaint Information Needed from the Investigational Center
In the event that the product complaint form cannot be completed, the investigator will provide 
the following information, as available:

investigational center number and principal investigator name

name, phone number, and address of the source of the complaint

clinical protocol number

patient identifier (patient study number) and corresponding visit numbers, if 
applicable

product name and strength for open-label studies

patient number, bottle, and kit numbers (if applicable) for double-blind or open-label 
studies

product available for return Yes/No

product was taken or used according to protocol Yes/No


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
description or nature of complaint

associated serious adverse event Yes/No

clinical supplies unblinded (for blinded studies) Yes/No

date and name of person receiving the complaint
Note: Reporting a product complaint must not be delayed even if not all the required information 
can be obtained immediately. Known information must be reported immediately. The sponsor 
will collaborate with the investigator to obtain any outstanding information.
2. Handling of Investigational Medicinal Product(s) at the Investigational Center(s)
The investigator is responsible for retaining the product in question in a location separate from 
the investigator’s clinical study supplies. The sponsor may request that the investigator return the 
product for further evaluation and/or analysis. If this is necessary, the clinical study monitor or 
designee will provide the information needed for returning the IMP.
If it is determined that the investigational center must return all IMP, the sponsor will provide the 
information needed to handle the return.
The integrity of the randomization code and corresponding blinded clinical supplies will be 
maintained whenever possible. A serious adverse event or the potential for a product quality 
problem existing beyond the scope of the complaint may be a reason to unblind the clinical 
supplies for an affected patient.
3. Adverse Events or Serious Adverse Events Associated with a Product Complaint
If there is an adverse event or serious adverse event due to product complaint, the protocol 
should be followed for recording and reporting (Section 7.1.2 and Section 7.1.5.3, respectively).
4. Documenting a Product Complaint
The investigator will record in the source documentation a description of the product complaint 
and any actions taken to resolve the complaint and to preserve the safety of the patient. Once the 
complaint has been investigated by the sponsor and the investigator, if necessary, an event 
closure letter may be sent to the investigational center where the complaint originated or to all 
investigational centers using the product.
Medical device incidents, including those resulting from malfunctions of the device, must be 
detected, documented, and reported by the investigator throughout the study.


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APPENDIX L. DATA MANAGEMENT AND RECORD KEEPING
Direct Access to Source Data and Documents
All patient data must have supportive original source documentation in the medical records, or 
equivalent, before they are transcribed to the case report form (CRF). Data may not be recorded 
directly on the CRF and considered as source data unless the sponsor provides written 
instructions specifying which data are permitted to be recorded directly to the CRF.
If data are processed from other institutions or by other means (eg, clinical laboratory, central 
image center, or electronic diary data), the results will be sent to the investigational center, where 
they will be retained but not transcribed to the CRF, unless otherwise noted in the protocol. 
These data may also be sent electronically to the sponsor (or organization performing data 
management).
The medical experts, study monitors, auditors, Independent Ethics Committee/Institutional 
Review Board (IEC/IRB), and inspectors from competent authority (CA) (or their agents) will be 
given direct access to source data and documents (eg, medical charts/records, laboratory test 
results, printouts, and videotapes) for source data verification, provided that patient 
confidentiality is maintained in accordance with national and local requirements.
The investigator must maintain the original records (ie, source documents) of each patient’s data 
at all times. The investigator must maintain a confidential patient identification list that allows 
the unambiguous identification of each patient.
Data Collection
Data will be collected using CRFs that are specifically designed for this study. The data collected 
on the CRFs will be captured in a clinical data management system (CDMS) that meets the 
technical requirements described in 21 Code of Federal Regulations Part 11 (USA) and 
documents of other concerned CAs. Before using the CDMS, it will be fully validated, and all 
users will receive training on the system and study-specific training. After they are trained, users 
will be provided with individual system access rights.
Data will be collected at the investigational center by appropriately designated and trained 
personnel, and CRFs must be completed for each patient who provided informed consent or 
assent, as applicable. Patient identity should not be discernible from the data provided on the 
CRF.
If data are processed from other sources (eg, central laboratory, bioanalytical laboratory, central 
image center, electronic diary data, and electronic patient-reported outcome tablet), these data 
will be sent to the investigational center, where they will be retained but not transcribed to the 
CRF, unless otherwise noted in the protocol. These data may also be sent electronically to the 
sponsor (or organization performing data management). All patient data must have supportive 
original source documentation in the medical records, or equivalent, before they are transcribed 
to the CRF. Data may not be recorded directly on the CRF and considered as source data unless 
the sponsor provides written instructions specifying which data are permitted to be recorded 
directly to the CRF.


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For patients who enter a study but do not meet entry criteria, at a minimum, data for screening 
failure reason, demography, and adverse events from the time of informed consent or assent, as 
applicable, will be entered in the CRF.
Data Quality Control
Data Management is responsible for the accuracy, quality, completeness, and internal 
consistency of the data from this study. Oversight will be carried out as described in the 
sponsor’s Standard Operating Procedures (SOPs) for clinical studies. Day-to-day data 
management tasks for this study are delegated to a contract organization, and these functions 
may be carried out as described in the SOPs for clinical studies at that organization. These SOPs 
will be reviewed by the sponsor before the start of data management activities.
Data will be verified by the study monitor using the data source and reviewed by Data 
Management using both automated logical checks and manual review. Data identified as 
erroneous, or data that are missing, will be referred to the investigational center for resolution 
through data queries. Any necessary changes will be made in the clinical database, and data 
review and validation procedures will be repeated as needed. Data from external sources will be 
compared with the information available in the CDMS, and any discrepancies will be queried.
Applicable terms will be coded according to the coding conventions for this study.
At the conclusion of the study, the CDMS and all other study data will be locked to further 
additions or corrections. Locking the study data represents the acknowledgement that all data 
have been captured and confirmed as accurate. All data collected will be approved by the 
investigator at the investigational center. This approval acknowledges the investigator’s review 
and acceptance of the data as being complete and accurate.
Archiving of Case Report Forms and Source Documents
Sponsor Responsibilities
The original CRFs will be archived by the sponsor. Investigational center-specific CRFs will be 
provided to the respective investigational centers for archiving.
Investigator Responsibilities
The investigator must maintain all written and electronic records, accounts, notes, reports, and 
data related to the study and any additional records required to be maintained under country, 
state/province, or national and local laws, including, but not limited to the following:

full case histories

signed informed consent forms

patient identification lists

CRFs for each patient on a per-visit basis

data from other sources (eg, central laboratory, bioanalytical laboratory, central image 
center, and electronic diary)

safety reports

financial disclosure reports/forms


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
reports of receipt, use, and disposition of the IMPs

copies of all correspondence with sponsor, the IEC/IRB, and any CA
The investigator will retain all records related to the study and any additional records required, as 
indicated by the protocol and according to applicable laws and regulations, until the contract 
research organization or sponsor notifies the institution in writing that records may be destroyed. 
If, after 25 years from study completion, or earlier in the case of the investigational center 
closing or going out of business, the investigator reasonably determines that study record 
retention has become unduly burdensome and sponsor has not provided written notification of 
destruction, then the investigator may submit a written request to the sponsor at least 60 days 
before any planned disposition of study records. After receipt of such request, the sponsor may 
make arrangements for appropriate archival or disposition, including requiring that the 
investigator deliver such records to the sponsor. The investigator shall notify the sponsor of any 
accidental loss or destruction of study records.


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APPENDIX M. PUBLICATION POLICY
All unpublished information given to the investigator by the sponsor shall not be published or 
disclosed to a third party without the prior written consent of the sponsor.
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 before submission. 
This allows the sponsor to protect proprietary information and to provide comments.
The sponsor will comply with the requirements for publication of study results: 
“Recommendations for the Conduct, Reporting, Editing, and Publication of Scholarly Work in 
Medical Journals” (www.ICMJE.org). Publication of the results will occur in a timely manner 
according to applicable regulations. In accordance with standard editorial and ethical practice, 
the sponsor will generally support publication of multicenter studies only in their entirety and not 
as individual investigational center data. In this case, a coordinating investigator will be 
designated by mutual agreement.
Authorship will be determined by mutual agreement and in line with the following International 
Committee of Medical Journal Editors authorship requirements:

substantial contributions to the conception or design of the work; or the acquisition, 
analysis, or interpretation of data for the work

drafting the work or revising it critically for important intellectual content

final approval of the version to be published

agreement to be accountable for all aspects of the work in ensuring that questions 
related to the accuracy or integrity of any part of the work are appropriately 
investigated and resolved
The publications committee established by the sponsor will oversee this process. Additional 
publications may follow. Policies regarding the publication of the study results are defined in the 
financial agreement.
No patent applications based on the results of the study may be made by the investigator nor may 
assistance be given to any third party to make such an application without the written 
authorization of the sponsor.


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APPENDIX N. MANAGEMENT OF STUDY ACTIVITIES DURING 
COVID-19
This appendix is to address the modification set-up in study conduct during the outbreak of the 
Coronavirus disease 2019 (COVID-19) pandemic.
The changes will be effective for the period of the COVID-19 pandemic and when the situation 
at specific sites/countries allows the return to regular study activities, this appendix will be void 
for those sites/countries.
The following sections of the protocol are affected:
Section 3.1. General Study Design and Study Schematic Diagram; Section 3.5. Schedule of 
Study Procedures and Assessments
In the event of an emergency situation (eg, the COVID-19 pandemic), in case a patient cannot 
return to the clinic for the scheduled visits (eg, due to quarantine, isolation, patient's concern, or 
closure of the site clinic), remote assessment of efficacy and safety scales via teleconference 
(TC) and/or videoconference (VC), with VC being the preferred method, may be allowed. The 
results of the scale rating will be directly entered into the eCRF per the usual process; otherwise, 
subject status should be NOT COMPLETED DUE TO: 'Other' 'COVID-19 logistical reasons 
prevented patient's continuation in the study'. If the patient does not continue in the study due to 
site closure, the subject status should be NOT COMPLETED DUE TO: 'Other' 'COVID-19 
logistical reasons prevented patient's continuation in the study'.
In the event that a patient completes the oral stabilization stage (Stage 1) but cannot come to the 
site for the baseline visit for randomization (eg, due to quarantine, isolation, patient's concern or 
closure of the site clinic), it may be possible to extend the duration of Stage 1 on a case-by-case 
basis, following discussion between the investigator and the sponsor study physician.
In addition, the test and placebo IMP (as applicable) may be administered according to the
schedule outlined in the protocol by unblinded study personnel, or home care service providers 
trained according to study specifications, via visits to the patient's place of residence. The 
patient's consent to the home visit will be collected in advance, where possible, by phone and 
documented in the patient’s chart. The IMP will be transported, prepared, and administered in a 
blinded fashion per the conditions specified in the pharmacy manual and the injection 
instructions, provided that proper barrier precautions can be effectively implemented to minimize 
any risk of exposure, and that site staff follow CDC guidelines and local health authority 
procedures. 
Modifications to other procedures and assessments (ECG, lab sample collection, 
pharmacokinetic sampling, etc) will be performed per implemented contingency measures 
according to sponsor instructions and the corresponding manual. For example, if central lab 
samples cannot be collected for safety assessments, sites may have patients visit a local reference 
lab to perform the assessments. At-home nursing visits may be used to perform safety 
assessments such as ECG, laboratory sample collection, vital signs, and nursing assessments to 
determine any new adverse events.


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These measures will be implemented on a case-by-case basis, and only when and where they are 
warranted due to the emergency situation. Preferably, the original protocol instructions will be 
followed whenever the new instructions are not required.
Section 5.1.1. Test Investigational Medicinal Product; Section 5.1.2. Placebo Investigational 
Medicinal Product; Table 4. Investigational Medicinal Products Used in the Study; Section 
5.2.1. Storage and Security; 
For the IMPs (TV-46000 and TV-46000 placebo), limited excursions at room temperature are 
permitted to support easier home administration, if needed (details provided in the pharmacy 
manual).
Section 5.2.3 Accountability   
Any syringes of IMP transported for home administration will be returned to the clinic to 
maintain accountability. Used needles will be disposed of immediately after administration in 
accordance with site (or the group home’s) SOP.
Section 5.9. Randomization and Blinding
In the event of an emergency situation (eg, COVID-19 pandemic), in case off-site IMP 
administration is warranted, the IMP will be transported, prepared, and administered in a blinded 
fashion per the conditions specified in the pharmacy manual and the injection instructions, 
provided that proper barrier precautions can be effectively implemented to minimize any risk of 
exposure, and that site staff follow CDC guidelines and local health authority procedures. 
Section 6. Assessment of Efficacy
In the event of an emergency situation (eg, the COVID-19 pandemic), in case a patient cannot 
return to the clinic for the scheduled visits (eg, due to quarantine, isolation, patient's concern, or 
closure of the site clinic), remote assessment of efficacy scales via TC and/or VC, with VC being 
the preferred method, may be allowed. The results of the scale rating will be directly entered into 
the eCRF per the usual process. 
These measures will be implemented on a case-by-case basis, and only when and where they are 
warranted due to the emergency situation. Preferably, the original protocol instructions will be 
followed whenever the new instructions are not required.
Section 7. Assessment of Safety
In the event of an emergency situation (eg, the COVID-19 pandemic), in case a patient cannot 
return to the clinic for the scheduled visits (eg, due to quarantine, isolation, patient's concern, or 
closure of the site clinic), remote assessment of safety scales (as well as inquiries regarding 
adverse events and use of concomitant medication) via TC and/or VC, with VC being the 
preferred method, may be allowed. The results of the scale rating will be directly entered into the 
eCRF per the usual process.  
Modifications to other procedures and assessments (ECG, lab sample collection, 
pharmacokinetic sampling, etc) will be performed per implemented contingency measures 
according to sponsor instructions and the corresponding manual. 
These measures will be implemented on a case-by-case basis, and only when and where they are 
warranted due to the emergency situation. Preferably, the original protocol instructions will be 
followed whenever the new instructions are not required.


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Section 7.4. Clinical Laboratory Tests
If central lab samples cannot be collected for safety assessments, sites may have a home nursing 
visit to collect the required samples or have patients visit a local reference lab to perform the 
assessments.
Section 7.6. Vital Signs; 7.7. Electrocardiography
At-home nursing visits may be used to perform safety assessments such as ECG, vital signs, and 
nursing assessments to determine any new adverse events.
Section 8.1. Pharmacokinetic Assessment
If pharmacokinetic samples cannot be collected due to limitations in ability to carry out the 
procedure, an at-home nursing vendor or site personnel could perform the sample collection, 
processing and shipment to the CRO (ICON) central lab via appropriate courier. The samples 
should be collected and processed as described in supporting documentation provided to the 
vendor or site nurses as applicable.
Section 9.5.3.3. Exploratory Efficacy Analysis
 
 
Section 10. Quality Control and Quality Assurance
Deviations from the study conduct due to emergency situations (eg, the COVID-19 pandemic), 
including implemented contingency measures and their impact (eg, patient discontinuation from 
treatment with investigational product and/or study, alternative procedures used to collect critical 
safety and/or efficacy data, etc), will be described in the appropriate sections of the CSR as 
applicable.  
Appendix C. Quality Control and Quality Assurance
Important Protocol Deviations
Deviations from the study conduct due to emergency situations (eg, the COVID-19 pandemic), 
including implemented contingency measures and their impact (eg, patient discontinuation from 
treatment with investigational product and/or study, alternative procedures used to collect critical 
safety and/or efficacy data, etc), will be described in the appropriate sections of the CSR as 
applicable.
Study Monitoring
In case of an emergency situation (eg, the COVID-19 pandemic), monitors may not be able to 
access the investigational centers for on-site visits in a timely manner. A remote monitoring risk 
mitigation plan will be utilized for sites where on-site monitoring visits are not permitted due to 
an increased public health risk, in accordance with IRB approval. Details are provided in the 
monitoring plan. 


Uncontrolled Study–Schizophrenia
Clinical Study Protocol with Amendment 01
Study TV46000-CNS-30078
167
Appendix F. Lost to Follow-Up
In case of an emergency situation (eg, COVID-19 pandemic), if a patient cannot return to the 
clinic for the scheduled visits, home visits may take place to mitigate the possibility of being lost 
to follow-up.
NOTE:
Appendix G. List of Prohibited Medications/ Section 5.7. Prior and Concomitant 
Medication or Therapy 
Although not an operational modification per se, this is to notify that chloroquine, which is a 
QTc prolongator, was added to the text as an example of a prohibited medication that may pose a 
significant risk to patient participation in the study (see also separate entry in summary of 
changes).
“In addition to those listed above, medications that may be expected to significantly interfere 
with the metabolism or excretion of risperidone and/or 9-OH risperidone, may be associated with 
a significant drug interaction with risperidone, or may pose a significant risk to patients’ 
participation in the study (eg, chloroquine, which is a QTc prolongator) are prohibited.”

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Uncontrolled Study - Schizophrenia
Statistical Analysis Plan
Study TV46000-CNS-30078
1
 
Statistical Analysis Plan 
Study TV46000-CNS-30078 with Protocol Amendment 01
A Study to Evaluate the Safety, Tolerability, and Effect of Risperidone Extended-Release
Injectable Suspension (TV-46000) for Subcutaneous Use as Maintenance Treatment in
Adult and Adolescent Patients with Schizophrenia
A Study to Evaluate Safety, Tolerability, and Effect of TV-46000 in Adults and Adolescents
with Schizophrenia
A Study to Test if TV-46000 is Safe for Maintenance Treatment of Schizophrenia
Safety and Tolerability Study (Phase 3)
IND number: 124384;
NDA number: 213586;
EudraCT number: 2019-000063-24
Approval Date: 07 July 2020 
Sponsor
Teva Branded Pharmaceutical 
Products R&D, Inc.
145 Brandywine Parkway West Chester, Pennsylvania 19380
United States
Prepared by:


Uncontrolled Study - Schizophrenia
Statistical Analysis Plan
Study TV46000-CNS-30078
2
STATISTICAL ANALYSIS PLAN APPROVAL


Uncontrolled Study - Schizophrenia
Statistical Analysis Plan
Study TV46000-CNS-30078
3
TABLE OF CONTENTS
TITLE PAGE...................................................................................................................................1
STATISTICAL ANALYSIS PLAN APPROVAL..........................................................................2
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS....................................................8
INTRODUCTION .........................................................................................................................10
1.
STUDY OBJECTIVES AND ENDPOINTS..............................................................11
1.1.
Primary and Secondary Study Objectives and Endpoints ..........................................11
1.2.
Exploratory Objectives and Endpoints.......................................................................11
2.
STUDY DESIGN .......................................................................................................16
2.1.
General Design ...........................................................................................................16
2.2.
Randomization and Blinding......................................................................................17
2.3.
Data Monitoring Committee.......................................................................................19
2.4.
Sample Size and Power Considerations .....................................................................19
2.5.
Sequence of Planned Analyses ...................................................................................19
2.5.1.
Planned Interim Analysis............................................................................................19
2.5.2.
Final Analyses and Reporting.....................................................................................19
3.
ANALYSIS SETS ......................................................................................................21
3.1.
Enrolled Patients Set...................................................................................................21
3.2.
Intent-to-Treat Analysis Set........................................................................................21
3.3.
Per-Protocol Analysis Set...........................................................................................21
3.4.
Safety Analysis Set.....................................................................................................21
3.5.
Pharmacokinetics Analysis Set...................................................................................21
4.
GENERAL ISSUES FOR DATA ANALYSIS..........................................................22
4.1.
General........................................................................................................................22
4.2.
Specification of Baseline Values................................................................................22
4.3.
Handling Withdrawals and Missing Data...................................................................22
4.3.1.
Ad-hoc Imputation for Safety Data ............................................................................22
4.3.2.
Missing Items in the Quality of Life Questionnaires..................................................23
4.3.3.
Handling of Adverse Events with Missing Dates.......................................................23
4.3.4.
Handling of Concomitant Medication with Missing Dates........................................23
4.4.
Study Days and Visits.................................................................................................23
5.
STUDY POPULATION.............................................................................................25


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Statistical Analysis Plan
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5.1.
General........................................................................................................................25
5.2.
Patient Disposition......................................................................................................25
5.3.
Demographics and Baseline Characteristics...............................................................25
5.4.
Medical History ..........................................................................................................26
5.5.
Prior Therapy and Medication....................................................................................26
5.5.1.
Pre Study Risperidone Exposure ................................................................................26
5.6.
Childbearing Potential and Methods of Contraception ..............................................26
5.7.
Study Protocol Deviations..........................................................................................27
6.
EFFICACY ANALYSIS ............................................................................................28
6.1.
General........................................................................................................................28
6.2.
Primary Efficacy Endpoint and Analysis ...................................................................28
6.3.
Secondary Efficacy Endpoints and Analysis..............................................................28
6.4.
Other Efficacy Endpoints Analysis ............................................................................28
6.4.1.
Proportion of Patients Who Experienced a Relapse in the Study...............................29
6.4.1.1.
Definition....................................................................................................................29
6.4.1.2.
Analysis ......................................................................................................................30
6.4.2.
Drug Attitudes Inventory 10-item Version.................................................................30
6.4.2.1.
Definition....................................................................................................................30
6.4.2.2.
Analysis ......................................................................................................................31
6.4.3.
Schizophrenia Quality of Life Scale...........................................................................32
6.4.3.1.
Definition....................................................................................................................32
6.4.3.2.
Analysis ......................................................................................................................33
6.4.4.
5-Level EuroQol Five Dimensions Questionnaire .....................................................33
6.4.4.1.
Definition....................................................................................................................33
6.4.4.2.
Analysis ......................................................................................................................33
6.4.5.
Healthcare Resource Utilization.................................................................................34
6.4.5.1.
Definition....................................................................................................................34
6.4.5.2.
Analysis ......................................................................................................................34
6.4.6.
Change in PANSS Total Score from Baseline to Endpoint........................................34
6.4.6.1.
Definition....................................................................................................................34
6.4.6.2.
Analysis ......................................................................................................................34
6.4.7.
CGI-I Score at Endpoint.............................................................................................35
6.4.7.1.
Definition....................................................................................................................35


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Statistical Analysis Plan
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6.4.7.2.
Analysis ......................................................................................................................35
6.4.8.
Personal and Social Performance Scale......................................................................35
6.4.8.1.
Definition....................................................................................................................35
6.4.8.2.
Analysis ......................................................................................................................36
7.
MULTIPLE COMPARISONS AND MULTIPLICITY ............................................37
8.
SAFETY ANALYSIS ................................................................................................38
8.1.
General........................................................................................................................38
8.2.
Duration of Exposure to Risperidone during Study ...................................................38
8.2.1.
Oral Stabilization Period – Stage 1.............................................................................38
8.2.2.
Relapse Prevention - Stage 2 ......................................................................................38
8.2.3.
Total of Exposure to Risperidone in the Study...........................................................39
8.3.
Study Drug Compliance .............................................................................................39
8.3.1.
Oral Stabilization Period – Stage 1.............................................................................39
8.3.1.1.
Numerical Example of Oral Drug Compliance during Stage 1..................................40
8.3.2.
Relapse Prevention - Stage 2 ......................................................................................40
8.4.
Adverse Events ...........................................................................................................40
8.5.
Deaths .........................................................................................................................41
8.6.
Clinical Laboratory Tests ...........................................................................................41
8.6.1.
Laboratory Values Meeting Hy’s Law Criteria..........................................................42
8.6.2.
Other Clinical Laboratory Tests .................................................................................43
8.6.2.1.
Virology and Thyroid Screening Tests.......................................................................43
8.6.2.2.
Human Chorionic Gonadotropin Tests.......................................................................43
8.6.2.3.
Urine Drug Screen ......................................................................................................43
8.6.2.4.
Prolactin......................................................................................................................43
8.6.2.5.
Glomerular Filtration Rate..........................................................................................43
8.7.
Physical Examinations................................................................................................44
8.8.
Vital Signs ..................................................................................................................44
8.9.
Electrocardiography....................................................................................................45
8.10.
Concomitant Medications or Therapies......................................................................46
8.11.
Columbia-Suicide Severity Rating Scale (C-SSRS)...................................................46
8.12.
Abnormal Involuntary Movement Scale (AIMS).......................................................47
8.13.
Simpson-Angus Scale (SAS)......................................................................................47
8.14.
Barnes Akathisia Rating Scale (BARS) .....................................................................48


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Statistical Analysis Plan
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8.15.
Calgary Depression Scale for Schizophrenia (CDSS)................................................48
8.16.
Clinical Global Impression-Severity of Suicidality (CGI-SS) ...................................48
8.17.
Clinical Global Impression of Severity (CGI-S) ........................................................48
8.18.
Structured Clinical Interview for DSM-5 (SCID-5)...................................................49
9.
TOLERABILITY VARIABLES AND ANALYSIS..................................................50
9.1.
Assessment of Local Tolerability and Pain ................................................................50
9.2.
All-cause Discontinuation Rate Assessment ..............................................................50
10.
PHARMACOKINETIC ANALYSIS.........................................................................52
11.
PHARMACOKINETIC/PHARMACODYNAMIC ANALYSIS..............................53
12.
BIOMARKER AND PHARMACOGENETICS ANALYSIS...................................54
13.
PLANNED INTERIM ANALYSIS ...........................................................................55
14.
STATISTICAL SOFTWARE ....................................................................................56
15.
CHANGES TO ANALYSES SPECIFIED IN THE STUDY PROTOCOL..............57
16.
REFERENCES ...........................................................................................................58
APPENDIX A.
LIST OF CONCOMITANT MEDICATIONS THAT MAY BE 
RELATED TO INCREASED RISK OF RELAPSE..................................................59


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LIST OF TABLES
Table 1:
Drug Attitudes Inventory 10-item Version – Standard of a Compliant 
Response.....................................................................................................................31
Table 2:
Criteria for Potentially Clinically Significant Laboratory Values..............................42
Table 3:
Criteria for Potentially Clinically Significant Vital Signs..........................................45
Table 4:
Oral Risperidone Doses and Corresponding TV-46000 Doses ..................................50


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8
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
Abbreviation
Term
AE
adverse event
AIMS
Abnormal Involuntary Movement Scale
ANCOVA
analysis of covariance
BARS
Barnes Akathisia Rating Scale
bpm
beats per minute
BMI
body mass index
CDSS
Calgary Depression Scale for Schizophrenia
CGI-I
Clinical Global Impression–Improvement
CGI-S
Clinical Global Impression of Severity
CGI-SS
Clinical Global Impression-Severity of Suicidality
CI
confidence interval
COVID-19
Coronavirus disease 2019
CRF
case report form
CSR
Clinical study report
C-SSRS
Columbia Suicide Severity Rating Scale
CYP
cytochrome P450
DAI-10
Drug Attitudes Inventory 10-item version
DSM-5
Diagnostic and Statistical Manual of Mental Disorders, 5th Edition
ECG
Electrocardiogram/Electrocardiography
EoT
End-of-Treatment Visit 
EQ-5D-5L
5-Level EuroQol Five Dimensions Questionnaire 
ER
Emergency room
ET
Early Termination 
GFR 
Glomerular filtration rate
ICF
Informed consent form
IMP
investigational medicinal product 
INN
international nonproprietary name
IRT
Interactive Response Technology


Uncontrolled Study - Schizophrenia
Statistical Analysis Plan
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ITT
Intent-to-Treat
MedDRA
Medical Dictionary for Regulatory Activities
msec
milliseconds
NDA
New Drug Application
PANSS
Positive and Negative Syndrome Scale
PP
Per-Protocol
PSP
Personal and Social Performance Scale
PT
Preferred term
q1m
every month
q2m
every 2 months
q4w
every 4 weeks
q8w
every 8 weeks
QTcF
QT interval corrected using Fridericia's formula
R&D
Research and Development
RTSM
Randomization and Trial Supply Management
SAS
Simpson-Angus Scale
SCID-5
Structured Clinical Interview for DSM-5
SD
Standard Deviation
SE
Standard Error
SI
standard international
SOC
system organ class
SOP
standard operating procedure
SQLS
Schizophrenia Quality of Life Scale 
ULN
upper limit of normal range
VAS
visual analogue scale
WHO
World Health Organization


Uncontrolled Study - Schizophrenia
Statistical Analysis Plan
Study TV46000-CNS-30078
10
INTRODUCTION
This Statistical Analysis Plan describes the planned analysis and reporting for Teva Branded 
Pharmaceutical Products R&D, Inc. study TV46000-CNS-30078 (A Study to Evaluate the 
Safety, Tolerability, and Effect of Risperidone Extended-Release Injectable Suspension (TV-
46000) for Subcutaneous Use as Maintenance Treatment in Adult and Adolescent Patients with 
Schizophrenia), and was written in accordance with GSD-SOP-704 (Final Statistical Analyses 
for Clinical Studies).
The reader of this Statistical Analysis Plan is encouraged to read the study protocol for details on 
the conduct of this study, the operational aspects of clinical assessments, and the timing for 
completing the participation of a patient in this study. 
The Statistical Analysis Plan is intended to be in agreement with the protocol, especially with 
regards to the primary endpoint and its respective analysis. However, the Statistical Analysis 
Plan may contain more details regarding the primary endpoint of interest, or other types of 
analyses (eg, other endpoints).When differences exist in descriptions or explanations provided in 
the study protocol and this Statistical Analysis Plan, the Statistical Analysis Plan prevails; the 
differences will be explained in the Clinical Study Report (CSR).


Uncontrolled Study - Schizophrenia
Statistical Analysis Plan
Study TV46000-CNS-30078
11
1.
STUDY OBJECTIVES AND ENDPOINTS
1.1.
Primary and Secondary Study Objectives and Endpoints
The primary objective and endpoint are presented below. There are no secondary study 
objectives and endpoints.
Objectives
Endpoints
The primary objective of the study is 
to evaluate the long-term safety and 
tolerability of TV-46000 administered 
in adult and adolescent patients with 
schizophrenia.
The primary endpoint is the frequency of all adverse 
events, including serious adverse events.
1.2.
Exploratory Objectives and Endpoints
Exploratory objectives and endpoints are as follows:


Uncontrolled Study - Schizophrenia
Statistical Analysis Plan
Study TV46000-CNS-30078
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Objectives
Endpoints
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Uncontrolled Study - Schizophrenia
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Objectives
Endpoints
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Objectives
Endpoints
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Objectives
Endpoints
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Uncontrolled Study - Schizophrenia
Statistical Analysis Plan
Study TV46000-CNS-30078
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2.
STUDY DESIGN
2.1.
General Design
This is a multicenter, double-blind, parallel-group study to evaluate the long-term safety, 
tolerability, and efficacy of TV-46000 administered q1m or q2m at doses of 50 to 250 mg sc 
(equivalent to 2 to 5 mg/day of oral risperidone) for up to 56 weeks in adult and adolescent 
patients with schizophrenia. As a precautionary measure, adolescent patients will receive doses 
equivalent to 2 to 4 mg/day oral risperidone.
Eligible female and male patients with schizophrenia who did not experience a relapse and 
completed the Phase 3 pivotal efficacy Study TV46000-CNS-30072 (roll-over patients) and new 
patients (who did not participate in Study TV46000-CNS-30072) may enter this long-term study 
if they meet the inclusion/exclusion criteria and provide informed consent or assent, as 
applicable.
For new patients, the study duration will consist of a screening period (up to 4 weeks), a
conversion/stabilization stage (12 weeks on oral risperidone, Stage 1), a double-blind, active-
treatment maintenance stage (up to 56 weeks; Stage 2), and a follow-up period (8 weeks). Per 
definition, an exacerbation in symptoms during Stage 1 (new patients) cannot be defined as a 
relapse event, since relapse events can only occur following stabilization and randomization. 
During the baseline visit, new patients who meet the stability criteria will be randomized in a 1:1 
manner to receive TV-46000 q1m or q2m sc injections at the TV-46000 dose equivalent to the 
oral dose on which they were stabilized in Stage 1 of this study and will enter Stage 2 of the 
study (double-blind maintenance stage).
Patients who require a stabilization dose below 2 mg/day will not be randomized in the study. As 
a precautionary measure, adolescent patients who will require a stabilization dose of more than 
4 mg/day during the stabilization stage will not be randomized.
For roll-over patients, the study duration will consist of a double-blind, active-treatment 
maintenance stage (up to 56 weeks; Stage 2) and a follow-up period (8 weeks). Roll-over 
patients will begin this study at the baseline visit and start at Stage 2 of the study (double-blind 
maintenance stage). For these patients, the end-of-treatment (EoT) visit in Study TV46000-CNS-
30072 will serve as the baseline visit. Some baseline procedures will be performed as part of the 
EoT visit in the TV46000-CNS-30072 study, and the results will be transferred to this study's 
clinical database. During Stage 2 of this study, patients who were treated with TV-46000 q1m or 
q2m during Study TV46000-CNS-30072 will continue their assigned arm and dose from Study 
TV46000-CNS-30072. Patients who were treated with placebo during Study TV46000-CNS-
30072 will be randomized in a 1:1 manner to receive TV-46000 q1m or q2m sc injections at the 
TV-46000 dose equivalent to the oral dose on which they were stabilized in Stage 1 of Study 
TV46000-CNS-30072 (see Section 2.2).
After new and roll-over patients are assigned to receive TV-46000 q1m or q2m sc injections 
during the baseline visit, the study will continue on an outpatient basis. The maximal dose of 
TV-46000 administered to adult patients will be equivalent to an oral risperidone dose of 


Uncontrolled Study - Schizophrenia
Statistical Analysis Plan
Study TV46000-CNS-30078
17
5 mg/day, and the maximal TV-46000 dose administered to adolescents will be equivalent to 
4 mg/day oral risperidone. 
Patients who started Stage 2 who relapse or meet 1 or more of the withdrawal criteria should be 
invited to perform the early termination (ET) visit as soon as possible within 4 weeks of the last 
injection.
End of study (EoS) is defined as the date when the last patient in Stage 2 has completed all 
efficacy and safety assessments at the final visit per protocol (Follow-up Visit 2).
Study procedures and assessments with their timing for the pre-treatment period (screening and 
Stage 1) are summarized in Table 1 of the study protocol. Study procedures and assessments 
starting from baseline, through the double-blind maintenance stage (Stage 2), EoT/ ET and 
follow-up are summarized in Table 2 of the study protocol.
2.2.
Randomization and Blinding
To avoid unblinding, all patients enrolled in Study TV46000-CNS-30078 will be assigned to a
treatment group via the Interactive Response Technology (IRT) at their baseline visit according
to the following specifications:

New patients will be randomized via the IRT to receive sc injections of either TV-46000 
q1m or TV-46000 q2m in a 1:1 ratio. Randomization will be stratified by the dose of oral 
risperidone on which the patient was stabilized during Stage 1 (2/3, 4, or 5 mg/day). The 
dose of TV-46000 will be equivalent to the 2 to 5 mg/day dose of oral risperidone on 
which the patient was stabilized in Stage 1. As a precautionary measure, adolescent 
patients who will require a stabilization dose of more than 4 mg/day during the 
stabilization stage will not be randomized. Patients who are randomized to TV-46000 
q1m will receive an sc injection of TV-46000 at baseline and every 4 weeks (q4w) 
thereafter. To ensure blinding, patients who are randomized to TV-46000 q2m will 
receive an sc injection of TV-46000 at baseline and every 8 weeks (q8w) thereafter and 
an sc injection of placebo 4 weeks after baseline and q8w thereafter.

Roll-over patients who were assigned to TV-46000 q1m during Study TV46000-
CNS-30072 will be assigned via the IRT to continue the same dosing frequency and same 
dose as in Study TV46000-CNS-30072. Note that the EoT visit in Study TV46000-CNS-
30072 will serve as the baseline visit for roll-over patients in this study (ie, roll-over 
patients receive their last injection of investigational medicinal product (IMP) at the EoT 
visit in Study TV46000-CNS-30072 and receive their next injection at week 4 in this 
study). They will receive an sc injection of TV-46000 at the EoT visit in Study TV46000-
CNS-30072 and q4w thereafter (ie, weeks 4, 8 and so on in this study).

Roll-over patients who were assigned to TV-46000 q2m during Study TV46000-
CNS-30072 will be assigned via the IRT to continue the same dosing frequency and same 
dose as in Study TV46000-CNS-30072. Note that the EoT visit in Study TV46000-CNS-
30072 will serve as the baseline visit for roll-over patients in this study (ie, roll-over 
patients receive their last injection of IMP at the EoT visit in Study TV46000-CNS-
30072 and receive their next injection at week 4 in this study). To maintain the blind, 
they will be injected q4w, but will alternate between TV-46000 sc and placebo injections. 
Their injection at week 4 will depend on their injection at the EoT visit of Study 


Uncontrolled Study - Schizophrenia
Statistical Analysis Plan
Study TV46000-CNS-30078
18
TV46000-CNS-30072 (ie, if their last injection in Study TV46000-CNS-30072 was 
placebo, then their Study TV46000-CNS-30078 week 4 injection will be TV-46000 and 
vice versa).

Roll-over patients who were assigned to placebo during Study TV46000-CNS-30072 
will be randomized via the IRT to receive sc injections of either TV-46000 q1m or TV-
46000 q2m in a 1:1 ratio. Randomization will be stratified by the dose of oral risperidone 
on which the patient was stabilized during Stage 1 (2/3, 4, or 5 mg/day). The dose of TV-
46000 will be equivalent to the 2 to 5 mg/day dose of oral risperidone (adolescent TV-
46000 doses will be equivalent to 2 to 4 mg/day oral risperidone) on which the patient 
was stabilized in Stage 1 of Study TV46000-CNS-30072. Note that the EoT visit in Study
TV46000-CNS-30072 will serve as the baseline visit for roll-over patients in this study 
(ie, roll-over patients receive their last injection of IMP at the EoT visit in Study 
TV46000-CNS-30072 and receive their next injection at week 4 in this study). Patients 
who are randomized to TV-46000 q1m will receive an sc injection of TV-46000 at week 
4 in this study and q4w thereafter. To ensure blinding, patients who are randomized to 
TV-46000 q2m will receive an sc injection of TV-46000 at week 4 in this study and q8w 
thereafter, and an sc injection of placebo at week 8 and q8w thereafter.
Patients and investigators will remain blinded to the identity of the treatment administered to
each patient. Due to the differences between TV-46000 and placebo and the alternation between
placebo and TV-46000 for the TV-46000 q2m arm, an unblinded nurse, who is not associated
with rating the patient (including assessment of the injection site if needed) and is independent
from the study team, will be required at each site to administer the drug.
Additional measures to mitigate the risk of unblinding are described in Section 5.9 of the study 
protocol.
The sponsor’s clinical personnel (and delegates) involved in the study will not be blinded to the
identity and dosing regimens of the IMPs received by the new patients during the course of this 
study.
Since the roll-over of patients from Study TV46000-CNS-30072 into this study is expected to 
occur prior to Study TV46000-CNS-30072 database lock, the sponsor’s clinical personnel (and 
delegates) involved in the TV46000-CNS-30072 study will be blinded to the identity of their 
IMP treatment assignments in the TV-46000-CNS-30072 and TV46000-CNS-30078 studies, 
until the TV46000-CNS-30072 database is locked for final analysis and the IMP assignment is 
known. However, certain personnel (ie, site unblinded pharmacist/nurse, IRT study staff, and 
Clinical Supply Chain) who have been unblinded since the beginning of the TV46000-CNS-
30072 study, will remain unblinded during the roll-over transition period until the database of 
Study TV46000-CNS-30072 is locked.
New patients and roll-over patients in the placebo group of Study TV46000-CNS-30072 will be
randomly assigned to treatment groups by means of a computer-generated randomization list.
The specifications for randomization will be under the responsibility and oversight of Teva
Global Statistics.
In the event of an emergency, it will be possible to determine to which treatment group and dose
the patient has been allocated by accessing the Randomization and Trial Supply Management
(RTSM) system. All investigational centers will be provided with details of how to access the


Uncontrolled Study - Schizophrenia
Statistical Analysis Plan
Study TV46000-CNS-30078
19
system for code breaking at the start of the study. The medical monitor or equivalent should be
notified following unblinding. Any unblinding of the IMP performed by the investigator must be
recorded in the source documents.
The randomization list will be assigned to the relevant treatment groups through a qualified
service provider, eg, via the RTSM system. The generation of the randomization list and
management of the RTSM system will be done by a qualified service provider under the
oversight of the responsible function at Teva.
The unblinded nurse at the investigational center who will dispense the IMPs will know the IMP
assignments for each patient. In addition, up to 2 other individuals from the investigational center 
may know the IMP assignments to provide quality assurance and oversight in their preparation
and administration, as necessary. These individuals will not be involved in the conduct of any
study procedures or assessments of any adverse events.
Additional details regarding maintenance of randomization and blinding can be found in Section 
5.10 of the study protocol.
2.3.
Data Monitoring Committee
There will be no Data Monitoring Committee/Data and Safety Monitoring Board in this study.
2.4.
Sample Size and Power Considerations
This study is safety-oriented in nature; therefore, no formal hypothesis testing is planned. Based 
on regulatory requirements, up to approximately 300 patients are planned to be enrolled in Stage 
2 of this study in order to collect data on at least 100 patients exposed to TV-46000 for at least 1 
year. Adolescent patients will only be enrolled in the US; any enrolled adolescents will be in 
addition to the aforementioned total.
2.5.
Sequence of Planned Analyses
2.5.1.
Planned Interim Analysis
There will be a planned data cut with statistical output produced before the New Drug 
Application (NDA) submission. This intermediary analysis is not a formal, pre-planned interim 
analysis but rather a "snapshot" of the data that will be performed when sufficient exposure and 
safety data are collected.
An interim CSR describing the data obtained until this time-point will be prepared for the 
submission. 
2.5.2.
Final Analyses and Reporting
All analyses identified in this Statistical Analysis Plan will be performed after the end of study as 
defined in the study protocol. 
This Statistical Analysis Plan and any corresponding amendments will be approved before 
interim database lock, in accordance with GSD-SOP-702: Statistical Analysis Plan (SAP).


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A full CSR detailing the final analyses will be prepared after study completion and the final 
database lock.
 


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3.
ANALYSIS SETS
3.1.
Enrolled Patients Set
The enrolled patients set will include all new patients who have met study eligibility 
requirements for Stage 1 and received at least one dose of oral risperidone in Stage 1 and all roll-
over patients from Study TV46000-CNS-30072.
3.2.
Intent-to-Treat Analysis Set
The intent-to-treat (ITT) analysis set will include all randomized patients who were randomized 
either in Study TV46000-CNS-30072 for roll-over patients or in Study TV46000-CNS-30078.
In the ITT analysis set, treatment will be assigned based on the TV-46000 treatment to which the 
patients were randomized in this study, regardless of which treatment they actually received.
The ITT analysis set will include all randomized patients, including new patients who did not 
take any IMP.
3.3.
Per-Protocol Analysis Set
The per-protocol analysis set will include all patients in the safety analysis set who have no 
important protocol deviations. In this analysis set, treatment will be assigned based on the 
treatment the patients actually received. If patients erroneously received a wrong drug 
assignment in some visits, a decision to which treatment group they will be assigned will be 
determined in a case-by-case manner before database lock. The PP analysis set will be discussed 
before database lock and findings will be documented in the study data review document.
3.4.
Safety Analysis Set
The safety analysis set will include all patients who receive at least 1 dose of TV46000 in TV-
46000-CNS-30072 study or in TV46000-CNS-30078 study. In the safety analysis set, treatment 
will be assigned based on the treatment the patients actually received, regardless of the treatment 
to which they were randomized, unless otherwise specified.
3.5.
Pharmacokinetics Analysis Set
The pharmacokinetics analysis set will include all patients from the safety analysis set who also 
have ≥1 plasma concentration measurement.


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4.
GENERAL ISSUES FOR DATA ANALYSIS
4.1.
General
Descriptive statistics for continuous variables include n, mean, standard deviation (SD), standard 
error (SE), median, minimum, and maximum. Descriptive statistics for categorical variables 
include patient counts and percentages, missing category will be displayed as appropriate. Least 
squares means and 95% confidence intervals (CIs) may be used for selected parameters.
For presentations by oral risperidone dose, the patient’s last dose up to and including visit 5, will 
be considered the oral risperidone dose. 
All tables will be presented for all patient (adult and adolescent) populations, unless otherwise 
specified. Separate summary tables for adolescents will be presented only if a sufficient number 
of adolescent patients is enrolled (>=10) according to the clinical judgement. 
4.2.
Specification of Baseline Values
Roll-over patients will begin this study at the baseline visit and start at Stage 2 of the study 
(double-blind maintenance stage). For these patients, the EoT visit in Study TV46000-CNS-
30072 will serve as the baseline visit. Some baseline procedures will be performed as part of the 
EoT visit in the TV46000-CNS-30072 study, and the results will be transferred to this study's 
clinical database.
For new patients, the baseline value of Stage 1 (Oral Conversion and Stabilization Stage) is the 
last observed value before the first oral risperidone administration as part of the conversion and 
stabilization stage, unless otherwise noted.
For the double-blind maintenance stage (Stage 2: Relapse Prevention), baseline is defined as the 
last observed data before the first study drug injection. However, for efficacy endpoints if the 
patient was already injected and some of the efficacy data was collected on the same day but 
after the injection, then this data will still be used as baseline.
4.3.
Handling Withdrawals and Missing Data
Despite the best efforts to obtain complete data, missing data is unavoidable. For all variables, 
only observed patient data will be used in the statistical analyses, ie, there is no plan to estimate 
missing data, unless otherwise specified. 
Ad-hoc imputation for safety summary tables will be performed only for the specific cases 
described below. There will be no imputation in the data listings (including ad-hoc imputation); 
all values will be displayed as recorded in the clinical database.
4.3.1.
Ad-hoc Imputation for Safety Data
Any adverse event with unknown severity will be considered as ‘severe’ for the tabulations. 
During Stage 2 of the study, for any adverse event with unknown relationship, the treatment will 
be considered as 'related'.


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Any laboratory values given as '<x' or '>x' in the database will be assigned with the absolute 
value of x without the sign for the descriptive statistics and the calculation of changes from 
baseline (eg, a value of <0 .1 will be imputed as 0.1 for the calculations).
4.3.2.
Missing Items in the Quality of Life Questionnaires 
Missing items will not be imputed. For SQLS, CDSS, AIMS, SAS and BARS questionnaires, 
however, if the number of missing items in a scale (or sub-scale) is less than half, then the 
missing items will be assigned with the value of the arithmetic mean of the non missing items in 
the scale within the patient and visit. 
4.3.3.
Handling of Adverse Events with Missing Dates
The date of First Study Treatment, referred to below, corresponds to the first injection of TV-
46000 (IMP) that the patient received in Study TV46000-CNS-30078. For the purpose of this 
study, oral risperidone is not considered an IMP. Any adverse event with incomplete start dates 
will be handled as described below, end dates will not be imputed. 

If only the day is missing, then the day will be imputed to the first day of the month, 
unless the adverse event month-year corresponds to the month-year of the Date of First 
Study Treatment. In that case, the day will be imputed with the Date of First Study 
Treatment, unless the adverse event end date occurred prior to Date of First Study 
Treatment.

If both the day and month are missing and the year is the year of the Date of First Study 
Treatment then the date will be imputed to Date of First Study Treatment, unless the 
adverse event end date occurred prior to Date of First Study Treatment, in which case the 
start day-month will not be imputed. In addition, if the Date of First Study Treatment 
year < year of ADVERSE EVENTS start year then start day-month will be imputed to 
01JAN. 
4.3.4.
Handling of Concomitant Medication with Missing Dates
For determination of prior vs concomitant medication, missing start or end month are imputed to 
JAN or DEC respectively and missing start or end day are imputed to day 01 and 30 respectively, 
unless the month is not missing then missing day is imputed to 28.
4.4.
Study Days and Visits
Study days are numbered relative to the first day of study drug administration, namely the 
beginning of the Stage 2. The start of treatment (Day 1) is defined as the date on which a patient 
receives the first dose of study drug, as recorded on the Case Report Form (CRF). Days will be 
numbered relative to treatment start (ie, ..., –2, –1, 1, 2, ...; with Day 1 being the first day of 
study drug administration and day –1 being the day before the first day of study drug 
administration).
For summary tables of safety, unscheduled visits will be mapped to the closest scheduled visit 
according to the allowed time window specified in Tables 1 and 2 of the study protocol. 
Unscheduled visits that occurred after ET/EoT visit will be mapped to follow-up visits. If both 


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ET/EoT and follow-up 1 visits occurred on the same day and the ET/EoT results are missing, the 
results from the follow-up 1 visit will be mapped to the ET/EoT visit, and vice versa.
For summary tables of efficacy, unscheduled visits will be mapped to windows between the 
scheduled visits according to the date of the visit. The visit windows will be labeled 'Unsc visit 
after visit X’ and will be presented sequentially in summaries with the scheduled visits.
For by-visit summaries, if there are multiple assessments at a post-baseline visit day, then the last 
non-missing assessment at that visit day will be used for the summary. If the multiple 
assessments include a scheduled assessment, the scheduled will be used.
For last safety assessment, the last available non-missing value will be used. For last efficacy 
assessment, the last available non-missing value not later than ET/EoT visit will be used. 
Unscheduled visits that could not be mapped will not be displayed in the by-visit summaries, but 
they will be considered for the endpoint/last assessment visit.


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5.
STUDY POPULATION
5.1.
General
The ITT analysis set (Section 3.2) will be used for study population summaries of the double 
blind treatment stage unless otherwise specified. Summary tables will be presented by treatment 
group and for all patients and by source of patients (new patients and roll-over patients). For the 
endpoints that are evaluated only in the adult population, the analysis will be conducted on the 
ITT subset of adults. The enrolled patients set (Section 3.1) will be used for data summaries for 
new patients before the double blind treatment stage.
It is intended to also present summary tables by age subgroups (adults/adolescents) as applicable.
However since the number of adolescent patients may be too sparse (below 10 randomized 
adolescents), these summary tables might not be presented.
In addition, and if data permit, coronavirus disease 2019 (COVID-19) subgroups (eg,COVID-19-
impacted patients/ COVID-19- non-impacted patients and/or home visits, before/after COVID-
19 pandemic, etc.) of the ITT analysis set and safety analysis set will be presented.
5.2.
Patient Disposition
The following will be summarized using descriptive statistics of data for all patients:

new patients screened in Stage 1; 

new patients who were screened and not enrolled in the Oral Conversion and 
Stabilization Stage (Stage 1) and reason for screen failure/not enrolled; 

new patients screened and enrolled in Stage 1;

new patients who were enrolled in Stage 1 but not randomized for the double blind stage 
(Stage 2) and reason for not randomized; 

all patients who were randomized; 

new patients who were randomized but not treated; 

all patients in the ITT, adult patients in the ITT, or adolescents in the ITT, PP, safety, and 
pharmacokinetics analysis sets; 

all patients who completed the treatment and/or study; 

patients who withdrew from the treatment or the study and reason for withdrawal from 
the treatment or the study including due to COVID-19.
Adolescent patient disposition may be summarized separately, if applicable.
5.3.
Demographics and Baseline Characteristics
Patient demographic and baseline characteristics, including age, age group (adolescents [ages 13-
17] and adults [18 years of age and above]), gender, race, ethnicity, baseline weight (kg), 


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baseline height (cm), baseline body mass index (BMI) (kg/m2) and categorization, and injection 
site will be summarized using the descriptive statistics. 
The randomization stratification factor levels (see Section 2.2), will be summarized using the 
descriptive statistics for each variable category.
Psychiatric history will be assessed using years since the initial diagnosis of schizophrenia for all 
patients and months since the most recent relapse for adults. 
The ITT analysis set, the ITT subset of adults, the ITT subset of adolescents, and safety analysis 
set will be used for the summaries. 
In addition, some of the demographic and screening characteristics may be summarized using the 
descriptive statistics for the enrolled patients set.
5.4.
Medical History
All medical history will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). The incidence of medical history abnormalities will be summarized using 
descriptive statistics by system organ class (SOC) and preferred term (PT). Patients are counted 
only once in each PT and SOC category. Summaries will be presented by treatment group and
for all patients and by source of patients.
5.5.
Prior Therapy and Medication
Any prior therapy, medication, or procedure a patient has had within 30 days before study drug 
administration will be recorded on the CRF. Trade name or international nonproprietary name 
(INN), indication, and dosage will be recorded. The sponsor will encode all therapy and 
medication according to the World Health Organization (WHO) drug dictionary (WHO Drug).
The incidence of prior therapies and medications will be summarized using descriptive statistics 
by therapeutic class and PT. Patients are counted only once in each therapeutic class category, 
and only once in each PT category. Prior therapies and medications will include all medications 
taken and therapies administered before the first day of study drug administration. This will be 
collected twice during the study: at screening (before Stage 1) and Stage 2 (at baseline) of the 
study. Note that the prior therapy and medication for Stage 2 will include the concomitant 
medications in Stage 1.
5.5.1.
Pre Study Risperidone Exposure
Pre-study risperidone treatment use for new patients will be defined based on patients' or 
investigator’s report on the first and last days of pre-study risperidone treatment. Summary of the 
number and percentage of patients exposed to risperidone will be summarized by treatment and 
all patients and by source of patients.
5.6.
Childbearing Potential and Methods of Contraception
For new female patients, information related to childbearing potential will be collected at each 
in-clinic visit at both study periods and information related to menopause will be collected at the 
screening visit (see Section 8.6.2.2). Data will be listed.


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For new female and male patients, methods of contraception will be collected at screening. Data 
will be listed.
5.7.
Study Protocol Deviations
Data from patients with any important protocol deviations as defined in Appendix C of the study 
protocol, and as recorded in protocol deviation spreadsheet during the study, will be summarized 
overall and for each category using descriptive statistics. 
Data pertaining to deviations will be reviewed and important protocol deviations will be 
determined by the study team on ongoing basis and documented in the Statistical Data Review 
meeting minutes prior to the database lock.


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6.
EFFICACY ANALYSIS
6.1.
General
 
. 
The enrolled patients analysis set (Section 3.1) will be used for data summaries during Stage 1 
(for new patients) of the study; summaries will be presented for new patients in this set and for 
all patients by the ITT or the ITT subset of adults as appropriate. Unless otherwise specified, for 
the enrolled analysis set, data will be presented by randomized, not-randomized patients and 
overall, as appropriate.
The pharmacokinetic analysis set will be used for all pharmacokinetic/pharmacodynamics 
analyses which will be presented in a separate statistical analysis plan and report.
In the event of an emergency situation (eg, the COVID-19 pandemic), in case a patient cannot 
return to the clinic for the scheduled visits (eg, due to quarantine, isolation, patient's concern, or 
closure of the site clinic), remote assessment of efficacy scales via TC and/or VC, with VC being 
the preferred method, may be allowed. The results of the scale rating will be directly entered into 
the eCRF per the usual process.
These measures will be implemented on a case-by-case basis, and only when and where they are
warranted due to the emergency situation. Preferably, the original protocol instructions will be
followed whenever the new instructions are not required.
6.2.
Primary Efficacy Endpoint and Analysis
As this is a safety-oriented study, there is no primary efficacy endpoint or analysis for this study 
(efficacy endpoints are exploratory only).
6.3.
Secondary Efficacy Endpoints and Analysis
There are no secondary efficacy endpoints for this study.
6.4.
Other Efficacy Endpoints Analysis 
 
 
 


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6.4.1.
Proportion of Patients Who Experienced a Relapse in the Study
6.4.1.1.
Definition
Patients meeting any 1 or more of the below relapse criteria are considered relapsed. Relapse is 
defined as 1 or more of the following items:
1. CGI-I of ≥5 (greater than or equal to minimally worse, ie, minimally worse, much 
worse or very much worse) AND
a) an increase of any of the following individual PANSS items: conceptual 
disorganization, hallucinatory behavior, suspiciousness, and unusual thought 
content, to a score of >4 with an absolute increase of ≥2 on that specific 
item since randomization, OR
b) an increase in any of the following 4 individual PANSS items: conceptual 
disorganization, hallucinatory behavior, suspiciousness, and unusual thought 
content, to a score of >4 and an absolute increase1 of ≥4 on the combined 
                                                
1 The absolute increase of the combined score is the sum of the increase of those scores (ignoring the decreases).


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score of these 4 PANSS items (conceptual disorganization, hallucinatory 
behavior, suspiciousness, and unusual thought content) since randomization. 
2. hospitalization due to worsening of psychotic symptoms (including partial 
hospitalization programs), excluding hospitalization for psychosocial reasons
3. CGI-SS of 4 (severely suicidal) or 5 (attempted suicide) on Part 1 and/or 6 (much 
worse) or 7 (very much worse) on Part 2
4. violent behavior resulting in clinically significant self-injury, injury to another 
person, or property damage.
For simplicity, the assigned numbers 1-4 of the aforementioned relapse criteria will be used 
henceforth.
It should be noted that criteria 2 and 4 could happen anytime during the study without regard to 
study visits, whereas criteria 1 and 3 are evaluated at the study in-clinic visits (including 
unscheduled visits) and thus could be recorded simultaneously at the same visit. 
Per definition, an exacerbation in symptoms during Stage 1 cannot be defined as a relapse event, 
since relapse events can only occur following stabilization and randomization. Therefore, for 
efficacy evaluation, relapse can occur from the first injection until the end of treatment (ie, EoT/
ET Visit). In the follow-up time window patients will be treated according to the investigator’s 
judgment and may not comply with the study protocol and therefore will not be counted for 
relapse.
6.4.1.2.
Analysis
The proportion of patients who experienced a relapse in the study will be analyzed.
The number and proportion of patients and Kaplan-Meier estimates of time to relapse that met 
each one of the relapse criteria 1-4 will be presented separately and overall. 
6.4.2.
Drug Attitudes Inventory 10-item Version
6.4.2.1.
Definition
The Drug Attitudes Inventory (DAI) initially consisted of 30 items which focused on the 
subjective effects of the neuroleptic medications in patients with schizophrenia. The scale was 
developed to obtain a more complete understanding of factors influencing medication 
compliance in these patients. 
A brief 10-item scale (DAI-10) that focuses on medication effects was constructed. It 
demonstrated a high correlation with medication compliance and treatment outcome. The DAI-
10 is used in this study. 
The response for each item is either “True” (T) or “False” (F) as applies to the patient. An 
interpretation is required because “true” may indicate either a positive or negative view about 
medications. Table 1 contains the standard of a compliant response for each DAI-10 
item/statement. 


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Table 1:
Drug Attitudes Inventory 10-item Version – Standard of a Compliant 
Response
Item
Statement
Compliant 
response
1
For me, the good things about medication outweigh the bad. 
T
2
I feel weird, like a "zombie", on medication
F
3
I take medications of my own free choice
T
4
Medications make me feel more relaxed
T
5
Medication makes me feel tired and sluggish
F
6
I take medication only when I am sick
F
7
I feel more normal on medication.
T
8
It is unnatural for my mind and body to be controlled by medications.
F
9
My thoughts are clearer on medication
T
10
By staying on medications, I can prevent getting sick.
T 
F = false; T = true
The scoring of the DAI-10 will be done as follows:
1. For each item, a compliant response as appears in Table 1 will be scored as plus 1; an 
incompliant response will be scored as minus 1.
2. The total score is the sum of the item scores from #1.
The total score ranges from -10 to +10. A positive total score indicates a positive attitude toward 
psychiatric medications and thus corresponds to a compliant response, and vice versa.
The DAI-10 will be assessed in adult patients only at screening (for new patients), baseline (for 
new patients and roll-over patients), the ET/EoT visit and at the follow-up visit 2 (8-weeks after 
the last dosing visit).
6.4.2.2.
Analysis
By visit change from baseline to each visit and endpoint in the DAI-10 total score will be 
calculated. Least squares means and 95% CI of change from baseline to endpoint will be 
performed using a repeated measures analysis of covariance (ANCOVA) model with treatment 
arm (trt: q1m and q2m), subject id (subjid) and study visit (avisit), stratification variable 
(rand_strata) as factors and baseline DAI-10 score (Baseline) as a covariate. If for some visits 
there are less than 15 observations, these visits will not be incorporated into the model, as 
convergence problems might occur. For these cases only mean with 95% CI approximation using 
t-distribution will be presented. If the number of observation is below 5 then 95% CI will not be 
calculated.
A sample of SAS® code for the repeated measures ANCOVA is as follows:


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Proc Mixed method=reml; 
Class trt rand_strata subjid avisit;
Model Change=trt avisit rand_strata Baseline /DDFM=KR CL;
Repeated avisit / subject= subjid type = un;
LSMeans trt*avisit /CL;
Run; 
The unstructured covariance matrix for repeated observations within patients will be used. In 
case that the model does not converge, the Maximum-Likelihood (ML) estimation method will 
be used instead of the default Restricted ML (REML). If the model still does not converge then a 
simpler covariance structures with less parameters will be used, according to the following order: 
Heterogeneous Autoregressive(1) [ARH(1)], Heterogeneous Compound Symmetry (CSH), 
Autoregressive(1) [AR(1)], and Compound Symmetry (CS). The Kenward-Rodger (KR) method 
will be used to calculate the denominator degrees of freedom. In addition, if data in a visit is too 
sparse (below 5 patients) confidence intervals will not be presented.
The DAI-10 total score change from baseline will also be summarized using descriptive statistics 
and least-squares means at each time point by treatment group and by source of patients. Shift 
table for items 1, 3, 7 and 10 will be displayed; all items may be presented in the shift table as 
applicable.  
6.4.3.
Schizophrenia Quality of Life Scale
6.4.3.1.
Definition
Schizophrenia Quality of Life Scale (SQLS) comprises 33 items categorized in 2 domains: 
psychosocial feelings (20 items - Items 3, 4, 5, 6, 8, 10, 11, 13, 15, 16, 17, 18, 19, 21, 22, 24, 25, 
27, 29, 30) and cognition and vitality (13 items – Items 1, 2, 7, 9, 12, 14, 20, 23, 26, 28, 31, 32, 
33). The items are scored on a five-point scale (1 - never, 2 - rarely, 3 - sometimes, 4 - often, 5 -
always). For all items, except the specific 4 items discussed below, higher scores indicate 
comparatively lower quality of life. 
The following four items have reversed scaling and refer to positive aspects of life:
7. I was able to carry out my day to day activities; 
12. I felt that I could cope; 
14. I slept well;
26. I felt happy.
The above are to be recoded such as 6 minus recorded score (eg. 6-ITEM_7) before the scale 
total is calculated. Individual domain and total scores are standardized by scoring algorithm to a 
0 (best health status) to 100 (worst health status) scale, with higher scores indicating 
comparatively lower quality of life. 
Therefore, the total score, namely TS, is calculated as the total of all 33 items minus the number 
of items answered (), divided by the maximum possible total score, namely 
 = 33 ×
4 = 132, and multiplied by 100.
 = 


× 100


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Similarly, each scale score, ‘Psychosocial feelings’ and ‘Cognition and vitality’ will be 
calculated in the same way using the total score and number of items in the scale.
SQLS will be assessed in adult patients only at screening (for new patients), baseline (for new 
patients and roll-over patients), week 12, and every 12 weeks thereafter, including the ET/EoT 
visit, and at follow-up visit 2 (8 weeks after the last dosing visit).
For handling the missing items per each scale score see Section 4.3.2.
6.4.3.2.
Analysis
The by visit change from baseline of the total score will be calculated. Least squares means and 
95% CI of change from baseline in the SQLS will be presented using a repeated measures 
ANCOVA method, with treatment arm (trt: q1m and q2m), stratification variables (rand_strata), 
subject id (subjid) and study visit (avisit), and baseline (Baseline, SQLS score) as a covariate. A
sample of SAS® code for the analysis for each post baseline visit could be found in 
Section 6.4.2.2.
SQLS total and domain score and change from baseline will be summarized using descriptive 
statistics (least-squares mean will be presented as appropriate) at each time point for all treatment
groups and by source of patients.
6.4.4.
5-Level EuroQol Five Dimensions Questionnaire
6.4.4.1.
Definition
The 5-Level EuroQol Five Dimensions Questionnaire (EQ-5D-5L) consists of the EQ-5D 
descriptive system and the EQ visual analogue scale (VAS). The EQ-5D descriptive system 
includes 5 dimensions: mobility, self-care, usual activities, pain/discomfort and 
anxiety/depression. The values for each of the dimensions are: 1=no problems, 2=slight 
problems, 3=moderate problems, 4=severe problems and 5=unable to/extreme problems. 
The EQ VAS records the respondent’s self-rated health on a vertical VAS where the endpoints 
are labeled ‘100=Best imaginable health state’ and ‘0=Worst imaginable health state’.
EQ-5D-5L will be assessed in adult patients only at screening (for new patients), baseline (for 
new patients and roll-over patients), week 12, and every 12 weeks thereafter, including the 
ET/EoT visit, and at follow-up visit 2 (8 weeks after the last dosing visit).
6.4.4.2.
Analysis
By visit change from baseline and to endpoint in each of the EQ-5D-5L domains will be 
calculated. The analysis of change from baseline to each visit and endpoint in each of the EQ-
5D-5L domains will be performed similarly to Section 6.4.2.2, using the appropriate baseline 
EQ-5D-5L domain as a covariate, respectively. 
The change from baseline for each of the EQ-5D-5L domains will also be summarized using 
descriptive statistics, and least squares means at each time point by treatment group and by 
source of patients as appropriate.  


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6.4.5.
Healthcare Resource Utilization
6.4.5.1.
Definition
The percentage of patients who were hospitalized, number of hospitalizations, and length of 
hospital stay (number of days); percentage of patients who had emergency room (ER) visits and 
number of ER visits (ie, not including protocol-mandated outpatient visits); and percentage of 
patients who had outpatient visits (ie, not including protocol-mandated outpatient visits) and 
number of outpatient visits will be calculated.
6.4.5.2.
Analysis
The parameters defined above in Section 6.4.5.1will be assessed in all patients (ie, both adults 
and adolescents) and will be summarized using descriptive statistics for both study periods, as 
applicable.
6.4.6.
Change in PANSS Total Score from Baseline to Endpoint 
6.4.6.1.
Definition
The PANSS comprises a total of 30 items. Each item is scored using 7 rating points, with an 
increasing level of psychopathology, as follows 1 – absent; 2 – minimal; 3 – mild; 4 – moderate; 
5 - moderate severe; 6 – severe; 7 – extreme. 
7 of the PANSS items constitute a Positive scale (P1-P7) with a maximum score of 49, 7 a 
Negative scale (N1-N7) with a maximum score of 49, and 16 a General Psychopathology scale
with a maximum score of 112. The score for these scales are generated by a summation of 
ratings. The total or overall PANSS score is the sum of all of the 30 items, and it will only be 
calculated if all the items are present. The maximum total score is 210.
PANSS will be assessed at all in-clinic visits during the study. 
Percent reduction of the total score from screening or baseline (=reference) will be conducted by 
calculating
Reduction(%) at visit k = 100-
100 ∙(%&'( )*%+, '& -.).& / −30)
%&'( )*%+, '& +,1,+,2*, -.).& −30
If total score at baseline or screening is 30 then the denominator will be set to 1(see Leucht et al 
2010).
6.4.6.2.
Analysis
The change in the PANSS total score from screening to each visit will be calculated for Stage 1
for new patients. The change from baseline in total score will be calculated to each visit and to 
endpoint for Stage 2 for all patients. The PANSS total score from baseline to endpoint analysis 
will be performed similarly to Section 6.4.2.2. 
PANSS total score and change from screening will be summarized using descriptive statistics for 
each dose at each time-point during Stage 1 for new patients. PANSS total score and change 
from baseline will be summarized using descriptive statistics for each treatment arm at each time


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point and to endpoint during Stage 2 for all patients, as well as for the follow up visits, using 
least squares means and 95% CI calculated by a repeated measures ANCOVA model.
Individual PANSS items and/or scales might be summarized using descriptive statistics during 
Stage 1, 2 or both. 
Percent reduction will be summarized in a frequency table, with percent reduction using the 
categories ≤0%, 1%-24%, 25%-49%, 50%-74%, 75%-100%.
6.4.7.
CGI-I Score at Endpoint
6.4.7.1.
Definition
The Clinical Global Impression–Improvement (CGI-I) scale permits a global evaluation of the 
patient’s improvement in symptoms overall. The CGI-I scale rates the patient’s improvement 
relative to his or her symptoms on a 7-point scale ranging from 1 (very much improved) to 7 
(very much worse).
The CGI-I will be administered by the investigator/trained rater at all in-clinic visits during the 
study according to the schedule of assessment (except for the screening and baseline visits). 
CGI-I during Stage 1 will be relative to screening for new patients; CGI-I during Stage 2 will be 
relative to the baseline visit for new and roll-over patients.
6.4.7.2.
Analysis
CGI-I will be analyzed in the same way as described in Section 6.4.2.2 except that the baseline 
Clinical Global Impression of Severity (CGI-S) will be included as a covariate in the model as 
the efficacy measure at baseline and the target variable of the actual value by visit will be 
analyzed rather than change from baseline for the parameter itself; subsequently this model is 
measuring change from a reference (baseline).
CGI-I will be summarized using descriptive statistics during Stage 1 – by oral dose, and during 
Stage 2 and the follow up visits – by treatment group and by source of patients. 
6.4.8.
Personal and Social Performance Scale
6.4.8.1.
Definition
The Personal and Social Performance Scale (PSP) is a clinician-rated instrument that measures 
personal and social functioning in patients with schizophrenia. The PSP is a 100-point single-
item rating scale, divided into 10 equal intervals. The score is based on the assessment of 
patient’s functioning in 4 categories in the past: 1) socially useful activities; 2) personal and 
social relationships; 3) self-care; and 4) disturbing and aggressive behaviors. These 4 patient 
functioning categories are assessed via the degree of difficulty ranging from 1 (absent) to very 
severe (6).
Higher PSP (also called total) scores represent better personal and social functioning, with 
ratings from 91 to 100 indicating more than adequate functioning, while scores under 30 
indicating functioning so poor that intensive supervision is required.


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PSP will be assessed for adult patients only at screening (for new patients), baseline (for new 
patients and roll-over patients), week 12, and after every 12 weeks thereafter, including ET/EoT 
visit, and at follow-up visit 2 (8 weeks after the last dosing visit).
6.4.8.2.
Analysis
By visit change from baseline in the PSP (also called total) score will be calculated. The PSP 
total score will be analyzed in the same way as described in Section 6.4.3.2 except that the 
baseline PSP score will be included in the model as the efficacy measure at baseline.
PSP total score and change from baseline will be summarized using descriptive statistics by 
treatment group and source of patients at each timepoint and to endpoint.
The areas of functioning assessments will be summarized using descriptive statistics by 
treatment group and source of patients at each timepoint and to endpoint. 


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7.
MULTIPLE COMPARISONS AND MULTIPLICITY
There are no primary efficacy endpoints in this study. Therefore no adjustments will be made for 
the preplanned multiple comparisons/endpoints.


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8.
SAFETY ANALYSIS
8.1.
General
Safety analyses for Stage 1 will be performed for new patients on enrolled patients set 
(Section 3.1), unless otherwise noted. Safety analyses will be performed for new patients and 
roll-over patients on the safety analysis set for Stage 2 (Section 3.4). Summaries of treatment 
emergent adverse events for Stage 1 will be presented on the Enrolled patients set (Section 3.1)
by randomized and not-randomized groups and overall, unless otherwise stated. Summaries of 
treatment emergent adverse events for Stage 2 will be presented by treatment group and by 
source of patients, unless otherwise stated.
Selected safety data will also be presented by site of injection (abdomen vs arm), as applicable.
Safety assessments and time points are provided in Table 1 and Table 2 of the study protocol.
For continuous variables, descriptive statistics (n, mean, standard deviation, median, minimum, 
and maximum) will be provided for actual values and changes from baseline to each time point, 
as appropriate. For categorical variables, patient counts and percentages will be provided as 
appropriate.
8.2.
Duration of Exposure to Risperidone during Study 
Duration of exposure to risperidone will be analyzed at the different study stages as the number 
of days a patient received drug (last day of study drug and first day of study drug). Duration of 
treatment calculation for the oral and the injectable risperidone will be different in order to 
account for the difference in frequency of administration and, for roll-over patients, will not take 
into account exposure in the TV46000-CNS-30072 study. The exposure at each stage will be 
summarized using descriptive statistics.
8.2.1.
Oral Stabilization Period – Stage 1 
For the individual new patient, duration of exposure to oral risperidone (days) during Stage 1 is 
the number of days the patient received the oral risperidone during the study (last day of oral 
risperidone drug – first day of oral risperidone + 1). In patients not randomized to Stage 2 of the 
study, in case of missing end of study date or a lost-to-follow-up patient, (planned) 
randomization date will be considered as last date of subject assessments.
Duration of treatment (days) will be summarized only for new patients using descriptive 
statistics.
8.2.2.
Relapse Prevention - Stage 2
Duration of treatment (days treated) during Stage 2 will be defined based on the first and last 
days of IMP injection in this study. Duration of treatment calculation for the different treatment 
regimens will be as follows:

q1m - last day – first injection day in this study + 29;

q2m - last day – first injection day in this study + 57.


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For roll-over placebo patients the first TV46000 dose is the week 4visit.
Weeks of IMP treatment using the categories ≤13 week, >13 to ≤26 weeks, >26 to ≤39 weeks, 
>39 to ≤52 weeks or >52 to ≤56 weeks will be summarized using descriptive statistics. Duration 
of treatment (weeks) will also be summarized using descriptive statistics.
8.2.3.
Total of Exposure to Risperidone in the Study 
For an individual new patient, total exposure to risperidone during the study is the sum of Stage 
1 and Stage 2. Total weeks on risperidone in the study using the categories ≤13 weeks, >13 to 
≤26 weeks, >26 to ≤39 weeks, >39 to ≤52 weeks or >52 to ≤56 weeks or more than 56 weeks 
will be summarized using descriptive statistics. Duration of study (weeks) will also be 
summarized using descriptive statistics.
For roll-over patients, total exposure to risperidone in Stage 2 of this study is described in 
Section 8.2.2.  
8.3.
Study Drug Compliance
8.3.1.
Oral Stabilization Period – Stage 1 
Per the study protocol, a new patient with the total compliance of less than 80% will be 
considered noncompliant during Stage 1 (i.e., compliance will be calculated only for new 
patients). This is an important criterion in regard to compliance with the study protocol, which is 
required for the patient to be eligible for randomization.
The compliance is defined as the ratio between the dose taken and the dose required:
% 3%45(.'2*, =
6*&7'( 8+79 &'/,2 (49)
:;5,*&,8 8+79 &% <, &'/,2 (49) × 100%
‘Actual drug taken’ will be calculated as the total amount of drug dispensed less total amount of 
drug returned, both during the entire oral stage, based on “study drug accountability – oral” field 
in the CRF. Drug dispensed (in mg) will be the number of dispensed tablets (Total Number 
Dispensed) multiplied by the corresponding dose (Dispensed Units). The total amount of drug 
dispensed will be the sum over all the visits where the drug dispensation occurred, both 
scheduled and unscheduled. The same calculation will be done to obtain the total amount of drug 
returned, replacing “dispensed” by “returned”.
‘Expected drug to be taken’ will be calculated as sum(dose × days to be taken), where ‘dose’ 
is the dose prescribed (with one exception, below) by the investigator from the 'Study drug 
administration - oral medication' field in the CRF and ‘days to be taken’ is the number of days 
between the corresponding 'Start Date of Treatment' dates from the same CRF or the 
randomization date (for patients with missing randomization data, or lost to follow up the last 
assessment data will be used). For patients that the oral dose prescribed is below 2mg/day, 
2mg/day will be used as the expected dose and not the actual dose (eg 1mg or 0.5mg a day).
If no drug was returned, it will be accounted for as '0' returned amount for this visit in the 
compliance calculation. It should be noted that if the investigator or the sponsor determines that 
the patient was not in compliance with the study protocol, the case will be evaluated on a case-


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by-case basis, and the investigator and the sponsor will determine whether the patient will be 
randomized to the double-blind period (Stage 2).
Oral drug compliance during Stage 1 will be categorized as <60%, 60% to < 80%, 80% to < 
100%, and ≥100% and summarized using descriptive statistics. A numerical example of 
compliance calculation during Stage 1 is given below.
8.3.1.1.
Numerical Example of Oral Drug Compliance during Stage 1
Assuming that after looking at the Start Dates of Treatment, the patient had a total 84 days of the 
oral period, of which of 2 days were on 1mg/day, 40 days on 3 mg/day and 42 days on 4 mg/day 
– the expected drug to be taken (mg) would be 2 × 2 + 3 × 40 + 4 × 42 = 292 mg.
For the entire oral stage period, the patient was dispensed a certain amount (2 tablets of 
1 mg/day, 68 tablets of 3 mg/day and 50 tablets of 4 mg/day) and returned a certain amount
(30 tablets of 3 mg/day and 10 tablets of 4 mg/day) –
•
the total drug dispensed would be 2 × 1 + 68 × 3 + 50 × 4 = 406 mg;
•
the total drug returned would be 30 × 3 + 10 × 4 = 130 mg;
•
Actual drug taken would be 406 −130 = 276 mg
Drug compliance would be Drug consumed/ Drug prescribed=276/292=95% (>80%)
% 3%45(.'2*, =
6*&7'( 8+79 &'/,2 (49)
:;5,*&,8 8+79 &% <, &'/,2 (49) × 100% = 276
292 × 100% = 95%
8.3.2.
Relapse Prevention - Stage 2
Not applicable. Drug compliance during Stage 2 will not be assessed.
8.4.
Adverse Events
For recording of adverse events, the study period is defined for each patient as the time period 
from signature of the ICF to the end of the follow-up period. All adverse events will be coded 
using the MedDRA. Each patient will be counted only once in each PT or SOC category for the 
analyses of safety. Summaries will be presented for all adverse events (overall and by severity), 
including adverse events determined by the investigator to be related to oral risperidone (Stage 1) 
or TV-46000 (Stage 2) (defined as related or with missing relationship) (overall and by severity), 
serious adverse events, and adverse events causing withdrawal from the study. Summaries will 
be presented by randomized, not-randomized and overall using the enrolled patients set (Stage 1) 
or treatment group and by source of patients using the safety analysis set (Stage 2).
Summaries will include treatment-emergent adverse events which are defined as adverse events 
occurring at or after the first day of oral risperidone until the last day of oral risperidone for new 
patients for Stage 1 and for Stage 2 as adverse events occurring at or after the first IMP injection.
No protocol-defined adverse events of special interest were identified for this study.
In case of the missing dates and severity, the imputation will be performed as described in 
Section 4.3.


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Multiple records with the same PT and adverse event onset date for the same patient, or with 
overlapping or consecutive dates, are counted only once selecting the adverse event with the 
highest severity and seriousness. For injection site reactions, multiple records with overlapping 
or consecutive dates are counted only once only if the injection site is the same, selecting the 
adverse event with the highest severity and seriousness. If the onset date of adverse events with 
the same PT is partially unknown or duration is < 24 hours, then these adverse events will be 
counted as separate adverse events, except for the cases where an adverse event with duration of 
< 24 hours has the same onset date as another adverse event with a longer duration, then the 
adverse events with the longer duration adverse events will be counted. The event rate per 100 
years (PY) of patient treatment exposure is calculated as 100*(Number of cases/PY).
Safety data collected in Stage 1 for new patients will also be summarized using descriptive 
statistics in the enrolled patients set. Adverse events that started in Stage 1 and ended in Stage 2 
will be reported only in oral phase.
Selected safety data will also be presented by site of injection (abdomen vs arm). 
Separate summaries for adolescent patients may be presented separately for some analyses, as 
applicable.
Patient listings of all adverse events, serious adverse events and adverse events leading to 
withdrawal and adverse events leading to death will be presented.
Summary of the number of adverse events per week following each sc injection will be 
presented.
8.5.
Deaths
If any patient dies during the study, a listing of deaths will be provided, and all relevant 
information will be discussed in the patient narrative included in the CSR.
8.6.
Clinical Laboratory Tests
The clinical laboratory tests (serum chemistry, hematology and urinalysis) are detailed in Table 7 
of the study protocol.
Laboratory test results will be presented in standard international (SI) units.
Summary statistics for chemistry, hematology, and urinalysis laboratory tests will be presented at
time points detailed in the schedule of assessment Tables 1 and 2 of the study protocol including 
last assessment (as a separate visit). Laboratory values and changes from screening or baseline 
(as appropriate) to each visit will be summarized using descriptive statistics. 
Boxplots for selected laboratory tests, including neutrophils, alanine aminotransferase, aspartate 
aminotransferase and bilirubin, will be presented by visit and treatment group and by source of 
patients.
Shifts (below, within, and above the normal range) from screening or baseline (as appropriate) to 
each visit and endpoint assessment will be summarized using patient counts.
Summaries of potentially clinically significant abnormal values will include all post-baseline 
values (including scheduled, unscheduled, and withdrawal visits). The incidence of potentially 


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clinically significant abnormal values will be summarized for laboratory variables using 
descriptive statistics with the criteria specified in Table 2.
Table 2:
Criteria for Potentially Clinically Significant Laboratory Values
Test
Criterion value
Serum chemistry
Alanine aminotransferase (ALT)
≥3x ULN
Aspartate aminotransferase (AST)
≥3x ULN
Alkaline phosphatase
≥3x ULN
Lactate dehydrogenase (LDH)
≥3x ULN
Blood urea nitrogen (BUN)
≥10.71 mmol/L
Creatinine
≥177 μmol/L
Uric acid                   Men
≥625 μmol/L
                             Women
≥506 μmol/L
Bilirubin (total)
≥2x ULN
  Potassium
≤3 mmol/L
≥6 mmol/L
  Calcium
≤1.5 mmol/L
≥3.5 mmol/L
Hematology
Hemoglobin           Men
≤115 g/L
                          Women
≤95 g/L
White blood cell (WBC) counts
≤3 x 109/L 
≥20 x 109/L
Absolute neutrophil counts (ANC)
≤1 x 109/L
Platelet counts
≤75 x 109/L 
≥700 x 109/L
ULN=upper limit of normal range.
8.6.1.
Laboratory Values Meeting Hy’s Law Criteria
All occurrences of possible drug-induced liver injury that meet Hy’s law criteria, defined as all
of the below, must be reported by the investigator to the sponsor as a serious adverse event:

ALT or AST increase of >3× the upper limit of the normal range (ULN)

total bilirubin increase of >2× ULN

absence of initial findings of cholestasis (ie, no substantial increase of alkaline 
phosphatase)
An adverse event that does not meet any of the criteria for seriousness listed above will be 
regarded as a non-serious adverse event.


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All incidences will be listed.
8.6.2.
Other Clinical Laboratory Tests
8.6.2.1.
Virology and Thyroid Screening Tests
At screening (new patients only) and baseline (new patients and roll-over patients), patients will 
be tested for HIV, hepatitis B surface antigen, hepatitis C antibody. Due to potential effects on 
clinical psychiatric symptoms, levels of thyroid hormones (thyroid stimulating hormone, 
triiodothyronine, and thyroxine) will also be assessed at these time points.
The data will be presented as listings.
8.6.2.2.
Human Chorionic Gonadotropin Tests
A FSH test will be performed at the screening visit (new patients only) for any female who has 
been without menses for at least 12 months to confirm post-menopausal status. Women may be 
allowed not to use contraceptives during the study if they had no menses for at least 12 months 
(without an alternative medical cause) and the FSH concentration is above 35 U/L.
A serum beta human chorionic gonadotropin (β-HCG) test will be performed for all women of 
child bearing potential at screening (new patients only), baseline, and the follow-up/exit visits 
(see Table 1 and Table 2 of the study protocol). At baseline, both a serum and a urine β-HCG test 
will be performed. Urine β-HCG (dipstick) test will be performed for women of child bearing 
potential at all visits where study drug is administered (prior to study drug administration). A 
negative result must be obtained prior to study drug administration.
The FSH, serum and urine β-HCG data will be listed.
8.6.2.3.
Urine Drug Screen
A urine drug screen will be performed at the time points specified in Table 1 and Table 2 of the 
study protocol. The urine drug screen detects the presence of drugs of abuse, including 
amphetamine, barbiturates, benzodiazepines, cocaine, opiates, and tetrahydrocannabinol.
Any findings will be listed.
8.6.2.4.
Prolactin
Blood samples will be obtained for prolactin test at the time points specified in Table 1 and 
Table 2 of the study protocol. The test results of the roll-over patients will remain blinded to the 
sponsor until the database of the TV46000-CNS-30072 study is locked and the IMP assignment 
is revealed.
The test results will be presented as described for all the clinical laboratory test results outlined 
in Section 8.6 above. In addition, shift tables from screening (for new patients) and baseline (new 
patients and roll-over patients) - from normal to 2x ULN and 5x ULN - will be presented.
8.6.2.5.
Glomerular Filtration Rate
Glomerular Filtration Rate (GFR) will be calculated based on plasma creatinine levels, weight, 
gender and age using the Cockcroft-Gault equation.


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The estimated GFR values and changes from baseline will be presented by visit using descriptive 
statistics. The individual GFR measurements will also be presented in the listing.
8.7.
Physical Examinations
Physical examinations, including height (to be obtained at the screening visit for new patients 
and at the baseline visit for adolescent roll-over patients) and weight, will be performed at the 
time points detailed in Table 1 and Table 2 of the study protocol. The full physical examination 
will consist of examining the following body systems: cardiovascular, respiratory, abdominal, 
skin, neurological, and musculoskeletal systems. The physical examination will also include 
examination of general appearance, including head, eyes, ears, nose, and throat; chest; abdomen; 
skin; lymph nodes; and extremities. Body weight and tympanic temperature will be measured at 
each visit. Systolic and diastolic blood pressure and pulse rate will be measured with the patient 
in a seated position. Any physical examination finding that is judged by the investigator as a 
clinically significant (except at the screening visit [new patients]) will be considered an adverse 
event, recorded on the CRF, and monitored as described in Section 7.1.2 of the study protocol.
Descriptive statistics for weight and height will be provided. All the data will be listed. Boxplots 
for weight will be presented by visit and treatment group.
In addition, BMI results and percent changes from screening to each visit in Stage 1 (new 
patients only) for the enrolled patients set and percent changes from baseline to each visit in 
Stage 2 (new patients and roll-over patients) for the safety analysis set will be presented. BMI 
shifts from reference to each visit by treatment group and by source of patients will be presented, 
where the reference is the screening measurement for Stage 1 (new patients only) and the
baseline measurement for Stage 2 (new patients and roll-over patients), using the following 
limits: ‘<0’, ‘≥0-5%’, ‘≥5-10%’ and ‘≥10%’.
8.8.
Vital Signs
Summary statistics for vital signs (blood pressure [systolic/diastolic], respiratory rate, tympanic 
temperature, and pulse) will be presented at the time points including last assessment (as a 
separate visit) detailed in Table 1 and Table 2 of the study protocol.
Vital signs values and changes from screening (for new patients) or baseline (for new patients 
and roll-over patients) to each visit will be summarized by stage of study using descriptive 
statistics. All the data will be listed.
Boxplots for selected vital signs, including pulse, systolic blood pressure and diastolic blood 
pressure, will be presented by visit and treatment group and by source of patients.
Summaries of potentially clinically significant abnormal values will include all post baseline 
values (including scheduled, unscheduled, and withdrawal visits). The incidence of potentially 
clinically significant abnormal vital sign values, specified by the criteria in Table 3, will be 
summarized using descriptive statistics. Systolic and diastolic blood pressure will be included in 
all summaries.


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Table 3:
Criteria for Potentially Clinically Significant Vital Signs
Vital Sign
Criterion value
Pulse
120 bpm
50 bpm
Systolic blood pressure
180 mm Hg
90 mm Hg
Diastolic blood pressure
105 mm Hg
50 mm Hg
Body temperature
≥38.3C
bpm = beats per minute; mm Hg = millimeters of mercury.
8.9.
Electrocardiography
A standard 12-lead ECG will be recorded at the time points detailed in Tables 1 and 2 of the
study protocol. Triplicate measurements will be performed at screening (for new patients) and 
baseline (for new patients and roll-over patients) and single measurements at all other in-clinic 
visits. 
Electrocardiogram (ECG) findings (normal and abnormal) at screening (for new patients) and 
baseline (for new patients and roll-over patients) will be summarized using descriptive statistics;
the data presentation will include both eResearch Technology (the central ECG vendor) and 
investigator interpretation. The average of the 3 ECG screening and baseline assessments will be 
calculated; if more measurements are taken, the 3 last measurements taken prior to first dose 
administration will be used both for the average calculation and for choosing the worst result for 
the interpretation.
If the investigator interpretation is missing, the following derivation rule will be used:
1. If ERT interpretation is 'normal' then investigator interpretation on the same date will be 
derived as 'normal';
2. Otherwise investigator interpretation will not be derived.
Shifts (normal and abnormal) from screening to baseline (for new randomized patients) and from 
baseline to overall result interpretation at each visit and last assessment will be summarized 
using patient counts. For overall result interpretation the worst post baseline finding for the 
patient (the abnormal finding if there are both normal and abnormal findings) will be used in the 
summaries. Summary statistics for ECG variables values will be presented. Actual values and 
changes from screening to baseline and from baseline to each visit and last assessment will be 
summarized using descriptive statistics.
The incidence of potentially clinically significant abnormal values for ECG variables will be 
summarized using descriptive statistics with the criteria specified below:

QT interval corrected using Fridericia's formula (QTcF) values >450 msec or 
>480 msec or >500 msec.

QTcF change from baseline values >30 or >60.


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
PR change from baseline ≥25% and a value >200.

QRS change from baseline ≥25% and a value >110.

Heart rate value <60 bpm or >100 bpm.
8.10.
Concomitant Medications or Therapies 
Concomitant therapies and medications, including medications that are taken on an as needed 
basis and occasional therapies, will be monitored during the study. Concomitant medications and 
treatments will be recorded from screening (for new patients) or from baseline (for roll-over 
patients) through the final visit. Details of prohibited medications may be found in Section 5.7 of 
the study protocol. All concomitant medications will be coded using the WHO Drug.
The incidence of concomitant therapies and medications will be summarized using descriptive 
statistics by therapeutic class category and PT. Patients are counted only once in each therapeutic 
class, and only once in each PT category.
A distinction will be made between the study stages. For Stage 1, concomitant therapies and 
medications will be presented for new patients using the enrolled patients set (Section 3.1) and 
will include all medications up to randomization day (Day 1), excluding the randomization day. 
For Stage 2, the concomitant therapies and medications will be presented using the safety 
analysis set and will include all medications from the day of randomization (baseline, Day 1) and 
up to the end of study as defined in the study protocol.
Descriptive statistics for allowed rescue medications (see Section 5.7 in the study protocol
and Appendix A) will be presented by treatment group and by source of patients and by study 
stage. 
8.11.
Columbia-Suicide Severity Rating Scale (C-SSRS)
The C-SSRS is a semi-structured interview that captures the occurrence, severity, and frequency 
of suicide-related thoughts and behaviors. Any positive answer to the behavior subcomponents at 
screening or baseline identifies a patient with “Suicidal Behavior at Screening” or “Suicidal 
Behavior at Baseline” respectively.
For new patients, the C-SSRS will be administered at screening (baseline/screening version), and 
the "since last visit" version will be administered at all post-screening visits and telephone 
contacts during the study. 
For roll-over patients, the "since last visit" version will be administered at baseline and all 
subsequent visits and telephone contacts during the study.
For the derivation of Screening Behavior, all assessments until the beginning of Stage 1 should 
be used for new patients, while for the derivation of Baseline Behavior, all assessments after the 
beginning of Stage 1 and till the beginning of Stage 2 should be used for new and roll-over 
patients. Same derivation will be done also for "Suicidal Ideation at Screening” and "Suicidal 
Ideation at Baseline”. A patient identified with either “Suicidal Behavior at Screening/Baseline” 
or with “Suicidal Ideation at Screening/Baseline” is also classified as with “Suicidal Behavior or 
Ideation at Screening/Baseline”.


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For post-screening/ post-baseline periods, any positive answer to the behavior subcomponents in 
any of the post screening or baseline assessments, according to the study period (Oral or sc), 
identifies a patient as with “Suicidal Behavior Post Dosing” for that period. Same derivation will 
be done also for Suicidal Ideation post Dosing” for both the oral and sc periods. A patient 
identified with either “Suicidal Behavior Post Dosing” or with “Suicidal Ideation Post Dosing” is 
also classified as with “Suicidal Behavior or Ideation Post Dosing”, the derivation should be 
done for both periods.
Frequency counts and percentages of the C-SSRS outcomes: Suicidal Behavior at 
Screening/Baseline, Suicidal Ideation at Screening/Baseline, Suicidal Behavior or Ideation at 
Screening/Baseline, Suicidal Behavior Post Dosing, Suicidal Ideation Post Dosing, Suicidal 
Behavior or Ideation Post Dosing, and shifts from screening/baseline for Stage 1/Stage 2 will be 
summarized.
8.12.
Abnormal Involuntary Movement Scale (AIMS)
The AIMS will be performed at the time points specified in Table 1 and Table 2 of the study 
protocol. The AIMS scores the occurrence of tardive dyskinesia in patients receiving neuroleptic 
medications. The AIMS is a 14-item scale that includes assessments of orofacial movements, 
extremity and truncal dyskinesia, examiner’s judgment of global severity, subjective measures of 
awareness of movements and distress, and a yes/no assessment of problems concerning teeth 
and/or dentures. Higher scores indicate greater severity of the condition.
AIMS total score will be calculated as a sum of items 1 through 7.
The AIMS total score and the individual score for each of the AIMS items 8-10 and changes 
from screening during Stage 1 for new patients will be presented using descriptive statistics. 
Shift from screening analysis of AIMS items 11-14 during Stage 1 will be presented.
The AIMS total score and the individual score for each of the AIMS items 8-10 and changes 
from baseline during Stage 2 for new patients and roll-over patients will be presented using 
descriptive statistics. Shift from baseline analysis of AIMS items 11-14 during Stage 2 will be 
presented. 
Enrolled patients set and ITT analysis set will be used as appropriate.
8.13.
Simpson-Angus Scale (SAS)
The SAS will be performed at the time points specified in Table 1 and Table 2 of the study 
protocol. The SAS is a 10-item instrument for the assessment of neuroleptic-induced 
parkinsonism. The items on the scale include measurements of hypokinesia, rigidity, glabellar 
reflex, tremor, and salivation. Each item is rated on a 5-point scale (0 to 4), with a higher score 
indicating greater severity of symptoms. The mean score is calculated by adding the individual 
item scores and dividing by 10.
The SAS mean score and changes from screening during Stage 1 will be presented for new 
patients using descriptive statistics by enrolled patients set.
The SAS mean score and changes from baseline during Stage 2 will be presented for new 
patients and roll-over patients using descriptive statistics by treatment group and by source of 
patients.


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8.14.
Barnes Akathisia Rating Scale (BARS)
The BARS will be performed at the time points specified in Table 1 and Table 2 of the study 
protocol. The BARS is an instrument that assesses the severity of drug-induced akathisia. The 
BARS includes 3 items for rating objective restless movements, subjective restlessness, and any 
subjective distress associated with akathisia that are scored on a 4-point scale of 0 to 3, and 
summed yielding a total score ranging from 0 to 9. The BARS also includes a global clinical 
assessment of severity scored on a scale of 0 to 5. Higher scores are indicative of greater severity 
of akathisia.
BARS total score, global clinical assessment of severity values, and changes from screening (for 
new patients) and baseline (for new patients and roll-over patients) to each visit will be 
summarized using descriptive statistics - during Stage 1 by enrolled patients set and during Stage 
2 by treatment group and by source of patients.
8.15.
Calgary Depression Scale for Schizophrenia (CDSS)
The CDSS will be performed at the time points specified in Table 1 and Table 2 of the study 
protocol. The CDSS is specifically designed to assess the level of depression separate from the 
positive, negative, and EPS in schizophrenia. This clinician-administered instrument consists of 
9 items, each rated on a 4-point scale from 0 (absent) to 3 (severe) that are added together to 
form the CDSS depression score of the patient. 
Descriptive statistics of CDSS depression score values and changes from screening (for new 
patients) and baseline (for new patients and roll-over patients) to each visit will be presented -
during Stage 1 by enrolled patients set and during Stage 2 by treatment group and by source of 
patients.
8.16.
Clinical Global Impression-Severity of Suicidality (CGI-SS)
The CGI-SS scale provides an overall clinician-rated assessment of the risk of suicidality. The 
CGI-SS consists of a 5-point scale in Part 1 ranging from 1 (not at all suicidal) to 5 (attempted 
suicide) and a 7-point scale in Part 2 ranging from 1 (very much improved) to 7 (very much 
worse).
The CGI-SS will be assessed at screening (for new patients) and all in-clinic visits during the 
study according to the schedule of assessment.
Descriptive statistics of CGI-SS Part 1 and 2 will be presented - during Stage 1 (for new patients) 
by enrolled patients set and during Stage 2 (for new patients and roll-over patients) by treatment 
group and by source of patients.
8.17.
Clinical Global Impression of Severity (CGI-S)
The CGI-S will be administered by the investigator/trained rater at all in-clinic visits. The CGI-S 
scale was developed to rate the severity of a patient’s condition on a 7-point scale ranging from 1
(normal, not at all ill) to 7 (among the most extremely ill patients).
Descriptive statistics of CGI-S Part 1 and 2 will be presented - during Stage 1 (for new patients) 
by enrolled patients set and during Stage 2 (for new patients and roll-over patients) by treatment 


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group and by source of patients. Shift tables from screening (for new patients) and baseline (new 
patients and roll-over patients) to each visit and last assessment will be presented.
8.18.
Structured Clinical Interview for DSM-5 (SCID-5)
The Structured Clinical Interview for DSM-5 (SCID-5) is a semi-structured interview guide for 
making DSM-5 diagnoses. It will be administered to new patients only at screening by a clinician 
or trained mental health professional that is familiar with the DSM-5 classification and 
diagnostic criteria.
The SCID-5 will be presented in listings.


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9.
TOLERABILITY VARIABLES AND ANALYSIS
9.1.
Assessment of Local Tolerability and Pain
In case an adverse event related to an injection site reaction is reported, an assessment of the sc 
injection site (ie, local tolerability [skin at injection site]) will be made. The presence and 
severity of erythema, swelling, induration, and pain at the injection site may be assessed using 
the scales described in the Protocol Section 7.8. 
Data will be summarized as follows: 

Descriptive analysis of frequency counts and percentages of the initial subject’s 
maximal (per injection type) scoring of erythema, edema, induration and nodule 
assessment, and of injection pain intensity assessment using the Numeric Pain Rating 
Scale (NPRS);

Descriptive analysis of subject’s mean time to stabilization, namely until the score of 
0, of erythema, edema, and of induration and nodule assessment.
This analysis will be presented by both 

treatment group (q1m and q2m) and the injection type (placebo or TV-46000), thus 
dividing the patients into non-intersecting groups, and distinguishing between the 2 
types of injections for patients randomized to the TV-46000 q2m group, and by low 
(≤0.3ml) and high (>0.3ml) volume (the cut off is equivalent to the 100 mg dosage, 
which is the only overlapping dose between the 2 regimens, see Table 4); 

injection type – injection type will be identical to the treatment arm for the TV-46000 
q1m patients, while the TV-46000 q2m patients will appear under 2 categories
(placebo or TV-46000).
Table 4:
Oral Risperidone Doses and Corresponding TV-46000 Doses
Oral Risperidone Doses and Corresponding TV-46000 Dosesab
2 mg/day 
(mL)
3 mg/day 
(mL)
4 mg/day 
(mL)
5 mg/day (Adults 
Only)
(mL)
TV-46000 q1m
50 mg (0.14 mL)
75 mg (0.21 mL)
100 mg (0.28 
mL)
125 mg (0.35 mL)
TV-46000 q2m
100 mg (0.28 mL)
150 mg (0.42 mL)
200 mg (0.56 
mL)
250 mg (0.70mL)
a Placebo dosing volume is 0.31 ml
b The administered volume corresponding to each dose is shown in parentheses next to it
9.2.
All-cause Discontinuation Rate Assessment
All-cause discontinuation rates and discontinuation rates due to adverse events (dropout rates) 
will be calculated as the number of patients who withdrew early for all reasons, and the number 


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of patients who withdrew early due to adverse events, respectively, divided by number of 
patients in each treatment group, and will be analyzed using descriptive statistics.
Time to all-cause discontinuation will be calculated as the discontinuation date minus the 
randomization date plus 1. The date of last contact will be used for the lost to follow-up patients. 
Kaplan Meier curves for the time to discontinuation as a result of all causes will be plotted by 
treatment group and by source of patients.
The ITT analysis set will be used for the analysis. Separate summaries for adolescent patients 
might be presented separately for some analyses, according to the total number of the 
adolescents.


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10.
PHARMACOKINETIC ANALYSIS
All concentration data will be summarized by age subset (adult, adolescent), treatment group
(q1m, q2m or oral), dose and visit using descriptive statistics (n, mean, standard deviation, 
median, minimum, geometric mean, and coefficient of variation). Drug concentrations over time 
[C(t)] reported by age subset, time (visit) and treatment will be presented for risperidone, 9-
hydroxyrisperidone (9-OH-risperidone), and total active moiety. Total active moiety is defined 
as the sum of risperidone and 9-OH-risperidone corrected by molecular weight, according to the 
following formula:
[6*&.-, H%.,&I] = [+.)5,+.8%2,] + [9 −KL −+.)5,+.8%2,] × (410/426)
Individual plasma concentrations of risperidone, 9-OH-risperidone, and total active moiety will 
be listed by age subset, treatment group, dose and visit. Unscheduled visits will be listed 
separately.
For summary tables, the values of 0.000 ng/mL will be replaced by half the LLOQ value i.e. 
0.05 ng/mL for Risperidone, 0.15 ng/mL for 9-OH-Risperidone, 0.05 ng/mL for total active 
moiety (a footnote will be added to tables to present LLOQ values for each analyte). Data from 
unscheduled visits and early termination visits will not be used in descriptive summaries.For 
listings if individual plasma concentration value is 0.000 ng/mL then this value is reported as 
BLQ.
Additional pharmacokinetic parameters may be determined if data permits (see Section 1.2). 
 
 
.
The analysis will include both structural model development and evaluation of the influence of 
patient covariates on pharmacokinetic variability. Example for potential covariates may be: 
Patient characteristics (demographics, CYP2D6 metabolizer status, and renal function), disease 
characteristics (disease state, prior treatment) and treatment characteristics (site of injection, and
interacting concomitant medication).
In addition, if data permits the pharmacokinetics of TV-46000 in adolescent population will be 
characterized in comparison to the adult population.
 
Population pharmacokinetics analysis results will be reported separately from the main study 
report.
Importantly, independent pharmacokinetic modeling and population-based modeling analysis 
will take place during the study conduct by an external vendor, while maintaining the blind, as 
described in the pharmacokinetics analysis plan.


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11.
PHARMACOKINETIC/PHARMACODYNAMIC ANALYSIS
 
 
 
 
 
 
 
 
 
 


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12.
BIOMARKER AND PHARMACOGENETICS ANALYSIS
Genetic variability in the metabolizer gene, CYP2D6, may be evaluated using descriptive 
statistics for an association with drug concentrations, pharmacokinetic parameters and safety 
variables.
 
 
 
The biomarker sample analyses will be performed if and when required. Since new techniques 
continue to be developed, the method and laboratory to be recommended for analyses cannot be 
anticipated.
Biomarker and pharmacogenetics analysis plans and results will be reported separately from the 
main study results.


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13.
PLANNED INTERIM ANALYSIS
There will be a planned data cut with statistical output produced before the New Drug 
Application submission. This intermediary analysis is not a formal, pre-planned interim analysis 
but rather a "snapshot" of the data that will be performed when sufficient exposure and safety 
data are collected.
An interim CSR describing the data obtained until this time-point will be prepared for the 
submission. 


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14.
STATISTICAL SOFTWARE
All data listings, summaries, and statistical analyses will be generated using SAS® version 9.4 or 
later.


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15.
CHANGES TO ANALYSES SPECIFIED IN THE STUDY 
PROTOCOL
For roll-over patients on-going adverse events that started in TV46000-CNS-30072 Study will 
not be counted as adverse events. Since the primary interest of the safety summary tables is to 
evaluate the incidence (risk) to experience AEs, taking on-going AEs that started during 
TV46000-CNS-30072 Study are prevalence cases and therefore bias the risk.


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16.
REFERENCES
Leucht S, Kissling W, Davis JM. The PANSS should be rescaled. Schizophr Bull. 
2010;36(3):461–2. 


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APPENDIX A. LIST OF CONCOMITANT MEDICATIONS THAT MAY
BE RELATED TO INCREASED RISK OF RELAPSE 
Antipsychotics, sleep aids and antidepressants that may potentially may indicate a need for 
symptoms reduction are listed below. This list is not exhaustive and may be updated at the 
Statistical Data Review meeting prior to data closure.
Medication Class
Standardized Medication Name
ANTIEPILEPTICS
LORAZEPAM
PSYCHOANALEPTICS
AMITRIPTYLINE
PSYCHOANALEPTICS
AMITRIPTYLINE HYDROCHLORIDE
PSYCHOANALEPTICS
BUPROPION
PSYCHOANALEPTICS
BUPROPION HYDROCHLORIDE
PSYCHOANALEPTICS
CITALOPRAM
PSYCHOANALEPTICS
CITALOPRAM HYDROBROMIDE
PSYCHOANALEPTICS
DOXEPIN
PSYCHOANALEPTICS
DULOXETINE
PSYCHOANALEPTICS
DULOXETINE HYDROCHLORIDE
PSYCHOANALEPTICS
ESCITALOPRAM
PSYCHOANALEPTICS
ESCITALOPRAM OXALATE
PSYCHOANALEPTICS
FLUOXETINE
PSYCHOANALEPTICS
FLUOXETINE HYDROCHLORIDE
PSYCHOANALEPTICS
MIRTAZAPINE
PSYCHOANALEPTICS
PAROXETINE
PSYCHOANALEPTICS
PAROXETINE HYDROCHLORIDE
PSYCHOANALEPTICS
SERTRALINE
PSYCHOANALEPTICS
SERTRALINE HYDROCHLORIDE
PSYCHOANALEPTICS
TRAZODONE
PSYCHOANALEPTICS
VENLAFAXINE
PSYCHOANALEPTICS
VENLAFAXINE HYDROCHLORIDE
PSYCHOANALEPTICS
VILAZODONE
PSYCHOANALEPTICS
VILAZODONE HYDROCHLORIDE
PSYCHOANALEPTICS
VORTIOXETINE
PSYCHOLEPTICS
ALPRAZOLAM
PSYCHOLEPTICS
AMISULPRIDE
PSYCHOLEPTICS
ARIPIPRAZOLE


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Medication Class
Standardized Medication Name
PSYCHOLEPTICS
ASENAPINE MALEATE
PSYCHOLEPTICS
BREXPIPRAZOLE
PSYCHOLEPTICS
BUSPIRONE
PSYCHOLEPTICS
BUSPIRONE HYDROCHLORIDE
PSYCHOLEPTICS
CARBAMAZEPINE
PSYCHOLEPTICS
CARIPRAZINE
PSYCHOLEPTICS
CARIPRAZINE HYDROCHLORIDE
PSYCHOLEPTICS
CHLORPROTHIXENE
PSYCHOLEPTICS
CHLORPROTHIXENE 
HYDROCHLORIDE
PSYCHOLEPTICS
CLONAZEPAM
PSYCHOLEPTICS
CLOZAPINE
PSYCHOLEPTICS
DIAZEPAM
PSYCHOLEPTICS
DULOXETINE HYDROCHLORIDE
PSYCHOLEPTICS
ESZOPICLONE
PSYCHOLEPTICS
FLUOXETINE
PSYCHOLEPTICS
FLUPENTIXOL DECANOATE
PSYCHOLEPTICS
FLUPHENAZINE
PSYCHOLEPTICS
FLUPHENAZINE DECANOATE
PSYCHOLEPTICS
HALOPERIDOL
PSYCHOLEPTICS
HALOPERIDOL DECANOATE
PSYCHOLEPTICS
HYDROXYZINE
PSYCHOLEPTICS
HYDROXYZINE EMBONATE
PSYCHOLEPTICS
HYDROXYZINE HYDROCHLORIDE
PSYCHOLEPTICS
ILOPERIDONE
PSYCHOLEPTICS
LEVOSULPIRIDE
PSYCHOLEPTICS
LITHIUM
PSYCHOLEPTICS
LITHIUM CARBONATE
PSYCHOLEPTICS
LORAZEPAM
PSYCHOLEPTICS
LURASIDONE
PSYCHOLEPTICS
LURASIDONE HYDROCHLORIDE
PSYCHOLEPTICS
MELATONIN
PSYCHOLEPTICS
OLANZAPINE
PSYCHOLEPTICS
PALIPERIDONE


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Medication Class
Standardized Medication Name
PSYCHOLEPTICS
PALIPERIDONE PALMITATE
PSYCHOLEPTICS
PAROXETINE
PSYCHOLEPTICS
PERPHENAZINE
PSYCHOLEPTICS
QUETIAPINE
PSYCHOLEPTICS
QUETIAPINE FUMARATE
PSYCHOLEPTICS
RISPERIDONE
PSYCHOLEPTICS
SERTRALINE HYDROCHLORIDE
PSYCHOLEPTICS
TASIMELTEON
PSYCHOLEPTICS
TEMAZEPAM
PSYCHOLEPTICS
THIORIDAZINE
PSYCHOLEPTICS
TIOTIXENE
PSYCHOLEPTICS
VALPROATE SEMISODIUM
PSYCHOLEPTICS
VENLAFAXINE
PSYCHOLEPTICS
ZIPRASIDONE
PSYCHOLEPTICS
ZIPRASIDONE HYDROCHLORIDE
PSYCHOLEPTICS
ZOLPIDEM
PSYCHOLEPTICS
ZOLPIDEM TARTRATE
PSYCHOLEPTICS
ZUCLOPENTHIXOL
PSYCHOLEPTICS
ZUCLOPENTHIXOL 
HYDROCHLORIDE